Chapter 5: Brain Cancer

Lyndon Kim; Howard Fine

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

23,380 (male: 12,820; female: 10,560. Estimated new cases for 2014 in the United States)

7.7 per 100,000 men 5.4 per 100,000 women

Deaths:

Estimated 14,320 in 2014 (male: 8,090; female: 6,230)

Median age at diagnosis:

57 years

Male to female ratio:

Slight male predominance in the incidence of malignant brain tumors

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Surveillance, Epidemiology and End Results (SEER) Program, available from http://seer.cancer.gov (accessed in 2013)

Work-up

Neuroimaging study (MRI of the brain preferred over CT)

No other staging work-up is required except:
Primary CNS lymphoma: MRI of spine, lumbar puncture, and ophthalmologic examination
PNET/medulloblastoma: MRI of spine and lumbar puncture when safe to do so

Pathology

Neuroepithelial Tumors
1. Glial tumors
  1. Astrocytic tumors (45–50%)
    - Glioblastoma multiforme (GBM grade IV): 50%
    - Anaplastic astrocytoma (AA grade III): 30%
    - Diffuse astrocytoma (grade II): 20%
    - Gliosarcoma (grade IV): <5% of GBM
    - Pilocytic astrocytoma (grade I): <1%
  2. Oligodendrogliomas/oligoastrocytomas (5–10%)
    - Oligodendroglioma (O grade II)
    - Anaplastic oligodendroglioma (AO grade III)
    - Oligoastrocytoma (OA grade II)
    - Anaplastic oligoastrocytoma (AOA grade III)
  3. Ependymal tumors (5%)
    - Myxopapillary ependymoma (grade I)
    - Ependymoma (grade II)
    - Anaplastic ependymoma (grade III)
    - Subependymoma
2. Neuronal and mixed glial-neuronal tumors (<1%)
  - Central neurocytoma
  - Dysembryoplastic neuroepithelial tumor
  - Desmoplastic infantile astrocytoma/ganglioma
  - Ganglioma
  - Paraganglioma
3. Nonglial tumors
  1. Embryonal tumors (<5%)
    - Primitive neuroectodermal tumors (PNET)
    - Medulloblastoma
    - Ependymoblastoma
  2. Choroid plexus tumors (<1%)
    - Choroid plexus papilloma
  3. Pineal tumors (<1%)
    - Pineoblastoma
    - Pineocytoma
Meningeal Tumors (15–28%)
- Benign meningioma (grade I): >90%
- Atypical meningioma (grade II): 6%
- Anaplastic meningioma (grade III): 2%
- Hemangiopericytoma
Germ Cell Tumors (<1%)
Nerve Sheet Tumors (4–8%)
- Schwannoma
Primary CNS Lymphoma (PCNSL) (1–5%)
Metastatic Tumors

Adesina AM et al. Histopathology of primary tumors of the central nervous system. In: Prados M, ed. Brain Cancer: American Cancer Society Atlas of Clinical Oncology. Hamilton, Ontario, Canada: BC Decker Inc.; 2002:16–47

Greenberg H et al. Brain Tumors. Oxford University Press, 1999:1–26

WHO Classification of Tumors. IARC Press, 2000:6–7

Staging

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Staging

(TNM staging does not apply to most brain tumors because they rarely metastasize. Ependymal tumors such as medulloblastoma are exceptions to this rule)

WHO Designation^✫

WHO Grade^✫

St. Anne–Mayo Grade^†

Grade

Nuclear Atypia

Mitosis

Endothelial Proliferation

Necrosis

Pilocytic astrocytoma

—

Astrocytoma grade 1 (no criteria present)

Diffuse astrocytoma

Usually −

—

Astrocytoma grade 2 (1 criterion present)

Anaplastic astrocytoma

III

—

Astrocytoma grade 3 (2 criteria present)

Glioblastoma

+, Active

Usually +

Astrocytoma grade 4 (3 or 4 criteria present)

^✫The current 2000 WHO grading system stratifies previous low-grade astrocytomas (WHO grades I and II) into different subtypes. WHO grade I pilocytic astrocytoma is characteristically well circumscribed, cystic, and localized. WHO grade II diffuse astrocytoma, like WHO grades III and IV, is characteristically infiltrative and progressive

^†In the St. Anne–Mayo grading system, the grades are based on the total number of criteria present. The criteria are similar to those in the WHO system: nuclear atypia, mitosis, endothelial proliferation, and necrosis

Daumas-Duport et al. Cancer 1988;62:2152–2165

Kleihues P et al. Histological Typing Tumours of the Central Nervous System. 2nd ed. WHO. Berlin: Springer-Verlag, 1993

WHO Classification of Tumors. Lyons, France: IARC Press, 2000:6–7

Prognosis

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Prognosis

Median Survival^✫

Grade I

>10 years

Grade II

5–8 years

Grade III

3–5 years

Grade IV

0.9–1 year

^✫Because oligodendrogliomas and oligoastrocytomas are uniquely sensitive to both chemotherapy and radiation therapy with better overall survival and prognosis, every effort should be made to look for oligodendroglial cell components and provide proper treatment options based on the pathology

Burger PC et al. Cancer 1985;56:1106–1111

Piepmeier J et al. Neurosurgery 1987;67:177–181

Expert Opinion

Grade I Astrocytoma (Pilocytic Astrocytoma)

Pilocytic astrocytoma is a rare tumor commonly seen in the pediatric or young adult population. The tumor is well circumscribed and MRI findings reveal a homogenously enhancing lesion with an associated macrocyst commonly seen in the cerebellum, brainstem, and optic pathways

Observation following surgery: Most patients can be cured with surgery alone. Following surgery, patients can be simply observed. The role of radiation therapy for incomplete resection remains undetermined

Grade II Astrocytomas (Diffuse Astrocytoma)

Diffuse astrocytoma patients can be seen in the young adult population. Although considered as a low grade, the prognosis is still not optimal with overall survival of 5–8 years. MRI usually reveals nonenhancing lesion that could be best seen on T2 or FLAIR images

Observation: Patients with the following good prognostic factors can be closely monitored with serial scans:
- Young age (<40 years)
- Asymptomatic
- Good performance score (KPS >70)
- Near or complete resection
- Small nonenhancing lesion
- Low Ki-67 or MIB-1 proliferative index
- Presence of IDH1 or IDH2 mutation
  
  Note: About a third of patients who have nonenhancing lesions may ultimately prove on biopsy to have anaplastic tumors. Thus, close surveillance (particularly early on until the natural course of the diseases becomes apparent) is recommended for all patients with diffuse astrocytomas for whom a watch-and-wait strategy is employed
Treatment: General indications for treatment include:
- Older patient (>40 years)
- Symptomatic
- Large or inoperable lesion
- Enhancement on imaging studies
- High Ki-67 or MIB-1 proliferative index
- Lack of IDH1 or IDH2 mutation
  1. Radiation therapy: Radiation therapy was considered as the standard treatment until the randomized phase III RTOG 9802 trial revealed a significantly longer survival for radiation therapy plus PCV chemotherapy over radiation therapy alone for high-risk low-grade gliomas. Radiation therapy can be still considered for those who could not tolerate chemoradiation therapy or chemotherapy. Delayed radiation-mediated neurotoxicity remains a concern, although prospective studies suggest it occurs less commonly than was once feared. Factors that increase the chance of clinically significant delayed radiation-induced neurotoxicity include:
    - Large radiation fields
    - Large fraction dose and total dose
    - Older age
    - Underlying neurodegenerative disease
    - Radiation of temporal and frontal lobes
      
      For patients considered at significant risk of radiation-induced neurotoxicity, treatment with temozolomide alone is a consideration, although the data suggest that the period of tumor control is generally relatively short
  2. Chemotherapy: Chemotherapy with deferred radiation therapy can be considered especially for those patients with large inoperable tumors or whose tumor has mutated IDH1 and IDH2 unable to tolerate radiation therapy or chemoradiation therapy. Recently, temozolomide, an oral agent, has shown efficacy in unirradiated low-grade gliomas. It causes no delayed neurotoxicity and can be considered as a treatment option for low-grade gliomas requiring treatment to defer radiation therapy. At a median follow-up of 45.5 months and after the tumors of 246/477 patients had progressed, there was no statistical difference in the primary end point, progression-free survival (PFS). Overall toxicity was mild. Grade 3 hematologic toxicity was observed in 9% of the temozolomide-treated patients [temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) low-grade glioma: a randomized phase III intergroup study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033), Baumert et al. Abstract 2007, ASCO 2013 Annual Meeting]
  3. Chemoradiation therapy: Radiation followed by PCV chemotherapy is now considered as the standard of care for patients with high-risk low grade gliomas (astrocytomas, oligoastrocytomas, oligodendrogliomas, and neurofibromatosis). Recent long-term follow-up result of the phase III RTOG 9802^✫ clinical trial revealed a significant survival benefit for patients who were randomized to radiation followed by PCV chemotherapy over radiation therapy alone. Median survival time was 13.3 years and 7.8 years, respectively. Additional molecular and genetic studies are ongoing to further identify patients who would most likely benefit from chemotherapy. Patients who are felt to be appropriate candidates for radiation therapy or chemotherapy should be considered for chemoradiation therapy

Grade III Astrocytoma (Anaplastic Astrocytoma)

Anaplastic astrocytoma is an aggressive tumor that has overall survival of 3–5 years. MRI often reveals heterogeneous enhancement that is usually intermixed with nonenhancing tumor, although as many as half of all anaplastic astrocytomas may be largely nonenhancing. Mitosis, endothelial proliferation, and atypia can be seen

Treatment:
1. Radiation therapy: Radiation therapy remains as standard of care
2. Chemotherapy: The standard of care for anaplastic gliomas had been surgery followed by radiotherapy. The role of chemotherapy for anaplastic astrocytomas remains unclear. In patients with newly diagnosed anaplastic gliomas (anaplastic oligodendroglioma, oligoastrocytoma, and astrocytoma), the NOA-04 phase III trial compared the efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence. The results showed comparable results with either initial radiotherapy or initial chemotherapy (Wick et al, 2009). [Median TTF hazard ratio HR = 1.2; 95% CI, 0.8–1.8, PFS HR = 1.0; 95% CI, 0.7–1.3, and overall survival HR = 1.2; 95% CI, 0.8–1.9] were similar for radiotherapy and procarbazine, lomustine, and vincristine (PCV)/temozolomide. A more recent phase III study of anaplastic gliomas (NOA-08) randomly assigned patients to receive either chemotherapy (PCV or temozolomide) versus radiation therapy as initial treatment. This study showed no difference in time to treatment failure, progression free survival, or overall survival [median overall survival 8.6 months (95% CI 7.3–10.2) in the temozolomide group and 9.6 months (8.2–10.8) in the radiotherapy group HR 1.09, 95% CI 0.84–1.42, noninferiority = 0.033], leading the authors to concluded temozolomide alone is noninferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma (Wick et al, 2012)
3. Chemoradiation Therapy: The use of concurrent and postirradiation temozolomide therapy, an approach employed in newly diagnosed glioblastoma (grade IV astrocytoma) also has become widely accepted for the treatment of other types of malignant gliomas

Wick W et al. J Clin Oncol 2009;27:5874–5880

Wick W et al. Lancet Oncol 2012;13:707–715

Grade IV Astrocytomas (Glioblastomas)

Glioblastomas are the most common malignant tumors of the elderly population. The tumor grows rapidly and causes significant morbidity and mortality with overall survival of 14–18 months. Imaging studies usually reveal a heterogeneously enhancing lesion or lesions with a significant amount of surrounding edema. Increased number of mitosis, endothelial proliferation, atypia, and necrosis are commonly seen

1. Treatment:

Chemoradiation therapy:

Initial therapy:

For patients age 18–70 years, combined radiation therapy with low-dose daily temozolomide followed by monthly temozolomide is the standard of care (Stupp et al, 2005)
Combined radiation therapy with low-dose daily temozolomide followed by monthly temozolomide can be also considered for patients who are older than 70 years with a good performance status
Alternatively, for patients 70 years or older with a poor performance status, temozolomide or radiation therapy alone can be an option. A 2- or 3-week course of hypofractionated radiation therapy could be an option for patients with poor performance status
Radiation therapy followed by one of the nitrosoureas (carmustine [BCNU] or lomustine [CCNU]) is an option for those who could not receive temozolomide

Recurrent disease:

Bevacizumab is the treatment of choice for patients for whom it is not medically or neurologically contraindicated (Kreisl et al, 2009)
Retreatment with a continuous low-dose (metronomic) temozolomide dosing schedule is an option especially for patients who have never been treated with bevacizumab and responded well to their original temozolomide with the last treatment greater than 6 months and whose tumor has a methylated MGMT status (see Table below)
Other molecular targeted drugs such as erlotinib can be considered for malignant gliomas expressing EGFR or EGFRviii
Second-line chemotherapeutic agents such as BCNU, CCNU, or carboplatin are also options
Participation in a well-designed clinical trial is highly recommended

Kreisl TN et al. J Clin Oncol 2009;27:740–745

Stupp R et al. N Engl J Med 2005;352:987–996

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Phase II Trials of Continuous Low-dose Temozolomide for Patients with Recurrent Malignant Glioma

Reference

TMZ Daily Dose, Schedule

ORR (%)

PFS6 (%)

Median OS (months)

Khan

75 mg/m², 42/70 days

Brandes

75 mg/m², 21/28 days

Wick

150 mg/m², 7/14 days

Perry

Early progression on adjuvant TMZ, 50 mg/m², 28/28 days

Progression on extended TMZ, 50 mg/m², 28/28 days

Rechallenge, 50 mg/m², 28/28 days

Kong

40–50 m², 28/28 days

Abacioglu

100 mg/m², 21/28 days

Verhoeff

50 mg/m², 28/28 days + bevacizumab 10 mg/kg q21d

Desjardins

50 mg/m², 28/28 days + bevacizumab 10 mg/kg q14d

Omuro

All patients, 50 mg/m², 28/28 days

Bevacizumab failures, 50 mg/m², 28/28 days

Bevacizumab naïve, 50 mg/m², 28/28 days

NA, not available; ORR, objective response rate (complete + partial responses); PFS6, progression-free at 6 months; TMZ, temozolomide

Abacioglu U et al. J Neurooncol 2011;103:585–593

Brandes AA et al. Br J Cancer 2006;95:1155–1160

Desjardins A et al. Cancer 2011;118:1302–1312

Khan RB et al. Neuro Oncol 2002;4:39–43

Kong DS et al. Neuro Oncol 2010;12:289–296

Omuro A et al. Neuro Oncol 2013;15:242–250

Perry JR et al. J Clin Oncol 2010;28:2051–2057

Verhoeff JJ et al. Ann Oncol 2010;21:1723–1727

Wick A et al. J Clin Oncol 2007;25:3357–3361

Oligodendroglioma (WHO grade II)

Oligodendrogliomas are rare tumors that can respond extremely well to radiation and chemotherapy. They appear as fried egg, round cells under the microscope and imaging studies that show calcifications can help establish the diagnosis. Co-deletion of 1p and 19q usually confers a good prognosis

Observation: Patients with the following good prognostic factors can be closely monitored with serial scans:
- Young age (<40 years)
- Asymptomatic
- Good performance score (KPS >70)
- Small non-enhancing lesion
- Nearly or completely resected tumor
- Low Ki-67 or MIB-1 proliferative index
- Co-deletion of 1p and 19q
- Presence of IDH1 or IDH2 mutation
Treatment:

General indications for treatment include: Older patient (>40 years)
- Symptomatic
- Poor performance score (<70)
- Large or inoperable, enhancing tumor
- High Ki-67 or MIB-1 proliferative index
- Lack of IDH1 or IDH2 mutation
- Intact 1p and 19q status
  1. Chemotherapy: If the tumor cannot be completely resected, radiation therapy or chemotherapy can be considered as oligodendrogliomas can respond to either treatment extremely well. However, because oligodendrogliomas with 1p, 19q co-deletion can be exquisitely sensitive to chemotherapy, temozolomide or PCV can be offered as alternative treatments, especially for young patients with good prognostic features, in order to avoid the potential for delayed neurotoxicity
  2. Radiation therapy: Radiation therapy is usually reserved for patients with poor prognostic features, who are unable to tolerate chemotherapy or for chemotherapy resistant and progressive disease
  3. Combined chemotherapy and radiation therapy: Recent RTOG 9802^✫ phase III trial for high-risk low-grade gliomas (astrocytomas, oligodendrogliomas, oligoastrocytomas, and neurofibromatosis) reveled a significant long-term survival benefit for patients who were randomized to radiation followed by PCV chemotherapy over radiation therapy alone. Median survival time was 13.3 years for radiation plus PCV arm and 7.8 years for radiation alone arm. Based on these findings, this combination therapy is now considered as the standard treatment for high-risk low-grade gliomas especially when oligodendrogliomas are well known to be extremely sensitive to radiation therapy and chemotherapy. Additional molecular and genetic studies are ongoing to further identify patients who would most likely benefit from chemotherapy. Patients who are felt to be appropriate candidates for radiation therapy or chemotherapy should be considered for chemoradiation therapy

Anaplastic Oligodendroglioma (WHO grade III)

Anaplastic oligodendrogliomas, like grade II oligodendrogliomas, can be extremely sensitive to radiation and chemotherapy. Co-deletion of 1p and 19q confers a good prognosis

Treatment: Combined chemotherapy with PCV and pre- or postradiation therapy is standard of treatment. Radiation therapy alone and chemotherapy alone are no longer considered as standard of care and they are reserved for patients who could not tolerate combination therapy
1. Combined chemotherapy and radiation therapy: Two recent long-term follow-up results from the phase III randomized trials for newly diagnosed anaplastic oligodendrogliomas revealed a significant survival benefit for combination PCV chemotherapy and radiation therapy over radiation therapy alone (van den Bent et al, 2012; Cairncross et al, 2012). These trials also validated the role of 1p, 19q as a predictive biomarker for survival. Therefore, PCV chemotherapy given either pre- or postradiation therapy is now considered as the standard of treatment. However, because PCV chemotherapy compared to temozolomide carries a greater toxicity with a less-favorable dosing schedule and administration, many still debate accepting PCV chemotherapy as standard of care. The role of concurrent radiation and postradiation chemotherapy with temozolomide, the treatment standard for glioblastomas, is now commonly adopted for the treatment of other malignant gliomas like anaplastic oligodendrogliomas

Cairncross JG et al. 2012 ASCO Annual Meeting. Abstract 2008b

van den Bent MJ et al. J Clin Oncol 2006;24:2715–2722

van den Bent MJ et al. J Clin Oncol 2012;43:2229

Medulloblastoma and Primitive Neuroectodermal Tumors

These tumors usually occur in children and young adults. They are aggressive in nature and have a high propensity to spread through the cerebrospinal fluid resulting in distant metastasis within the central nervous system. A thorough staging work up, including a careful examination of the cerebrospinal fluid and spine, are required. Medulloblastoma usually arises in the posterior fossa causing hydrocephalus and associated obstructive symptoms, including headaches, nausea, vomiting, and gait difficulties requiring urgent ventriculoperitoneal shunt placement to relieve the intracranial pressure

Treatment:
1. Radiation Therapy: Craniospinal radiation therapy is the standard of care
2. Chemotherapy: Chemotherapy is usually provided after the completion of radiation therapy. When chemotherapy is considered, craniospinal radiation dose can be reduced to minimize the toxicity (Packer et al, 2006). For recurrent disease, stereotactic radiation therapy, chemotherapy or high dose chemotherapy with stem cell rescue can be considered

Packer et al. J Clin Oncol 2006;24:4202–4208

Primary Central Nervous System Lymphomas

Primary central nervous system lymphomas are rare non-Hodgkin lymphomas arising within the central nervous system without systemic involvement. They occur mostly in the elderly population and in patients who are immunocompromised. The most common type is diffuse large B-cell lymphoma and they invariably express CD20. MRI findings usually reveal homogenously enhancing lesion(s) involving periventricle or splenium (butterfly lesion). If a primary central system lymphoma is suspected, a stereotactic biopsy is sufficient to establish the diagnosis as this tumor can be successfully treated with radiation and methotrexate containing chemotherapy with high cure rates. However, in the presence of significant mass effect, partial or total resection can be considered. As an initial work up, a thorough examination of eyes and cerebrospinal fluid are required because of the propensity to involve these sites. If a primary central nervous system lymphoma is suspected, the administration of steroids is discouraged as steroids can be oncolytic and could cause a decrease in the size of the tumor making the diagnosis difficult. Steroids are usually administered after a biopsy or surgery

Treatment:
1. Chemotherapy: High-dose methotrexate (3.5–8 g/m²) given alone or as part of multiagent regimen remains as the standard therapy (Batchelor et al, 2003). Even at high dose as a single agent the treatment is well tolerated and causes minimal side effects. The complete response and survival rates are found to be comparable or better than radiation therapy. Delayed neurotoxicity commonly seen in long-term survivors of whole-brain radiation therapy is less frequent. Because of high central nervous system penetration of the drug, patients with ocular, cerebrospinal fluid or leptomeningeal involvement can be safely treated with high-dose methotrexate alone without concurrent radiation or intraocular or intrathecal chemotherapy. CD20-directed rituximab in combination with high-dose methotrexate is also commonly used (Chamberlain and Johnston, 2010). Patients who receive high-dose methotrexate alone can be treated with rituximab as maintenance therapy following high-dose methotrexate. For recurrence, retreatment with high-dose methotrexate with and without rituximab, (Chamberlain and Johnston, 2010) topotecan, (Voloschin et al, 2008) high-dose cytarabine or temozolomide can be considered. If chemotherapy is not considered as a good option because of the patient's high comorbidities, renal failure, or inability to tolerate chemotherapy, radiation therapy could be an alternative option
  
  Recent long-term follow-up results of a phase II high-dose methotrexate-based multiagent chemotherapy followed by consolidation, reduced-dose radiation therapy, and high-dose cytarabine for newly diagnosed primary central nervous system lymphoma patients revealed a high rate of response and overall survival with favorable cognitive outcomes compared to historical controls treated with whole-brain radiation therapy alone (Morris et al, 2013). A randomized phase III Radiation Therapy Oncology Group trial based on an earlier phase II regimen with or without reduced-dose whole-brain radiation therapy is currently underway
  
  In newly diagnosed primary central nervous system lymphoma patients who responded to a chemotherapy trial, a phase II study of a methotrexate-based chemotherapy regimen followed by high-dose chemotherapy with autologous stem cell transplantation and reduced-dose whole-brain radiation therapy revealed an encouraging high response rate and survival results that warrants further investigation in a larger phase III trial (Colombat et al, 2006)
2. Radiation therapy: Radiation therapy was a standard of care in the past, but because of high treatment failure and high incidence of delayed neurotoxicity commonly seen in long-term survivors, this approach is no longer considered as first-line therapy. However, radiation therapy is still considered for patients who have poor performance status and/or are unable to tolerate chemotherapy or for recurrent disease

Batchelor TJ Clin Oncol 2003;21:1044–1049

Chamberlain and Johnston. Neuro Oncol 2010;2:736–744

Colombat P et al. Bone Marrow Transplant 2006;38:417–420

Morris PG et al. J Clin Oncol 2013;31:3971–3979

Voloschin AD et al. J Neurooncol 2008;86:211–215

Meningiomas

Meningiomas are rare brain tumors arising from the meninges. They usually affect the elderly population and have a slight female preponderance. Calcifications and bone involvement can be seen on CT scan. MRI scan usually reveals a dural-based homogenously enhancing lesion that has a typical tail sign

Treatment options include observation of asymptomatic patients and surgery for those who have symptoms

Benign Meningiomas (Grade I):

Observation: Grade I meningiomas are slow growing benign tumors that have an excellent prognosis with overall survival greater than 10 years. They can be simply followed without any therapeutic intervention
Treatment:
1. Surgery: If the tumor grows and or a patient becomes symptomatic, surgery may be indicated

Atypical Meningiomas (Grade II):

Observation: For most atypical meningioma (grade II) patients, close observation following surgery is usually sufficient if the patient is asymptomatic and the pathology showed a low Ki-67 or MIB-1 proliferation index
Treatment:
1. Radiation therapy: Radiation can be considered if the patient is symptomatic and or the pathology showed a high Ki-67 or MIB-1 proliferation index

Malignant meningiomas (Grade III):

Malignant meningiomas (grade III) are a rapidly growing tumor that carries a poor prognosis with overall survival less than 2–3 years. MRI scan typically reveals a significant vasogenic edema

Treatment:
1. Surgery followed by radiation therapy: For recurrent tumors, surgery, additional radiation therapy, or stereotactic radiation therapy can be considered. Immunomodulating agents, such as α-interferon (Chamberlain and Glantz, 2008) and somatostatin analogs for somatostatin receptor-positive tumors (positive octreotide scan) (Chamberlain et al, 2007) have shown some modest responses that can be durable. Chemotherapeutic agents, such as hydroxyurea (Chamberlain, 2012) and platinum compounds, also have shown some modest benefits. Bevacizumab, as a single agent or in combination with chemotherapy (Lou et al, 2012), can be safely administered and it appears to have encouraging antitumor effects. Further trials to investigate the efficacy and side effects are warranted

Chamberlain M. J Neurooncol 2012;107:315–321

Chamberlain M, Glantz MJ. Cancer 2008;113:2146–2151

Lou E et al. J Neurooncol 2012;109:63–70

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Targeted Therapy for Recurrent High-grade Meningioma (Adapted from Chamberlain MC and Johnston SK, 2011)

Inhibitor [Reference]

Target

Number of Patients

Radiographic RR (%)

Progression-free Survival

Median

6-months

Bevacizumab [Nayak, 2011]

VEGF

4.0 months

Sunitinib [Kaley, 2010]

VEGFR

5.1 months

36%

Vatalanib [Grimm, 2010]

VEGFR

5.8

3.65 months

37.5%

Imatinib [Wen, 2006 and Wen, 2009]

PDGFR

2.0 months

29.4%

Erlotinib [Norden, 2010]

EGFR

2.0 months

25%

Pasireotide [Hammond, 2011]

SST

4.0 months

12%

Sandostatin LAR [Chamberlain, 2007]

SST

3.0 months

25%

EGFR, epidermal growth factor receptor; NS, not stated; PDGFR, platelet-derived growth factor receptor; RR, response rate; SST, somatostatin receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor

Chamberlain MC et al. Neurology 2007;69:969–973

Chamberlain MC, Johnston SK. J Neurooncol 2011;104:765–771

Grimm SA et al. J Clin Oncol 2010;29(15S):151s (Abstract #2046)

Hammond S et al. J Clin Oncol 2011;29(15S):150s (Abstract #2040)

Kaley TJ et al. Neuro Oncol 2010;12(s4):iv75–iv76

Nayak L et al. Neurology 2011;76:A96 (Abstract P02.011)

Norden AD et al. J Neurooncol 2010;96:211–217

Wen PY et al. Neuro Oncol 2009;11:853–860

Wen PY et al. Clin Cancer Res 2006;12:4899–4907

REGIMEN: TEMOZOLOMIDE

Listen

Regimen: Temozolomide

Bower M et al. Cancer Chemother Pharmacol 1997;40:484–488

Cycle 1:

Temozolomide 150 mg/m² per day; administer orally for 5 consecutive days, on days 1–5 of a 4-week cycle (total dosage/cycle = 750 mg/m²)

Cycle 2 and subsequent cycles:

Temozolomide 200 mg/m² per day; administer orally for 5 consecutive days, on days 1–5, every 4 weeks (total dosage/cycle = 1000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

G ≤1 myelosuppression in cycle 1

Escalate temozolomide dosage to 200 mg/m² per day, days 1–5

WBC <3000/mm³ or platelets <100,000/mm³ on day 1 of any cycle

Delay retreatment for 1 week

After a 1-week delay, if WBC <2000/mm³ or platelets <75,000/mm³

Reduce temozolomide dosage by 25%

After a 1-week delay, if WBC <1000/mm³ or platelets <25,000/mm³

Reduce temozolomide dosage by 50%

Efficacy (N = 103)

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Efficacy (N = 103)

Objective response

11%

Stable disease

47%

Median survival

5.8 months

Progression-free survival at 6 months

22%

The study included 18 patients not evaluable for response

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Efficacy (N = 103)

NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma with Procarbazine, Lomustine, and Vincristine (PCV) or Temozolomide (TMZ)

Wick W et al. J Clin Oncol 2009;27:5874–5880

TTF, PFS, and OS

Radiotherapy (n = 139)

PCV or TMZ (n = 135)

Median

95% CI

Median

95% CI

TTF, months

42.7+

43.8

37.4–NR

Anaplastic astrocytoma

32.0

23.3–NR

29.4

19.0–NR

Anaplastic oligoastrocytoma

54+

Anaplastic oligodendroglioma

54+

Treatment failure at 48 months, %

55.5

46.3–64.6

46.4

36.7–56.2

PFS, months

30.6

16.3–42.8

31.9

21.1–37.3

Anaplastic astrocytoma

10.8

8.9–28.3

18.2

12.1–24.2

Anaplastic oligoastrocytoma

Anaplastic oligodendroglioma

52.1

36.5–NR

52.7

33.9–NR

OS, months

72.1

82.6

OS at 48 months, %

72.6

63.8–81.4

64.6

54.6–74.7

NR, not reached; OS, overall survival; PFS, progression-free survival; TTF, time to treatment failure

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Efficacy (N = 103)

Temozolomide Chemotherapy Alone Versus Radiotherapy Alone for Malignant Astrocytoma in the Elderly: The NOA-08 Randomized, Phase III Trial^✫

Wick W et al. Lancet Oncol 2012;13:707–715

Entire Temozolomide Group^†

Overall survival at 6 months

66.7% (95% CI 60.0–73.0)

Overall survival at 1 year

34.4% (95% CI 27.6–41.4)

Median overall survival

8.6 months (95% CI 7.3–10.2)

Event-free survival at 6 months

30.1% (95% CI 23.6–36.6)

Event-free survival at 1 year

12.0% (95% CI 7.9–17.1)

Median event-free survival

3.3 months (95% CI 3.2–4.1)

Patients with Methylated MGMT Promoter

Median overall survival

NR (95% CI 10.1–NR)^‡

Median event-free survival

8.4 months (95% CI 5.5–11.7)^§

95% CI, 95% confidence interval; MGMT, O₆-methylguanine-DNA-methyltransferase; NR, not reached

^✫Designed as a noninferiority trial

^†Values are for ITT (intent-to-treat) population. The noninferiority of temozolomide for overall survival and event-free survival were also confirmed in the per-protocol population

^‡Compared with 7 months (95% CI 5.7–8.7) for patients with an unmethylated tumor MGMT promoter

^§Compared with 3.3 months (95% CI 3.0–3.5) for patients with an unmethylated tumor MGMT promoter

Toxicity (N = 101)

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Toxicity (N = 101)

% CTC Grade

None

Hematologic

Neutropenia

Thrombocytopenia

Anemia

Lymphopenia

Nonhematologic

Nausea

Vomiting

Constipation

Mucositis

Increased ALT

Increased ALP

Increased bilirubin

None

Mild

Moderate

Severe

Lethargy^✫

Anorexia^✫

^✫No CTC grading available. National Cancer Institute (USA) Common Toxicity Criteria (CTC) and Common Terminology Criteria for Adverse Events (CTCAE), all versions. At: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm [accessed December 7, 2013]

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Toxicity (N = 101)

NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma (Anaplastic Oligodendroglioma, Oligoastrocytoma, Astrocytoma) with Procarbazine, Lomustine, and Vincristine (PCV) or Temozolomide (TMZ)

Wick W et al. J Clin Oncol 2009;27:5874–5880

Toxicity in the First and Recurrence Treatments

Grade 2/3 Adverse Event According to CTCAE

TMZ (N = 108)

Allergic reaction

1 (0.9%)

Alopecia/local skin reaction

Cephalgia

1 (0.9%)

Diarrhea

3 (2.8%)

Hematologic (grades 3 to 4)

6 (5.6%)

Herpes zoster infection

2 (1.8%)

Infection (grades 2 to 4)

2 (1.8%)

Obstipation

2 (1.8%)

Polyneuropathy

Pneumonia

2 (1.8%)

Pneumonitis

Tumor bleed, thromboembolic events

3 (2.8%)

Transaminase elevation

2 (1.8%)

CTCAE, National Cancer Institute (USA) Common Terminology Criteria for Adverse Events

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Toxicity (N = 101)

Wick W et al. Lancet Oncol 2012;13:707–715

(N = 195)

Numbers of Grades 2–4 Adverse Events^✫

Grade 2

Grade 3

Grade 4

Hematologic Toxic Effects

Neutropenia

Lymphocytopenia

Thrombocytopenia

Nonhematologic Toxic Effects

Liver enzyme elevation

Infection

Thromboembolic event

Asthenia/fatigue

Nausea/vomiting

Weight loss/inappetence

Neurologic symptoms

Seizures

Cutaneous (dermatitis, allergic rash, alopecia)

^✫Note: N = 195 refers to number of patients. However, number of events are total events and if the grade of an adverse event had returned to 1, subsequent events of grades 2 to 4 were counted as new events, so that a patient could have more than 1 event

Patient Population Studied

A multicenter phase II trial of 103 patients with progressive or recurrent supratentorial high-grade gliomas

Therapy Monitoring

Weekly: CBC with differential
Every 4 weeks: Serum electrolytes, mineral panel, and LFTs

REGIMEN: TEMOZOLOMIDE WITH RADIATION THERAPY

Listen

Regimen: Temozolomide with Radiation Therapy

Stupp R et al. J Clin Oncol 2002;20:1375–1382

Stupp R et al. N Engl J Med 2005;352:987–996

Temozolomide with radiation therapy:

Temozolomide 75 mg/m² per day; administer orally, continually, 7 days/week for 6–7 weeks in a fasting state 1 hour before radiation therapy (RT), and in the morning in a fasting state on days without RT (total dosage/6- to 7-week cycle = 3150–3675 mg/m²)

Radiation therapy once daily at 2 Gy/fraction for 5 days/week for a total of 60 Gy

Adjuvant temozolomide starting 4 weeks after completing RT:

Temozolomide 200 mg/m² per day; administer orally for 5 consecutive days, on days 1–5 every 28 days for up to 6 cycles (total dosage/cycle = 1000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Toxicity (N = 287)

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Toxicity (N = 287)

Temozolomide with Radiation Therapy (N = 287)

Toxicity

% CTC Grade

G3/G4

Hematologic Toxicity

Leucopenia

N/A

Neutropenia

N/A

Thrombocytopenia

N/A

Anemia

N/A

Any

N/A

Nonhematologic Toxicity

Fatigue

Other constitutional symptoms

Rash/other dermatologic

Infection

Vision

Nausea/vomiting

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Toxicity (N = 287)

Adjuvant Temozolomide After RT (N = 287)

Toxicity

% CTC Grade

G3/4

Hematologic Toxicity

Leukopenia

N/A

Neutropenia

N/A

Thrombocytopenia

N/A

Anemia

N/A

Any

N/A

Nonhematologic Toxicity

Fatigue

Other constitutional symptoms

Rash/other dermatologic

Infection

Vision

Nausea/vomiting

CTC, National Cancer Institute (USA) Common Toxicity Criteria, version 2.0. At: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm [accessed December 7, 2013]

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

WBC <3000/mm³ or platelets <100,000/mm³ on day 1 of any cycle

Delay retreatment for 1 week

After a 1-week delay, if WBC <2000/mm³ or platelets <75,000/mm³

Reduce temozolomide dosage by 25%

After a 1-week delay, if WBC <1000/mm³ or platelets <25,000/mm³

Reduce temozolomide dosage by 50%

Adapted from Stupp R et al. J Clin Oncol 2002;20: 1375–1382, in which dose modifications were not specified

Patient Population Studied

A multicenter phase III trial of 573 patients with newly diagnosed GBM in which 287 patients received temozolomide with RT

Efficacy (N = 287)

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Efficacy (N = 287)

Median Survival

14.6 months

1-Year survival

61.1%

2-Year survival

26.5%

Therapy Monitoring

Weekly: CBC with differential
Every 4 weeks: Serum electrolytes, chemistry panel, and LFTs

REGIMEN: CARMUSTINE (BCNU)

Listen

Regimen: Carmustine (BCNU)

Levin VA et al. Cancer Treat Rep 1976;60:719–724

Walker MD et al. J Neurosurg 1978;49:333–343

Carmustine 80 mg/m² per dose; administer intravenously in 100–250 mL 5% dextrose injection (D5W) over at least 60 minutes for 3 consecutive days, on days 1–3, every 6–8 weeks (total dosage/cycle = 240 mg/m²)

Carmustine 200 mg/m²; administer intravenously in 100–500 mL D5W over at least 60 minutes, given on day 1, every 6–8 weeks (total dosage/cycle = 200 mg/m²)

Note: Both schedules are comparable. However, there is no good rationale for the 3-day treatment schedule

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: MODERATE (3-day regimen) to HIGH (1-day regimen)

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A phase III randomized study of supportive care alone in 303 patients with newly diagnosed malignant gliomas versus BCNU and/or radiation therapy

Walker MD et al. J Neurosurg 1978;49:333–343

Efficacy (N = 222)

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Efficacy (N = 222)

Therapy

Median Survival

Best conventional care only

14 weeks

Carmustine only

18.5 weeks

Radiation therapy only

36 weeks

Radiation therapy + carmustine

34.5 weeks

Note: The addition of carmustine to radiation therapy failed to alter median survival significantly. However, there was a significantly greater surviving percentage of patients at the end of 18 months among those who received combination therapy

Walker MD et al. J Neurosurg 1978;49:333–343

Toxicity (N = 51 for BCNU Group)

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Toxicity (N = 51 for BCNU Group)

% Patients

Thrombocytopenia: Platelets <100,000/mm³

Platelets <50,000/mm³

Leukopenia: WBC <4000/mm³

WBC <2000/mm³

Anemia

Occasional; no profound anemia encountered

Nausea

Occasional

Vomiting

Occasional

Elevated LFTs

Occasional

Therapy Monitoring

Weekly: CBC with differential
A minimum of every 6 weeks: LFTs, BUN, creatinine
Every 2–3 cycles: Pulmonary function test

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Nadir prior cycle: WBC 2000–3000/mm³ or platelets 25,000–75,000/mm³

Delay treatment until WBC ≥3000/mm³ and platelets ≥100,000/mm³, then resume treatment with carmustine dosage reduced by 10–25%

Nadir prior cycle: WBC <2000/mm³ or platelets <25,000/mm³

Delay treatment until WBC ≥3000/mm³ and platelets ≥100,000/mm³, then resume treatment with carmustine dosage reduced by 25–50%

Cumulative carmustine dosage >1400 mg/m² or worsening forced vital capacity (FVC) or carbon monoxide diffusing capacity (DL_co)

Discontinue carmustine

Note: Usually no more than 5–6 cycles (total cumulative dose of 1000–1200 mg/m²) of carmustine is recommended. Patients receiving >1400 mg/m² cumulative carmustine dosage have a higher risk of developing pulmonary toxicity. Patients with a baseline FVC or DL_co <70% are particularly at risk. BiCNU^® (carmustine for injection); product label, May 2011. Ben Venue Laboratories, Inc., Bedford, OH

Notes

Two meta-analyses showed a survival benefit for patients treated with nitrosoureas after radiation

Fine HA et al. Cancer 1993;71:2585–2597

Stewart LA et al. Lancet 2002;359:1011–1018

REGIMEN: LOMUSTINE (CCNU)

Listen

Regimen: Lomustine (CCNU)

Batchelor TT, J Clin Oncol 31:3212–3218

Lomustine 110 mg/m²; administer orally as a single dose on day 1, every 6–8 weeks for a total of 6 cycles (total dosage/cycle = 110 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is MODERATE–HIGH

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

WBC nadir during the prior cycle 2000–3000/mm³, or platelets 25,000–75,000/mm³

Reduce lomustine dosage by 10–25%

WBC nadir during the prior cycle <2000/mm³, or platelets <25,000/mm³

Reduce lomustine and dosage by 25–50%

Cumulative lomustine dosage >1100 mg/m², or worsening forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLco)^✫

Discontinue lomustine

^✫Note: Usually no more than a total of 6–7 cycles of lomustine (660–770 mg/m²) is recommended. Patients receiving cumulative lomustine dosages >1100 mg/m² are at increased risk for developing pulmonary toxicity. Patients with baseline FVC or DLco<70% are particularly at risk

(CCNSB™ (lomustine) Capsules; May 2013 product label. Next Source Biotechnolgy, LLC, Miami, FL)

Patient Population Studied

Patients with recurrent glioblastoma, prior treatment with a temozolomide-containing chemotherapy regimen, prior treatment with radiation, Karnofsky performance status (KPS) ≥70, Mini-Mental Status Examination score ≥15, and who had not received any prior anti-VEGF therapy or cranial radiation within 3 months before study entry

Toxicity

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Toxicity

Grades 3/4 Adverse Events

Placebo + Lomustine (n = 64)

Number

Any AE, ≥ grade 3

60.9

Thrombocytopenia

Neutropenia

3.1

Fatigue

9.4

Leukopenia

4.7

Platelet count decreased

1.6

Anemia

Hypertension

ALT increased

GGT increased

3.1

WBC decreased

4.7

Diarrhea

1.6

Pulmonary embolism

6.3

Lymphopenia

7.8

Convulsion

4.7

Intracranial hemorrhage

3.1

AE, adverse event; GGT, γ-glutamyltransferase

Efficacy

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Efficacy

Best Overall Response

Lomustine + Placebo (n = 56)

Number

Overall response rate

8.9

Complete response (CR)

—

Partial response (PR)

8.9

Stable disease

41.1

Unconfirmed CR

—

Unconfirmed PR

3.6

28.6

Nonevaluable

8.9

Median reduction in contrast-enhanced tumor area

+14% increase

APF6 proportions

25%

Corticosteroid usage

+5%

Median progression-free survival

82 days (first quartile = 42 days, third quartile = 168 days)

Median overall survival

9.8 months

REGIMEN: CARBOPLATIN

Listen

Regimen: Carboplatin

Yung WK et al. J Clin Oncol 1991;9:860–864

Carboplatin 400 mg/m²; administer intravenously over 30 minutes to 2 hours in 250 mL 5% dextrose injection (D5W) or 0.9% sodium chloride injection (0.9% NS) on day 1, every 4 weeks (total dosage/cycle = 400 mg/m²)

Carboplatin (calculated dose) AUC = 5–7 mg/mL · min; administer intravenously over 30 minutes to 2 hours in a volume of D5W or 0.9% NS sufficient to produce a concentration ≥0.5 mg/mL, on day 1, every 4 weeks (total dosage/cycle calculated to produce an AUC = 5–7 mg/mL · min)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE–HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Carboplatin dose is based on a formula described by Calvert et al. to achieve a target area under the plasma concentration versus time curve (AUC)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be calculated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the FDA identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States will use the standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommended for patients with normal renal function capping an estimated GFR at 125 mL/min for any targeted AUC value. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm [accessed February 26, 2014]

Patient Population Studied

A study of 30 patients with recurrent malignant gliomas

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Day 1 WBC <3000/mm³ or platelets <50,000/mm³

Delay treatment until WBC ≥3000/mm³ and platelets ≥100,000/mm³

ANC nadir <500/mm³ or platelets <50,000/mm³

Reduce carboplatin dosage by 25%

Cycle 1 ANC nadir ≥1500/mm³ and platelet nadir ≥100,000/mm³

Increase carboplatin dosage by 12.5%

Toxicity (N = 29)

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Toxicity (N = 29)

Nonhematologic Toxicity

Percent Cycles with Toxicity

Toxicity

Mild

Moderate

Severe

Nausea/vomiting

2.4

Malaise

—

Hematologic Toxicity at 400 mg/m²

Toxicity

Percent of Patients

Neutropenia (ANC <500/mm³)

Thrombocytopenia^✫ <50,000/mm³

^✫Although the incidence of thrombocytopenia in this study was low, significant thrombocytopenia often follows carboplatin treatment

Efficacy (N = 29)

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Efficacy (N = 29)

Partial response (PR)

Minor response (MR)

Stable disease (S)

34%

Median time to progression (PR/MR/S)

26 weeks

Median survival time (PR/MR/S)

50 weeks

Therapy Monitoring

Weekly: CBC with differential
Every 28 days: LFTs. BUN, serum creatinine, serum calcium, magnesium, and uric acid
Every other cycle: Urine for creatinine clearance
When clinically indicated: Audiogram

Notes

Adjust the dose based on hematologic toxicity and/or urine creatinine clearance

REGIMEN: PROCARBAZINE, LOMUSTINE (CCNU), VINCRISTINE (PCV)

Listen

Regimen: Procarbazine, Lomustine (CCNU), Vincristine (PCV)

Levin VA et al. Cancer Treat Rep 1980;64:237–241

Special instructions:

Because procarbazine is a weak monoamine oxidase inhibitor, one should restrict tyramine-containing foods in patients receiving procarbazine

Anon. Med Lett Drugs Ther 1989;31:11–12

DaPrada M et al. J Neural Transm 1988;26:31–56

McCabe BJ. J Am Diet Assoc 1986 86:1059–1064

Lomustine (CCNU) 110 mg/m²; administer orally as a single dose on day 1, every 6–8 weeks (total dosage/cycle = 110 mg/m²)

Procarbazine 60 mg/m² per day; administer orally for 14 consecutive days on days 8–21, every 6–8 weeks (total dosage/cycle = 840 mg/m²)

Vincristine 1.4 mg/m² per dose (maximum single dose = 2 mg); administer by intravenous injection over 1–2 minutes for 2 doses, on days 8 and 29, every 6–8 weeks (total dosage/cycle = 2.8 mg/m², but not >4 mg/cycle)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 and days 8–21 is MODERATE–HIGH

Emetogenic potential on day 29 is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Nadir prior cycle: WBC 2000–3000/mm³ or platelets 25,000–75,000/mm³

Reduce lomustine and procarbazine dosages by 10–25%

Nadir prior cycle: WBC <2000/mm³ or platelets <25,000/mm³

Reduce lomustine and procarbazine dosages by 25–50%

Severe neurotoxicity, eg, painful paresthesia or peripheral weakness

Discontinue vincristine

Cumulative lomustine dosage >1100 mg/m² or worsening forced vital capacity (FVC) or carbon monoxide diffusing capacity (DL_co)^✫

Discontinue lomustine

^✫Note: Usually no more than a total of 6–7 cycles (660–770 mg/m²) of lomustine is recommended. Patients receiving >1100 mg/m² cumulative lomustine dosage have a higher risk of developing pulmonary toxicity. Patients with a baseline FVC or DLco <70% are particularly at risk

(CCNSB^™ (lomustine) Capsules; May 2013 product label. NextSource Biotechnolgy, LLC, Miami, FL)

Efficacy (N = 46)

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Efficacy (N = 46)

Objective response (OR)

26%

Stable disease (SD)

35%

Median time to progression (OR + SD)

26 weeks

Progression-free survival at 12 months

30%

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Efficacy (N = 46)

NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma with Procarbazine, Lomustine, and Vincristine (PCV) or Temozolomide (TMZ)

Wick W et al. J Clin Oncol 2009;27:5874–5880

TTF, PFS, and OS

Radiotherapy (n = 139)

PCV or TMZ (n = 135)

Median

95% CI

Median

95% CI

TTF, months

42.7+

43.8

37.4–NR

Anaplastic astrocytoma

32.0

23.3–NR

29.4

19.0–NR

Anaplastic oligoastrocytoma

54+

Anaplastic oligodendroglioma

54+

Treatment failure at 48 months, %

55.5

46.3–64.6

46.4

36.7–56.2

PFS, months

30.6

16.3–42.8

31.9

21.1–37.3

Anaplastic astrocytoma

10.8

8.9–28.3

18.2

12.1–24.2

Anaplastic oligoastrocytoma

Anaplastic oligodendroglioma

52.1

36.5–NR

52.7

33.9–NR

OS, months

72.1

82.6

OS at 48 months, %

72.6

63.8–81.4

64.6

54.6–74.7

OS, overall survival; PFS, progression-free survival; TTF, time to treatment failure

Toxicity (N = 72)

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Toxicity (N = 72)

%G1

%G2

%G3

%G4

Hematologic

Leukopenia

Thrombocytopenia

Nonhematologic

Nausea/vomiting

Neuropathy

Occasionally a rash is observed

Northern California Oncology Group Criteria

Levin VA et al. J Neurosurg 1985;63:218–223. Toxicity data obtained from a similar study

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Toxicity (N = 72)

Wick W et al. J Clin Oncol 2009;27:5874–5880

Toxicity in the First and Recurrence Treatments

Grades 2/3 Adverse Event According to CTCAE

PCV (N = 100)

Allergic reaction

13 (13%)

Alopecia/local skin reaction

Cephalgia

Diarrhea

Hematologic (grades 3 to 4)

22 (22%)

Herpes zoster infection

4 (4%)

Infection (grades 2 to 4)

4 (4%)

Obstipation

Polyneuropathy

16 (16%)

Pneumonia

3 (3%)

Pneumonitis

1 (1%)

Tumor bleed, thromboembolic events

3 (3%)

Transaminase elevation

23 (23%)

CTCAE, National Cancer Institute (USA) Common Terminology Criteria for Adverse Events, all versions. At: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm [accessed December 7, 2013]

Patient Population Studied

A phase II study of 46 patients with recurrent malignant brain tumor

Therapy Monitoring

Weekly: CBC with differential
Before each treatment: LFTs
Every 3–4 cycles: Pulmonary function test

Notes

This regimen has been particularly effective for the treatment of high risk low grade gliomas following radiation therapy, anaplastic oligodendrogliomas and oligoastrocytomas

Cairncross JG et al. Ann Neurol 1988;23:360–364

Kim L et al. J Neurosurg 1996;85:602–607

REGIMEN: ADJUVANT PROCARBAZINE, LOMUSTINE (CCNU), AND VINCRISTINE (PCV) NEWLY DIAGNOSED ANAPLASTIC OLIGODENDROGLIOMA

Listen

Regimen: Adjuvant Procarbazine, Lomustine (CCNU), and Vincristine (PCV) Newly Diagnosed Anaplastic Oligodendroglioma

van den Bent MJ et al. J Clin Oncol 2013;31:344–350

van den Bent MJ et al. J Clin Oncol 2006;24:2715–2722

Special instructions:

Because procarbazine is a weak monoamine oxidase inhibitor, clinicians should guide patients who receive the drug in limiting their dietary intake of tyramine-containing foods and beverages

Anon. Med Lett Drugs Ther 1989;31:11–12

DaPrada M et al. J Neural Transm Suppl 1988;26:31–56

McCabe BJ. J Am Diet Assoc 1986;86:1059–1064

PCV chemotherapy started within 4 weeks after the end of RT

Lomustine 110 mg/m²; administer orally as a single dose on day 1, every 6 weeks for a total of 6 cycles (total dosage/cycle = 110 mg/m²)

Procarbazine 60 mg/m² per day; administer orally for 14 consecutive days on days 8–21, every 6 weeks for a total of 6 cycles (total dosage/cycle = 840 mg/m²)

Vincristine 1.4 mg/m²; administer per dose (maximum single dose = 2 mg); administer by intravenous injection over 1–2 minutes for 2 doses, on days 8 and 29, every 6 weeks for a total of 6 cycles (total dosage/cycle = 2.8 mg/m²; maximum dose/cycle = 4 mg)

Radiotherapy within 6 weeks after surgery. 45 Gy is administered to the planning target volume-1 (PTV-1) in twenty-five 1.8-Gy fractions, 5 days/week over 5 weeks. Thereafter, a boost of 14.4 Gy (up to a cumulative dose of 59.4 Gy) is delivered to the PTV-2 in 8 fractions of 1.8 Gy, 1 fraction per day, 5 fractions per week. PTV-2 is to include the nonenhancing tumor area and/or the enhancing area as visible on the postoperative CT scan with contrast with a 1.5-cm margin; in case of a nonenhancing tumor on CT scan, a postoperative MRI scan with and without gadolinium is recommended to further define the tumor volume

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 and days 8–21 is MODERATE–HIGH

Emetogenic potential on day 29 is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Note: Treatment at the time of progression was left to the discretion of local investigators, but the study protocol strongly advised treating physicians to consider (PCV) chemotherapy, especially for patients in the RT-only arm

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

WBC nadir during the prior cycle 2000–3000/mm³, or platelets 25,000–75,000/mm³

Reduce lomustine and procarbazine dosages by 10–25%

WBC nadir during the prior cycle <2000/mm³, or platelets <25,000/mm³

Reduce lomustine and procarbazine dosages by 25–50%

Severe neurotoxicity; eg, painful paresthesia or peripheral weakness

Discontinue vincristine

Cumulative lomustine dosage >1100 mg/m², or worsening forced vital capacity (FVC) or carbon monoxide diffusing capacity (DL_co)^✫

Discontinue lomustine

Patient Population Studied

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Patient Population Studied

Patient Characteristic

Radiotherapy Plus PCV (N = 185)

Radiotherapy Only (N = 183)

Number of Patients (Percent)

Age, years: median (range)

48.6 (18.6–68.7)

49.8 (19.2–68.7)

Sex: Male/Female

102/83

110/73

WHO performance status: 0/1/2

155 (84)/30 (16)

153/30/84/16

Previous resection for low-grade tumor: Yes/No

27 (15)/156 (84)

25 (14)/157 (86)

Enhancement of the tumor: Yes/No

144 (78)/33 (18)

140 (77)/29 (16)

Tumor localization: Frontal/Elsewhere

89 (48)/96 (52)

84 (47)/98 (53)

MMSE score: 27–30/<27

116 (63)/46 (25)

14 (62)/53 (29)

Extent of resection^✫

Biopsy

Partial resection

Total resection

27 (15)

100 (54)

58 (31)

25 (14)

83 (45)

75 (41)

Pathology

Oligodendroglioma

Oligoastrocytoma

Missing

139 (75)

44 (24)

2 (1)

126 (69)

56 (31)

1 (1)

1p/19q determined

1p/19q loss

1p loss

19q loss

No loss

155

42 (27)

24 (15)

18 (12)

71 (46)

156

36 (23)

24 (15)

20 (13)

76 (49)

MMSE, Mini-Mental State Examination; PCV, procarbazine, lomustine, and vincristine

^✫The extent of resection as assessed by the neurosurgeon

Toxicity

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Toxicity

Most patients who discontinued PCV prematurely did so for (usually asymptomatic) hematologic toxicity or for tumor progression
A quality-of-life analysis that was part of this study has shown that patients in the RT/PCV arm complained more frequently of nausea/vomiting, loss of appetite, and drowsiness during and shortly after PCV chemotherapy
However, no long-term effects of PCV chemotherapy on quality of life were identified

G3/4 Toxicity in the Patients Who Started PCV Chemotherapy (N = 161)

Toxicity

Grade 3

Grade 4

Number of Patients (Percent)

WBC count

43 (27)

5 (3)

Neutrophils

39 (24)

13 (8)

Platelets

23 (14)

11 (7)

Hemoglobin

10 (6)

1 (1)

Any hematologic toxicity

51 (32)

23 (14)

Nausea

9 (6)

—

Vomiting

10 (6)

—

Polyneuropathy

3 (2)

—

Allergic skin reactions

2 (1)

—

PCV, procarbazine, lomustine, and vincristine

Efficacy

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Efficacy^✫

Median and 5-Year Overall Survival and Progression-Free Survival According to Assigned Treatment in the Various Subgroups

Overall Survival

Progression-free Survival

Median

95% CI

% 5-y

95% CI

Median

95% CI

% 5-y

95% CI

Intent-to-treat Population (N_RT = 183; N_RT/PCV = 185)

30.6

21.5–44.5

37.0

30.0–44.0

13.2

9.2–17.9

16.0–27.9

RT/PCV

42.3

28.7–62.0

43.4

36.2–50.5

24.3

17.4–40.7

37.5

30.5–44.4

1p/19q Status

Deleted 1p/19q (N = 80)

111.8

75.7–134.3

73.0

55.6–84.4

49.9

27.8–101.8

46.0

29.6–60.9

RT/PCV

76.2

60.3–86.4

156.8

68.1–NR

71.4

55.2–82.7

HR, 0.56 (95% CI, 0.31–1.03); P = 0.0594

HR, 0.42 (95% CI, 0.24 to 0.74); P = 0.002

Nondeleted 1p/19q (N = 236)

21.1

17.6–28.7

25.1

17.7–33.0

8.7

7.1–11.7

13.5

8.1–20.3

RT/PCV

25.0

18.0–36.8

31.6

23.3–40.2

14.8

9.9–21.1

25.4

17.8–33.7

HR, 0.83 (95% CI, 0.62–1.10); P = 0.185

HR, 0.73 (95% CI, 0.56–0.97); P = 0.026

IDH Status

Mutated (N = 81)

64.8

36.9–111.8

52.8

35.5–67.4

36.0

17.2–58.6

33.3

18.8–48.6

RT/PCV

68.2

52.3–79.8

71.2

47.1–NR

59.1

43.2–71.9

Wild type (N = 97)

14.7

11.9–19.1

16.0

7.5–27.4

6.8

5.4–8.6

4.0

0.74–12.1

RT/PCV

19.0

14.6–30.2

21.3

11.0–33.8

10.0

7.8–18.2

17.0

8.0–29.0

MGMT Promoter

Methylated (N = 136)

43.3

21.9–66.2

41.9

29.6–53.8

15.2

8.7–34.5

21.0

11.9–31.8

RT/PCV

70.9

42.0–136.8

54.8

42.7–65.4

55.6

20.4–73.6

48.0

36.2–58.8

Unmethylated (N = 47)

15.6

11.4–19.1

8.3

1.4–23.3

7.1

4.4–8.7

4.2

0.3–17.6

RT/PCV

16.3

9.1–30.3

17.4

5.4–35.0

9.8

4.6–15.4

17.4

5.4–35.0

Confirmed Anaplastic Oligodendroglial Histology at Central Review (N_RT = 126; N_RT/PCV = 131)

28.7

19.3–41.7

33.0

25.0–41.3

10.4

8.4–16.9

17.9

11.8–25.1

RT/PCV

35.0

24.2–56.2

41.5

33.0–49.8

19.1

15.2–40.0

35.4

27.3–43.6

HR, 0.73 (95% CI, 0.55–0.96)

CI, confidence interval; IDH, isocitrate dehydrogenase; MGMT, O₆-methylguanine-DNA methyltransferase; NR, not reached; PCV, procarbazine, lomustine, and vincristine; RT, radiotherapy

^✫The increase in OS was achieved despite the fact that the median number of PCV cycles was 3, with only 30% of patients completing the intended 6 cycles; most patients that discontinued PCV prematurely did so for (usually asymptomatic) hematologic toxicity or for tumor progression

Therapy Monitoring

Weekly: CBC with differential
Before each treatment: LFTs
Every 3–4 cycles: Pulmonary function tests

REGIMEN: HIGH-DOSE TAMOXIFEN

Listen

Regimen: High-Dose Tamoxifen

Couldwell WT et al. Clin Cancer Res 1996;2:619–622

Initial dose and schedule:

Tamoxifen 20 mg/dose; administer orally, twice daily for 4 days (total dose/4 days = 160 mg)

If tolerated advance dose as follows:

Increase the tamoxifen dose every week in increments of 20 mg/dose (40 mg/day) to achieve after 1 month the target doses indicated below

Target dose for females:

Tamoxifen 80 mg/dose; administer orally, twice daily, continually (total dose/30 days = 4800 mg)

Target dose for males:

Tamoxifen 100 mg/dose; administer orally, twice daily, continually (total dose/30 days = 6000 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A phase II study of 32 patients with recurrent malignant gliomas

Efficacy (N = 32)

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Efficacy (N = 32)

Clinical and radiographic responses

25%

Stable disease

19%

Median survival

10.1 months

Toxicity (N = 32)

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Toxicity (N = 32)

% Patients

Deep vein thrombosis

Nausea

Hot flashes

Fatigue

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Deep venous thrombosis

Discontinue tamoxifen

Nausea/vomiting

Hold tamoxifen. Restart previously tolerated dose when symptoms resolve to G ≤1

G3 fatigue

Hold tamoxifen. Restart previously tolerated dose when symptoms resolve to G ≤1

Therapy Monitoring

Weekly: CBC with differential
Weekly while escalating dose: LFTs, BUN, and serum creatinine
Every 2 months when not escalating dose: LFTs, BUN, and serum creatinine

REGIMEN: ERLOTINIB (TARCEVA)

Listen

Regimen: Erlotinib (TARCEVA)

Prados MD et al. Neuro Oncol 2006;8:67–78

Raizer JJ et al. Proc Am Soc Clin Oncol 2004;22:107s (abstract #1502)

Yung A et al. Proc Am Soc Clin Oncol 2004;22:120s (abstract #1555)

Patients receiving non–enzyme-inducing antiepileptic drugs (NEIAED)

Erlotinib 200 mg per day; administer orally, continually, every day of a 4-week cycle (total dosage/cycle = 5600 mg)

Patients receiving enzyme-inducing antiepileptic drugs (EIAED)

Erlotinib 500 mg per day; administer orally, continually, every day of a 4-week cycle (total dosage/cycle = 14,000 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

Loperamide 4 mg orally initially after the first loose or liquid stool, then

Loperamide 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil^®)
Initial adult dose is two tablets four times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as two tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Pulmonary symptoms (dyspnea, cough, fever)

Hold erlotinib

Interstitial lung disease

Discontinue erlotinib

G1/2 diarrhea

Administer loperamide, 2 mg orally several times a day; if symptoms do not improve, hold erlotinib until symptoms resolve and then reduce dose

G2+/3/4 diarrhea

Reduce dose, or hold erlotinib until symptoms resolve and then reduce dose

G1/2 rash, skin reaction

Hold erlotinib. Administer supportive care. If symptoms resolve, restart the same dose

G2+/3/4 rash, skin reaction

Hold erlotinib. Administer supportive care. If symptoms resolve, restart at a reduced dose

Patient Population Studied

A phase I study of 83 patients with stable or progressive malignant primary glioma (Prados et al.)
A phase II study of 48 patients with glioblastoma in first relapse
A phase II study of 45 patients with recurrent malignant gliomas not on EIAED

Yung A et al. Proc Am Soc Clin Oncol 2004;22:120s (abstract #1555)

Toxicity (N = 83)

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Toxicity^✫ (N = 83)

% All Grades

% G1

% G2

% G3

% G4

Rash

Fatigue

Diarrhea

White blood cell count

Headache

Liver dysfunction

Constipation

Nausea/vomiting

Dry mouth

Platelet count

Pruritus

Infection

1^†

Kidney dysfunction

^✫Includes all patients on erlotinib alone or combined with temozolomide)

^† Grade 5; thought to be temozolomide-associated myelosuppression with infection

Prados MD et al. Neuro Oncol 2006;8:67–78

Toxicity (N = 22)

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Toxicity (N = 22)

Adverse Event

% of All Patients

No EIAED

+ EIAED

% Erlotinib Alone

% Erlotinib + Temozolomide

% Erlotinib Alone

% Erlotinib + Temozolomide

Rash

Thrombocytopenia

Fatigue

Diarrhea

4.5

Neutropenia

Headache

4.5

Liver dysfunction

4.5

Nausea/vomiting

4.5

Infections

4.5

Kidney dysfunction

4.5

Prados MD et al. Neuro Oncol 2006;8:67–78

Efficacy (N = 57)

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Efficacy (N = 57)

Partial response

14%

PFS >6 months

10.5% (including 4/6 with PR)

Prados MD et al. Neuro Oncol 2006;8:67–78

Efficacy (N = 48)

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Efficacy (N = 48)

Complete response

Partial response

Stable disease

21%

Yung A et al. Proc Am Soc Clin Oncol 2004;22:120s (abstract #1555)

Efficacy (N = 45)

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Efficacy (N = 45)

Glioblastoma Multiforme (GBM)—30 Patients

Stable disease

13%

Median progression-free survival

12 weeks

Anaplastic Glioma—15 Patients

Partial response

Stable disease

13%

Median progression-free survival

8.6 weeks

Raizer JJ et al. Proc Am Soc Clin Oncol 2004;22: 107s (abstract #1502)

Therapy Monitoring

Weekly: CBC with differential
Every 4 weeks: Serum electrolytes, mineral panel, and LFTs

Notes

This regimen might be useful particularly for patients whose tumor expresses EGFR or EGFRviii, which are commonly found in GBM

REGIMEN: BEVACIZUMAB (AVASTIN) ± IRINOTECAN

Listen

Regimen: Bevacizumab (AVASTIN) ± Irinotecan

Kreisl T et al. J Clin Oncol 2009;27:740–745

Initial therapy:

Bevacizumab 10 mg/kg per dose; administer intravenously in 100 mL 0.9% sodium chloride injection, USP (0.9% NS) every 14 days on a 28-day cycle (total dosage/cycle = 20 mg/kg)

First dose is administered over 90 minutes
Second dose may be administered over 60 minutes, if the first dose was well tolerated
Third and subsequent doses may be administered over 30 minutes, if doses administered over 60 minutes were well tolerated

Therapy after documented tumor progression:

Bevacizumab 10 mg/kg per dose; administer intravenously in 100 mL 0.9% NS every 14 days on a 28-day cycle (total dosage/cycle = 20 mg/kg), plus

Irinotecan

Patients receiving non–enzyme-inducing antiepileptic drugs (NEIAED)

125 mg/m²; administer intravenously over 90 minutes in 250 mL 0.9% NS or 5% dextrose injection, USP (D5W), every 14 days on a 28-day cycle (total dosage per cycle = 250 mg/m²)
Patients receiving enzyme-inducing antiepileptic drugs (EIAED)

340 mg/m²; administer intravenously over 90 minutes in 250 mL 0.9% NS or D5W every 14 days on a 28-day cycle (total dosage per cycle = 680 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with bevacizumab alone is MINIMAL

Emetogenic potential with bevacizumab + irinotecan is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Acute cholinergic syndrome

Atropine sulfate 0.25 –1 mg administer subcutaneously or intravenously if abdominal cramping or diarrhea develop during or within 1 hour after irinotecan administration

If symptoms are severe, add as primary prophylaxis at least 30 min before irinotecan during subsequent cycles
For irinotecan, acute cholinergic syndrome may be characterized by: abdominal cramping, diarrhea, diaphoresis, hypotension, flushing, bradycardia, rhinitis, increased salivation, meiosis, and lacrimation

Diarrhea management

Latent or delayed onset diarrhea^✫:

Loperamide 4 mg orally initially after the first loose or liquid stool, then

Loperamide 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil^®)

Initial adult dose is two tablets four times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as two tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide 100 –150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Toxicity (N = 48)

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Toxicity (N = 48)

Toxicity

% G1

% G2

% G3

% G4

Thromboembolic events

4.2

8.4

Hypertension

8.4

4.2

Hypophosphatemia

4.2

6.3

Thrombocytopenia

4.2

2.1

Hepatic dysfunction

2.1

Proteinuria

2.1

Bowel perforation

2.1

Patient Population Studied

A phase II study of 48 patients with recurrent glioblastoma

Efficacy (N = 48)

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Efficacy (N = 48)

Partial response

71%

6-Month survival rate

57%

6-Month progression-free survival

29%

Median overall survival

31 weeks

Median progression-free survival

16 weeks

Note: Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses

Therapy Monitoring

Every 2 weeks: CBC with differential, urinalysis for urine protein: creatinine ratio, BP check
Every 4 weeks: CBC with differential, serum electrolytes, mineral panel, and LFTs

Treatment Modifications: Bevacizumab-Related Adverse Events

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Treatment Modifications: Bevacizumab-Related Adverse Events

Note: There are no recommended dose reductions for the use of bevacizumab. Consequently, bevacizumab use is either temporarily interrupted or discontinued

Adverse Event

Toxicity Grade

Dose Modification/Action to Be Taken

Allergic reactions or Acute infusional reactions/cytokine release syndrome

G1–3

Premedications should be given before the next dose, and infusion time may not be shortened for subsequent infusions

For patients with G3 reactions, bevacizumab infusion should be stopped and not restarted on the same day. At a physician's discretion, bevacizumab may be permanently discontinued or reinstituted with premedications and at a rate designed to complete administration over 90 ± 15 minutes. If bevacizumab is reinstituted, the patient should be closely monitored for a duration comparable to or longer than the duration of the previous reactions

Discontinue bevacizumab

Arterial thrombosis

Cardiac ischemia/infarction
CNS ischemia (TIA, CVA)
Any peripheral or visceral arterial ischemia/thrombosis

G2 (if new or worsened after starting bevacizumab therapy)

Discontinue bevacizumab

G3/4

Discontinue bevacizumab

Venous thrombosis

G3 or asymptomatic G4

Hold bevacizumab treatment. If the planned duration of full-dose anticoagulation is <2 weeks, bevacizumab should be withheld until the full-dose anticoagulation period is over. Prophylaxis against pulmonary emboli can be accomplished through placement of an IVC filter
If the planned duration of full-dose anticoagulation is >2 weeks, permanently discontinue bevacizumab
If thromboemboli worsen/recur upon resumption of therapy, discontinue bevacizumab

G4 (symptomatic)

Discontinue bevacizumab

Hypertension (Treat with antihypertensive medications as needed. The goal of BP control should be consistent with general medical practice)

If BP is controlled medically

Continue bevacizumab

Persistent or symptomatic HTN

Hold bevacizumab. If treatment is delayed for >4 weeks because of uncontrolled hypertension, discontinue bevacizumab

Discontinue bevacizumab

Proteinuria (Proteinuria should be monitored by urine analysis for urine protein:creatinine [UPC] ratio prior to every dose of bevacizumab)

UPC ratio <3.5

Continue bevacizumab

UPC ratio ≥3.5

Hold bevacizumab until UPC recovers to <3.5. If therapy is held for >2 months because of proteinuria, discontinue bevacizumab

G4 or nephrotic syndrome

Discontinue bevacizumab

Wound dehiscence requiring medical or surgical intervention

Discontinue bevacizumab

GI perforation, GI leak or fistula

Discontinue bevacizumab

REGIMEN: HIGH-DOSE METHOTREXATE FOR PRIMARY CNS LYMPHOMA

Listen

Regimen: High-Dose Methotrexate for Primary CNS Lymphoma

Batchelor T et al. J Clin Oncol 2003;21:1044–1049

Induction phase:

Methotrexate every 14 days until complete response (CR) or a maximum of 8 cycles are delivered

Consolidation phase:

For patients achieving a CR during induction, give 2 cycles of methotrexate every 14 days, then give:

Maintenance phase:

Eleven cycles of methotrexate every 28 days

Hydration before, during, and after methotrexate:

Before methotrexate administration:

5% Dextrose injection (D5W) or 5% dextrose/0.45% sodium chloride injection (D5W/0.45% NS) with 50–100 mEq sodium bicarbonate injection/L; administer intravenously at 100–150 mL/hour

Adjust infusion rate to achieve and maintain a urine output ≥100 mL/hour for ≥4 hours before starting methotrexate
Adjust sodium bicarbonate to produce a urine pH within the range ≥7.0 to ≤8.0 before starting methotrexate

During methotrexate administration:

No additional hydration (see below)

After methotrexate administration:

D5W or D5W/0.45% NS with 50–100 mEq sodium bicarbonate injection/L; administer intravenously at 100–150 mL/hour until serum methotrexate concentration <0.1 μmol/L

Adjust infusion rate to maintain urine output ≥100 mL/hour
Adjust sodium bicarbonate to maintain urine pH ≥7.0 to ≤8.0

Methotrexate 8000 mg/m² in 500–1000 mL D5W with 50–100 mEq sodium bicarbonate per dose; administer intravenously over 4 hours (total dosage every 14 days [induction and consolidation cycles] and every 28 days [maintenance cycles] = 8000 mg/m²)

(Add sodium bicarbonate in amounts sufficient to produce a bicarbonate concentration equivalent to fluid used for the same volume of hydration fluid given over a 4-hour period)

Leucovorin calcium 25 mg per dose; administer intravenously every 6 hours for 4 doses, starting 24 hours after methotrexate administration began

Six hour after the last dose of intravenously administered leucovorin, start oral leucovorin or continue with intravenous leucovorin calcium every 6 hours if patient is nauseated or vomiting otherwise:

Leucovorin calcium 25 mg per dose; administer orally or intravenously every 6 hours until serum methotrexate concentration <0.1 μmol/L

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A multicenter phase II trial of 25 patients with newly diagnosed non–AIDS-related primary CNS lymphoma (PCNSL). Previous radiation therapy was not allowed

Efficacy (N = 24)

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Efficacy (N = 24)

Complete response^✫

50%

Partial response

21%

Stable disease

4.2%

Median progression-free survival

12.8 months

Median overall survival

>22.8 months

^✫Median number of cycles to CR = 6

Treatment Modifications

Methotrexate dosage is based on a measured creatinine clearance before treatment commences. For any creatinine clearance <100 mL/min, methotrexate dosage is calculated by multiplying the planned dosage (8000 mg/m²) by the ratio between the measured creatinine clearance (Clcr) and 100

Example:

For a measured Clcr = 75 mL/min:

Thus, the adjusted methotrexate dosage is:

Toxicity

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Toxicity

(N = 25 Patients; N = 287 Cycles)

Toxicity

% Patients

G ≥3/4 toxicity

No G3/4 toxicity

Leukoencephalopathy

—

Batchelor T et al. J Clin Oncol 2003;21:1044–1049

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Toxicity

(N = 31 Patients; N = 375 Cycles)^✫

Toxicity

% Cycles

Leukopenia (<2000 WBC/mm³)

Nonoliguric acute renal failure

G3 mucositis

Leukoencephalopathy

—

Acute cerebral dysfunction

—

Delayed methotrexate clearance^†

Guha-Thakurta N et al. J Neurooncol 1999;43:259–268

^✫Treatment:

1. Methotrexate 8000 mg/m² for ≥3 induction cycles

2. Methotrexate 3500–8000 mg/m²/cycle until CR

3. Methotrexate 3500 mg/m²/month for 3 months

4. Methotrexate 3500 mg/m²/3 months indefinitely

Median: 10 cycles/patient (range: 3–30 cycles)

^†Risk factors for delayed methotrexate clearance:

1. Cycle intervals <10 days

2. Concurrent SIADH or diabetes insipidus

3. Acute renal failure

4. "Third-space" fluid compartments (eg, effusions)

Therapy Monitoring

Before each treatment cycle:

CBC with differential
Serum electrolytes
LFTs
24-hour urine collection for creatinine clearance

During hospitalization:

Check urine output and pH frequently
Daily CBC with differential and serum electrolytes
Monitor daily methotrexate levels starting the day after methotrexate administration begins and continue until serum methotrexate concentrations are <0.1 μmol/L. In patients with renal impairment or pleural effusion, continue leucovorin and check serum methotrexate concentrations daily until methotrexate is undetectable

Notes

The regimen is for the treatment of primary central nervous system lymphoma for which radiation therapy has been deferred
In patients with renal impairment or an effusion, consider empirically continuing leucovorin calcium administration until serum methotrexate concentrations become undetectable

CNS LYMPHOMA REGIMEN: RITUXIMAB, METHOTREXATE, PROCARBAZINE, AND VINCRISTINE FOLLOWED BY CONSOLIDATION, REDUCED-DOSE WHOLE-BRAIN RADIOTHERAPY, AND CYTARABINE (R-MPV → RT + C) NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA

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CNS Lymphoma Regimen: Rituximab, Methotrexate, Procarbazine, and Vincristine Followed by Consolidation, Reduced-Dose Whole-Brain Radiotherapy, and Cytarabine (R-MPV → RT + C) Newly Diagnosed Primary CNS Lymphoma

Morris PG et al. J Clin Oncol 2013;31:3971–3979

Shah GD et al. J Clin Oncol 2007;25:4730–4735

Induction Chemotherapy: Five 14-Day Cycles

Premedication for rituximab:

Acetaminophen 650–1000 mg orally, plus

Diphenhydramine 25–50 mg orally or intravenously, 30–60 minutes before starting rituximab

Rituximab 500 mg/m²; administer intravenously in 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W), USP, diluted to a concentration within the range 1–4 mg/mL on day 1, every 2 weeks, for 5–7 cycles (total dosage/cycle = 500 mg/m²)

Notes on rituximab administration:

Administer initially at a rate of 50 mg/h. If hypersensitivity or infusion reactions do not occur during the first 30 minutes, increase the rate by 50 mg/h every 30 minutes as tolerated to a maximum rate of 400 mg/h
During subsequent treatments, if previous rituximab administration was well tolerated, start at 100 mg/hour and increase by 100 mg/hour every 30 minutes as tolerated to a maximum rate of 400 mg/hour
Interrupt rituximab administration for fever, chills, edema, congestion of the head and neck mucosa, hypertension, and other serious adverse events. Resume rituximab administration after adverse events abate

Methotrexate 3500 mg/m²; administer intravenously over 2 hours on day 2, every 2 weeks, for 5–7 cycles (total dosage/cycle not including intrathecal therapy = 3500 mg/m²)

Note: For logistical practicality and efficiency, parenteral admixtures containing methotrexate may include a portion or all of the fluid and sodium bicarbonate needed to meet hydration and urinary alkalinization requirements during methotrexate administration

Hydration before, during, and after methotrexate:

Administer 1500–3000 mL/m² per day. Use a solution containing a total amount of sodium not greater than 0.9% sodium chloride injection (ie, ≤154 mEq/1000 mL), by intravenous infusion during methotrexate administration and for at least 24 hours afterward

Commence fluid administration 2–12 hours before starting methotrexate, depending upon a patient's fluid status
Urine output should be at least 100 mL/h before starting methotrexate infusion
Maintain hydration at a rate that maintains urine output of at least 100 mL/h until the serum methotrexate concentration is <0.05 μmol/L
Adverse effects attributable to methotrexate are related to systemic methotrexate concentrations and the duration for which concentrations are maintained

Sodium bicarbonate 50–150 mEq/1000 mL is added to parenteral hydration solutions to maintain urine pH ≥7.0 to ≤8.0

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Base Solution Sodium Content

Sodium Bicarbonate Additive

Total Sodium Content

0.45% Sodium Chloride Injection (0.45% NS)

77 mEq/L

50–75 mEq

125–152 mEq/L

0.2% Sodium Chloride Injection (0.2% NS)

34 mEq/L

100–125 mEq

134–159 mEq/L

5% Dextrose Injection (D5W)

125–150 mEq

125–150 mEq/L

D5W/0.45% NS

77 mEq/L

50–75 mEq

125–152 mEq/L

D5W/0.2% NS

34 mEq/L

100–125 mEq

134–159 mEq/L

Leucovorin calcium 25 mg/m²; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–30 minutes every 6 hours starting 24 hours after methotrexate administration began, for at least 72 hours (≥12 doses) or until serum methotrexate concentrations are ≤0.05 μmol/L or undetectable, every 2 weeks, for 5–7 cycles

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Leucovorin Rescue Guidelines

Clinical Situation

Serum Methotrexate Concentration^✫

Leucovorin Dosage, Schedule, and Duration

Normal Methotrexate Elimination

≤10 μmol/L at 24 hours, or
≤1 μmol/L at 48 hours, or
≤0.2 μmol/L at 72 hours

Give leucovorin calcium 25 mg/m² intravenously every 6 hours until serum methotrexate concentrations are <0.1 μmol/L (<1 × 10^–7 mol/L or <100 nmol/L), then give leucovorin calcium 25 mg orally every 6 hours for 8 doses

Delayed/Late Methotrexate Elimination

≥10 μmol/L at 24 hours, or
≥1 μmol/L at 48 hours, or
≥0.1 μmol/L at 72 hours, or
≥0.05 μmol/L at 96 hours or
≥100% increase in serum creatinine concentration at 24 hours after methotrexate administration

Give leucovorin calcium 100 mg/m² intravenously every 3 hours
When serum methotrexate concentration results are <0.1 μmol/L the leucovorin dosage may be decreased to 10 mg/m² intravenously given every 3 hours until the serum methotrexate concentration is <0.05 μmol/L or undetectable

^✫After methotrexate administration began

Methotrexate concentration conversions: 1 μmol/L = 10^–6 mol/L = 1000 nmol/L)

Vincristine 1.4 mg/m² (maximum dose = 2.8 mg); administer by intravenous injection over 1–2 minutes on day 2, every 2 weeks, for 5–7 cycles (total dosage/cycle = 1.4 mg/m²; maximum dose/cycle = 2.8 mg)

Procarbazine 100 mg/m² per day; administer orally for 7 consecutive days on days 1 through 7, only during odd-numbered cycles (cycles 1, 3, 5 ± 7; ie, every 4 weeks) for 3 or 4 cycles (total dosage/cycle = 700 mg/m²)

For patients with cerebrospinal fluid cytologically positive for lymphoma:

Preservative-free methotrexate 12 mg; administer intrathecally via intraventricular catheter or reservoir (eg, Ommaya) once per cycle between days 5 and 8, every 2 weeks, for 5–7 cycles

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is MINIMAL

Emetogenic potential on day 2 during odd-numbered cycles (with procarbazine) is MODERATE–HIGH

Emetogenic potential on day 2 during even-numbered cycles (without procarbazine) is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with:

Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection

Begin use during odd-numbered cycles on day 8 (24 hours after the last dose of procarbazine)
Begin use during even-numbered cycles 24 hours after serum methotrexate concentrations are <0.01 μmol/L(<1 × 10^–8 mol/L, <10 nmol/L, or undetectable)
Discontinue daily filgrastim use at least 24 hours before resuming myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Infusion reactions associated with rituximab

Fevers, chills, and rigors

Interrupt rituximab administration for severe symptoms, and give:
- Acetaminophen 650 mg; administer orally for fever. For persistent or recurrent symptoms, repeat administration every 4–6 hours as needed during rituximab administration
- Diphenhydramine 25–50 mg; administer orally or by intravenous injection for pruritus, hypotension, or angioedema. For persistent or recurrent symptoms, repeat administration every 4–6 hours as needed during rituximab administration
- Meperidine 12.5–25 mg; administer by intravenous injection every 10–20 minutes as needed for shaking chills (generally, cumulative doses >100 mg are not needed; use repeated doses with caution in persons with moderate or more severely impaired renal function)
If rituximab administration was interrupted, resume infusion at a slower rate than the maximum rate previously attempted. Rate escalation may be reattempted at smaller incremental steps with close monitoring. Do not exceed the maximum recommended rate of 400 mg/hour

Dyspnea or wheezing without allergic findings (urticaria, or tongue or laryngeal edema)

Interrupt rituximab administration immediately
Give hydrocortisone 100 mg; administer by intravenous injection (or an alternative steroid with equivalent glucocorticoid potency)
Give a histamine (H₂) receptor antagonist (ranitidine 50 mg, cimetidine 300 mg, or famotidine 20 mg); administer intravenously over 15–30 minutes
After symptoms resolve, resume rituximab administration at 25 mg/hour with close monitoring. Do not increase the administration rate

CONSOLIDATION AFTER RADIOTHERAPY: TWO 28-DAY CYCLES

Cytarabine 3000 mg/m² per day (maximum daily dose = 6000 mg); administer intravenously in 25–500 mL 0.9% NS or D5W over 3 hours for 2 days (2 doses), on days 1 and 2, every 28 days (total dosage/cycle = 6000 mg/m²; maximum dose/cycle = 12,000 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day; administer by subcutaneous injection, or
Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL; administer by subcutaneous injection for 1 dose

Begin use from 24–72 hours after cytarabine is completed
Continue daily filgrastim use until ANC ≥10,000/mm³ on two measurements separated temporally by ≥12 hours
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment. Do not administer pegfilgrastim within 14 days before resuming myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended; consider use during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Keratitis prophylaxis

Steroid ophthalmic drops (prednisolone 1% or dexamethasone 0.1%) by intraocular instillation daily until 24 hours after high-dose cytarabine is completed

Patients with CSF evidence of malignancy received 12 mg of intra-Ommaya methotrexate between cycles

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Response Assessment After Five Induction Chemotherapy Cycles^✫

Assessment

Plan

Complete Response (CR)

Reduced-dose whole-brain radiotherapy (rdWBRT) (23.40 Gy in 1.8-Gy fractions × 13 fractions) 3–5 weeks after chemotherapy completion. Opposed lateral radiation fields were used to include the whole brain down to the level of C2 (so-called German helmet shape) and excluded the anterior two-thirds of the orbit

Partial Response (PR)

Two additional cycles of R-MPV, and, if a CR was achieved, rdWBRT was given as previously described. Otherwise, a standard dose of WBRT (45 Gy in 25 fractions) was offered

Stable or progressive disease

Standard WBRT. Patients with ocular involvement were irradiated without orbital shielding to the full dose of 23.40 Gy (patients in CR) or to a dose of 36 Gy (patients with less than a CR)

^✫Response was assessed using International PCNSL Collaborative Group criteria, based on imaging, corticosteroid use, and CSF cytology and slit-lamp examination in case of CSF or ocular involvement

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

WBC nadir during the previous cycle 2000–3000/mm³, or platelets 25,000–75,000/mm³

Reduce procarbazine dosage by 10–25%

WBC nadir during the previous cycle <2000/mm³, or platelets <25,000/mm³

Reduce procarbazine dosage by 25–50%

Severe neurotoxicity; eg, painful paresthesia or peripheral weakness

Discontinue vincristine

Leucovorin doses

See leucovorin guidelines

Patient Population Studied

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Patient Population Studied

Clinical Characteristics (N = 30)

Characteristic

Age (years), median/range

57 (30–76)

Sex, Male/Female

17/13

Karnofsky performance score, median/range

70 (50–90)

Positive CSF

Ocular involvement

Efficacy

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Efficacy

Response Rate to R-MPV (n = 27)

Complete Response

Partial Response

Overall Response

Time Point

Number (Percent)

After ≥5 cycles

12 (44%)

13 (59%)

25 (93%)

After all cycles

21 (78%)

4 (15%)

25 (93%)

R-MPV, rituximab, methotrexate, procarbazine, and vincristine

Efficacy

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Efficacy^✫

Reduced-dose Whole-brain Radiotherapy (rdWBRT) (N = 31)

Median PFS^†

7.7 years

Median OS^†

Not reached

Median PFS <60 years^†

Not reached

P = 0.02

Median PFS ≥60 years^†

4.4 years

Median OS <60 years^†

Not reached

P = 0.17

Median OS ≥60 years^†

Not reached

1-year PFS

84% (95% CI, 71–97%)

2-year PFS

77% (95% CI, 63–92%)

3-year PFS

71% (95% CI, 55–87%)

1-year OS

94% (95% CI, 85–100%)

2-year OS

90% (95% CI, 80–100%)

3-year OS

87% (95% CI, 75–99%)

5-year OS

80% (95% CI, 66–94%)

1-year PFS patients <60 years

94% (95% CI, 82–100%)

2-year PFS patients <60 years

94% (95% CI, 82–100%)

3-year PFS patients <60 years

88% (95% CI, 71–100%)

1-year PFS patients ≥60 years

73% (95% CI, 51–96%)

2-year PFS patients ≥60 years

60% (95% CI, 35–85%)

3-year PFS patients ≥60 years

53% (95% CI, 28–79%)

Entire Cohort (N = 52)

Median PFS^‡

3.3 years

Median OS^‡

6.6 years

Median PFS <60 years^‡

7.7 years

P = 0.09

Median PFS ≥60 years^‡

1.4 years

Median OS <60 years^‡

Not reached

P = 0.14

Median OS ≥60 years^‡

5.5 years

1-year PFS

65% (95% CI, 52–78%)

2-year PFS

57% (95% CI, 44–71%)

3-year PFS

51% (95% CI, 38–65%)

1-year OS

85% (95% CI, 75–94%)

2-year OS

81% (95% CI, 70–91%)

3-year OS

77% (95% CI, 65–88%)

5-year OS

70% (95% CI, 57–83%)

1-year PFS patients <60 years

68% (95% CI, 50–86%)

2-year PFS patients <60 years

64% (95% CI, 45–83%)

3-year PFS patients <60 years

64% (95% CI, 45–83%)

1-year PFS patients ≥60 years

63% (95% CI, 45–81%)

2-year PFS patients ≥60 years

47% (95% CI, 28–66%)

3-year PFS patients ≥60 years

38% (95% CI, 19–57%)

^✫The favorable regimen performance in patients expected to have a poor prognosis (elderly and low KPS) abrogated the predictive value of the Memorial Sloan Kettering Cancer Center RPA class, and no differences were seen in PFS or OS according to methotrexate pharmacokinetic parameters

^†Median follow-up of 5.9 years for survivors

^‡Median follow-up of 5.6 years for survivors

Therapy Monitoring

Weekly: CBC with differential
Before each treatment: serum creatinine and liver function tests
Every 3–4 cycles: pulmonary function test

Toxicity (N = 52)

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Toxicity (N = 52)^✫

Acute renal failure

Septic shock

Fatal febrile neutropenia >2 cycles

G4/5 neutropenia^†

13%

G3 anemia

10%

G3 thrombocytopenia

27%

G3 lymphopenia

40%

G3 neutropenia

20%

^✫Median number of R-MPV (rituximab, methotrexate, procarbazine, and vincristine) cycles received was 5 (range: 0–7)

^†Includes 2 of the first 5 treated patients; the protocol was the amended to require prophylactic filgrastim

Toxicity

Exploratory Neuropsychological and Imaging Correlates

(N = 12 treated with rdWBRT)

At baseline: Cognitive impairment present in several domains
After induction chemotherapy: significant improvement in executive (P <0.01) and verbal memory (P <0.05)
During follow-up: no evidence of significant cognitive decline except for motor speed (P <0.05)
During follow-up: no evidence of depressed mood, and self-reported quality of life remained stable during the follow-up period
At baseline: 5/12 patients had G ≥2 white matter disease
After induction chemotherapy: 1/12 patients had G ≥2 white matter disease
At 4-year evaluation: 5/12 patients had G2 and 2/12 patients had G3 white matter disease
During follow-up: no patient developed Fazekas scores of 4 or 5

REGIMEN: HIGH-DOSE METHOTREXATE AND RITUXIMAB WITH DEFERRED RADIOTHERAPY NEWLY DIAGNOSED PRIMARY B-CELL CNS LYMPHOMA

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Regimen: High-Dose Methotrexate and Rituximab with Deferred Radiotherapy Newly Diagnosed Primary B-CELL CNS Lymphoma

Chamberlain MC, Johnson SK. Neuro Oncol 2010;12:736–744

INDUCTION (≥4 BI-WEEKLY CYCLES)

Methotrexate; administer intravenously over 6 hours on day 1, every 2 weeks

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Methotrexate Dosage

Estimated or measured creatinine clearance

≥60 mL/minute (≥1 mL/s)

<60 mL/minute (<1 mL/s)

Methotrexate

8000 mg/m² (total dosage/2-week cycle = 8000 mg/m²)

4000 mg/m² (total dosage/2-week cycle = 4000 mg/m²)

Notes: For logistical practicality and efficiency, parenteral admixtures containing methotrexate may include a portion or all of the fluid and sodium bicarbonate needed to meet hydration and urinary alkalinization requirements during methotrexate administration

Hydration before, during, and after methotrexate:

Administer intravenously 1500–3000 mL/m² per day. Administer a solution containing a total amount of sodium not greater than 0.9% sodium chloride injection (ie, 154 mEq/1000 mL) by intravenous infusion during methotrexate administration and for at least 24 hours afterward

Commence fluid administration 2–12 hours before starting methotrexate, depending upon a patient's fluid status
Urine output should be at least 100 mL/hour before starting methotrexate infusion
Urine pH should be ≥7.0 but ≤8.0 before, during, and after methotrexate administration
Maintain hydration at a rate that maintains urine output of at least 100 mL/hours until the serum methotrexate concentration is <0.1 μmol/L
Adverse effects attributable to methotrexate are related to systemic methotrexate concentrations and the duration for which concentrations are maintained

Sodium bicarbonate 50–150 mEq/1000 mL is added to parenteral hydration solutions to maintain urine pH ≥7.0 to ≤8.0

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Base Solution Sodium Content

Sodium Bicarbonate Additive

Total Sodium Content

0.45% Sodium chloride injection (0.45% NS)

77 mEq/L

50–75 mEq

125–152 mEq/L

0.2% Sodium chloride injection (0.2% NS)

34 mEq/L

100–125 mEq

134–159 mEq/L

5% Dextrose injection (D5W)

125–150 mEq

125–150 mEq/L

D5W/0.45% NS

77 mEq/L

50–75 mEq

125–152 mEq/L

D5W/0.2% NS

34 mEq/L

100–125 mEq

134–159 mEq/L

Leucovorin calcium 10 mg/m²; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–30 minutes every 6 hours starting 24 hours after methotrexate administration begins, and continue until serum methotrexate concentrations are ≤0.1 μmol/L, every 2 weeks for a minimum of 4 cycles. When serum methotrexate concentrations are ≤0.1 μmol/L, discontinue intravenous hydration and leucovorin, then:

Give leucovorin calcium 25 mg; administer orally every 6 hours for 2 days (8 doses), and
Continue hydration orally with >1500 mL/m² (>50 fluid ounces/m²) for 3 days after intravenous hydration is discontinued

Rituximab 375 mg/m²; administer intravenously in 0.9% NS or D5W diluted to a concentration within the range 1–4 mg/mL between days 7 and 10 every 2 weeks for a minimum of 4 cycles; ie, within a 2-week cycle, during the week when methotrexate is not given (total dosage/2-week cycle = 375 mg/m²)

Notes on rituximab administration:

Administer initially at a rate of 50 mg/hour. If hypersensitivity or infusion reactions do not occur during the first 30 minutes, increase the rate by 50 mg/hour every 30 minutes as tolerated to a maximum rate of 400 mg/hour
During subsequent treatments, if previous rituximab administration was well tolerated, start at 100 mg/hour and increase the rate by 100 mg/hour every 30 minutes as tolerated to a maximum rate of 400 mg/hour
Interrupt rituximab administration for fever, chills, edema, congestion of the head and neck mucosa, hypertension, and other serious adverse events. Resume rituximab administration after adverse events abate

MAINTENANCE (4-WEEK CYCLES)

Methotrexate; administer intravenously over 6 hours on day 1, every 4 weeks

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Methotrexate Dosage

Estimated or measured creatinine clearance

≥60 mL/minute (≥1 mL/s)

<60 mL/minute (<1 mL/s)

Methotrexate

8000 mg/m² (Total dosage/4-week cycle = 8000 mg/m²)

4000 mg/m² (Total dosage/4-week cycle = 4000 mg/m²)

Hydration before, during, and after methotrexate:

Commence fluid administration 2–12 hours before starting methotrexate, depending upon a patient's fluid status
Urine output should be at least 100 mL/hour before starting methotrexate infusion
Urine pH should be ≥7.0 but ≤8.0 before, during, and after methotrexate administration
Maintain hydration at a rate that maintains urine output of at least 100 mL/hour until the serum methotrexate concentration is <0.1 μmol/L
Adverse effects attributable to methotrexate are related to systemic methotrexate concentrations and the duration for which concentrations are maintained

Sodium bicarbonate 50–150 mEq/1000 mL is added to parenteral hydration solutions to maintain urine pH ≥7.0 to ≤8.0

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Base Solution Sodium Content

Sodium Bicarbonate Additive

Total Sodium Content

0.45% Sodium Chloride Injection (0.45% NS)

77 mEq/L

50–75 mEq

125–152 mEq/L

0.2% Sodium Chloride Injection (0.2% NS)

34 mEq/L

100–125 mEq

134–159 mEq/L

5% Dextrose Injection (D5W)

125–150 mEq

125–150 mEq/L

D5W/0.45% NS

77 mEq/L

50–75 mEq

125–152 mEq/L

D5W/0.2% NS

34 mEq/L

100–125 mEq

134–159 mEq/L

When serum methotrexate concentrations are ≤0.1 μmol/L, discontinue intravenous hydration and leucovorin, then:
- Give leucovorin calcium 25 mg; administer orally every 6 hours for 2 days (8 doses), and
- Continue hydration orally with >1500 mL/m² (>50 fluid ounces/m²) for 3 days after intravenous hydration is discontinued

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Leucovorin Rescue Guidelines

Clinical Situation

Serum Methotrexate Concentration^✫

Leucovorin Dosage, Schedule, and Duration

Normal methotrexate elimination

≤10 μmol/L at 24 hours, or
≤1 μmol/L at 48 hours, or
≤0.2 μmol/L at 72 hours

Give leucovorin calcium 10 mg/m² intravenously every 6 hours until serum methotrexate concentrations are <0.1 μmol/L (<1 × 10⁻⁷ mol/L, or <100 nmol/L), then give leucovorin calcium 25 mg orally every 6 hours for 8 doses

Delayed/late methotrexate elimination

≥10 μmol/L at 24 hours, or
≥1 μmol/L at 48 hours, or
≥0.1 μmol/L at 72 hours, or
≥0.05 μmol/L at 96 hours, or
≥100% increase in serum creatinine concentration at 24 hours after methotrexate administration

Give leucovorin calcium 100 mg/m² intravenously every 3 hours
When serum methotrexate concentration results are <0.1 μmol/L the leucovorin dosage may be decreased to 10 mg/m² intravenously given every 3 hours until the serum methotrexate concentration is <0.05 μmol/L or undetectable

^✫After methotrexate administration is begun

Methotrexate concentration conversions: 1 μmol/L = 10⁻⁶ mol/L = 1000 nmol/L

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

G ≥3 hematologic toxicity on day 1 of a cycle or G >1 nonhematologic toxicity on day 1 of a cycle

Withhold treatment until all hematologic toxicity has resolved to G ≤2 and all nonhematologic toxicity has resolved to G ≤1

G ≥4 toxicity ascribed to methotrexate

Reduce the methotrexate dosage by 50%

G ≥3 toxicity ascribed to methotrexate after the dosage has been reduced by 50%

Discontinue methotrexate

Patient Population Studied

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Patient Population Studied

Patient Characteristics N = 40

Forty patients (25 men; 15 women), ages 18–93 years (median: 61.5 years), with newly diagnosed B-cell primary central nervous system lymphoma (PCNSL). Histopathology was determined by stereotactic biopsy in 29 patients, resective surgery in 9 patients, cerebrospinal fluid (CSF) flow cytometry in 1, and vitrectomy in 1 patient

Variables

Number of Patients (Percent)

Age, Median (range)

61.5 y (18–93 y)

≥50 y/≥70 y

33 (82.5)/17(42.5)

Sex, Male/Female

25 (62.5)/15 (37.5)

Location of tumor

Frontal

18 (45)

Temporal

3 (7.5)

Parietal

9 (22.5)

Corpus callosum

9 (22.5)

Deep gray nuclei

5 (12.5)

Occipital

2 (5)

Cerebellum

3 (7.5)

Brainstem

1 (2.5)

Subarachnoid/ventricular

2 (5)

Multilobar

12 (30)

Extent of initial surgery

Subtotal resection

9 (22.5)

Biopsy

29 (72.5)

Vitrectomy

1 (2.5)

Response to up-front chemotherapy

Complete response

24 (60)

Partial response

8 (20)

Progressive disease

8 (20)

Progression-free survival to up-front chemotherapy

Median (range)

21 mo (2–78 mo)

Salvage therapy at recurrence

Temozolomide

9 (22.5)

Procarbazine, Lomustine (CCNU), Vincristine

5 (12.5)

Methotrexate

1 (2.5)

Whole brain irradiation

8 (20)

Response to salvage therapy

Complete response

2 (9)

Partial response

12 (67)

Progressive disease

4 (22)

Progression-free survival to salvage therapy

Median (range)

6 mo (1 − 38+ mo)

Overall survival

Median (range)

29 mo (6 − 80+ mo)

Alive and disease free

20 (50)

≤50 y of age

7/9 (78)

>50 y of age

8/31 (26)

>60 y of age

0/20 (0)

Toxicity

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Toxicity

Total

Anemia

Fatigue

Hepatic

Hyperglycemia

Neutropenia without fever

Nausea

Renal

Thrombophlebitis

Totals

Treatment Monitoring

CBC with differential every week
Serum creatinine and liver function tests at the beginning of each cycle
Serum creatinine levels and serum methotrexate concentrations at 24 hours, 48 hours, and 72 hours after administration of methotrexate began, continuing at least until a serum methotrexate concentration ≤0.1 μmol/L is achieved

Efficacy (N = 40)

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Efficacy (N = 40)

Following induction with 4–6 cycles of methotrexate/rituximab (N = 40)

Complete radiographic response

24 (60%)

Partial radiographic response

8 (20%)^✫

Progressive disease

8 (20%)

Following maintenance methotrexate (N = 40)

Progression during maintenance

4 (10%)

At conclusion of induction and maintenance methotrexate (N = 28)^†

Complete radiographic response

27/28

Partial radiographic response

1/28

Median OS

33.5 months (11–80 months)

Median PFS

21.0 months (95% CI, 13.8–28.2)

Entire cohort (N = 40)

Median overall survival, entire cohort

29.0 months (95% CI, 19.7–38.3)

Probability of disease-free survival, <50 years

86% (6/7)

Probability of disease-free survival, 50–59 years

33% (4/12)

Probability of disease-free survival, 60–69 years

25% (1/4)

Probability of disease-free survival, >70 years

0 (0/17)

^✫Six of the 8 patients (75%) with a PR to induction methotrexate/rituximab converted to a complete response with maintenance methotrexate

^†6–8 months of total therapy

RECURRENT MENINGIOMA: LONG-ACTING OCTREOTIDE ACETATE

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Recurrent Meningioma: Long-Acting Octreotide Acetate

Chamberlain MC et al. Neurology 2007;69:969–973

Long-acting octreotide acetate 30 mg; administer by intramuscular injection (intragluteally) every 4 weeks (total dose/cycle = 30 mg)

Note: If after 2 cycles of therapy a patient has achieved stable disease or a better response and has tolerated a 30-mg dose, the dose of long-acting octreotide acetate may be increased to 40 mg every 4 weeks for the third and subsequent cycles of therapy (total dose/cycle = 40 mg)

Note: For patients not previously treated with subcutaneously-administered octreotide acetate, it is recommended to start with the administration of subcutaneous octreotide at a dosage of 0.1 mg 3 times daily for a short period (approximately 2 weeks) to assess the response and systemic tolerability of octreotide before initiating the treatment with long-acting octreotide acetate

Note: Limited published data indicate somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450. Use with caution drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (eg, quinidine, terfenadine)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

Asymptomatic gallstones

Continue long-acting octreotide acetate depending on reassessment of the benefit-to-risk ratio. Either way, no action is required except to continue monitoring with increased frequency if treatment with long-acting octreotide acetate is continued

Symptomatic gallstones

Long-acting octreotide acetate may be either stopped or continued, depending on reassessment of the benefit-to-risk ratio. Either way, the gallstones should be treated like any other symptomatic gallstones

Efficacy

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Efficacy

Partial response

4/16

Stable disease

5/16

Progressive disease

7/16

6-Month progression-free survival

44% (7/16)

Median duration of response

5.0 months (range: 2–20+ months)

Median overall survival

7.5 months (range: 3–20+ months)

Treatment/Therapy Monitoring

Ultrasound examination of the gallbladder prior to commencing octreotide treatment and at approximately 6-month intervals throughout treatment
Monitor vitamin B₁₂ levels in patients who have a history of vitamin B₁₂ deprivation

Toxicity

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Toxicity

Adverse Drug Reactions Reported in Clinical Studies

Gastrointestinal Disorders

Very common

Diarrhea, abdominal pain, nausea, constipation, flatulence

Common

Dyspepsia, vomiting, abdominal bloating, steatorrhea, loose stools, discoloration of feces

Nervous System Disorders

Very common

Headache

Common

Dizziness

Endocrine Disorders

Common

Hypothyroidism, thyroid dysfunction (eg, decreased TSH, decreased total T₄, and decreased free T₄)

Hepatobiliary Disorders

Very common

Cholelithiasis

Common

Cholecystitis, biliary sludge, hyperbilirubinemia

Metabolism and Nutrition Disorders^✫

Very common

Hyperglycemia

Common

Hypoglycemia, impaired glucose tolerance, anorexia

Uncommon

Dehydration

General Disorders and Administration Site Reactions

Very common

Localized pain at injection site

Laboratory Investigations

Common

Elevated transaminase levels

Uncommon

Depressed vitamin B₁₂ levels and abnormal Schilling tests

Skin and Subcutaneous Tissue Disorders

Common

Pruritus, rash, alopecia

Respiratory Disorders

Common

Dyspnea

Cardiac Disorders

Common

Bradycardia

Uncommon

Tachycardia

Very common: ≥1/10; Common: ≥1/100, <1/10; Uncommon: ≥1/1000, <1/100

^✫Note: Because of its inhibitory action on growth hormone, glucagon, and insulin release, long-acting somatostatin may affect glucose regulation. Postprandial glucose tolerance may be impaired. In some instances, a state of persistent hyperglycemia may be induced as a result of chronic administration

Patient Characteristics and Individual Efficacy

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Patient Characteristics and Individual Efficacy

Age/Gender

PATH

LOC

SUR

RT, Gy

SUR

EBRT

SRT

CHEMORx

KPS

#Cy

RESP

M/62

I/Yes

LFP

RCS

Celebrex (SD)

PR/12^✫

12^✫

M/83

III/Yes

Falx

STR

PR/15^✫

15^✫

F/41

I/No

LSW

STR

TAM 30 (SD)

HU 4.5 (PD)

PR/8

20+

M/67

III/No

GTR

SD/8^✫

8^✫

F/65

III/No

LTP

STR

58.4

12.9

TMZ + erlotinib2 (PD)

PD/2

F/68

II/No

RSW

STR

58.4

αIFN 12 (SD)

PR/6

11+

F/26

III/Yes

Spine

CSF

GTR

59.4

HU 2 (PD)

TMZ 2 (PD)

PD/2

F/45

I/No

RSB

RSF

CbPA

STR

SD/5^✫

5^✫

F/52

I/No

LCS

HU 3 (PD)

SD/20

20+

F/87

II/Yes

STR

PD/3

F/51

I/No

GTR

HU 3 (PD)

PD/3

8+^†

M/61

I/No

GTR

HU 3 (PD)

PD/3

7+^†

F/51

III/No

STR

Thal 13 (SD)

HU 3 (PD)

PD/3

7+^†

F/84

II/No

RCS

HU 3 (PD)

SD/5^✫

5^✫

FX/74

I/No

LSW

GTR

HU 3 (PD)

PD/3

M/72

I/No

LCS

HU 6 (PD)

PR/6

Column descriptions (in left-to-right order): Age/Gender (in years); PATH, histology, WHO grade/multifocal; LOC, tumor location; SUR, surgery; RT, radiotherapy; Gy, Gray; EBRT, external beam radiotherapy; SRT, stereotactic radiotherapy; CHEMORx, chemotherapy, number of cycles^✫ (best response); KPS, Karnofsky performance status; #Cy, number of cycles (cycle defined as 4 weeks); RESP, response assessment/duration in months; OS, overall survival

LOC (tumor location) (in order listed): LF, left frontal; LFP, left frontoparietal; RCS, right cavernous sinus; LT, left temporal; SS, sphenoid sinus; CS, cavernous sinus; LSW, left sphenoid wing; BF, bifrontal; LTP, left temporoparietal; RSW, right sphenoid wing; RT, right temporal; RF, right frontal, RSB, right skull; base; CbA, cerebellopontine angle; LS, left sphenoid; LCS, left cavernous sinus

Other (alphabetically): αIFN, interferonalfa; Bx, biopsy; CR, complete response; GTR, gross total resection; HU, hydroxyurea; NE, nonevaluable; PD, progressive disease; PR, partial response; SD, stable disease; STR, subtotal resection; TAM, tamoxifen; Thal, thalidomide; TMZ, temozolomide

^✫Alive on octreotide acetate

^†Alive

RECURRENT MENINGIOMA: INTERFERON ALFA

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RECURRENT MENINGIOMA: INTERFERON ALFA

Chamberlain MC, Glantz MJ. Cancer 2008;113:2146–2151

Interferon alfa-2b 10 million Units/m²; administer subcutaneously every-other-day for 4 weeks (total dose/week [4 doses] = 40 million Units/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Toxicity

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Toxicity

All Grades

Alopecia

Anemia

Constipation

Diarrhea

Fatigue

Granulocytopenia

Infection, neutropenia

Leukopenia

Nausea

Thrombocytopenia

Thrombophlebitis

Vomiting

Totals

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

G3/4 hematologic toxicity on day 1 of a cycle

Withhold interferon alfa-2b until all hematologic toxicity is G ≤2, then resume at 50% of the previous dose

G2/3/4 nonhematologic toxicity on day 1 of a cycle

Withhold interferon alfa-2b until all nonhematologic toxicity is G ≤1, then resume at 50% of the previous dose if toxicity was G3/4

G3/4 hematologic or nonhematologic toxicity after dosage reduced to 50%

Discontinue therapy

ALT/AST >5× to 10× the upper limit of normal range

Withhold interferon alfa-2b until adverse reactions abate, then resume at 50% of the previous dose

Efficacy

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Efficacy

Intention to Treat (N = 35)

Median OS

8 months (range: 3–28 months; 95% confidence interval, 5.6–10.4 months)

PFS at 6 months

54%

PFS at 12 months

31%

Median time to tumor progression

7 months (range: 2–24 months; 95% confidence interval, 4.9–9.1 months)

Treatment Monitoring

CBC with differential, serum electrolytes, BUN, creatinine, and liver function tests initially 3 times per week, then every week, and, eventually, monthly
Serum TSH level at start of treatment and at 3 and 6 months

Patient Characteristics and Individual Efficacy

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Patient Characteristics and Individual Efficacy

Therapy at Disease Recurrence

Age/Gender

PATH

Tumor Location

Adjuvant Rx

SUR

RTGy

CHEMORx

Interferon-α Therapy

SUR

RTGy

EBRT

SRT

#Cy

RESP

65/M

1/+

LF/LP/LCS

STR

HU2 (PD)

SD/14

84/M

1/+

LF/LT/Falx

STR

HU4 (PD)

SD/16

49/F

1/−

RCS/RSW

STR

STR×2

HU6 (SD)

SD/12

68/F

1/−

GTR

STR

HU3 (PD)

SD/12

58/F

1/−

STR

HU9 (SD)

SD/8

70/F

1/−

LSW

STR

50.4

STR

HU6 (SD)

SD/14

36/F

1/+

LT/LF

STR

STR×3

HU2 (PD)

SD/9

55/F

1/−

LSB/CbPA

STR

HU6 (SD)

SD/8

59/F

1/−

RSS/RCS

HU3 (PD)

SD/20

88/F

1/−

GTR

STR

HU6 (PD)

SD/14

54/F

1/−

GTR

HU3 (PD)

SD/7

66/M

1/−

LF/LP

STR

HU3 (PD)

PD/3

57/F

1/−

GTR

STR

HU3 (PD)

SD/7

80/F

1/−

LCS

HU3 (PD)

SD/24

54/M

1/+

LF/RP

STR

STR×2

TMZ 2 (PD)

SD/6

87/F

1/−

STR

HU 3 (PD)

SD/14

58/F

1/−

STR

TMZ 2 (PD)

SD/4

69/M

1/−

GTR

TMZ 4 (SD)

SD/4

66/F

1/−

STR

TMZ 4 (SD)

SD/4

53/F

1/−

TMZ 2 (PD)

SD/4

54/F

1/−

STR

TMZ 4 (SD)

PD/4

66/F

1/−

Lten

STR

TMZ 4 (SD)

PD/2

67/F

1/−

LCS

TMZ 4 (PD)

PD/2

59/F

1/−

GTR

STR

CPT 1 (SD)

SD/4

61/F

1/−

STR

CPT 2 (SD)

PD/3

54/F

1/−

CPT 1 (SD)

PD/3

55/F

1/−

STR

CPT 2 (SD)

PD/3

66/F

1/−

Lten

STR

CPT 2 (SD)

PD/3

47/F

1/−

GTR

CPT 1 (SD)

PD/3

61/F

1/−

STR

HU 3 (PD)

SS 3 (PD)

SD/8

61/M

1/−

RFP

GTR

GTR×2

HU 3 (PD)

SS 3 (PD)

SD/7

61/F

1/−

LCS

STR

50.4

STR

Bev +Cel^✫

SD/3

42/F

1/+

RF/RP

STR

50.4

HU 6 (PD)

SD/4

4^†

70/F

1/−

GTR

HU 4 (SD)

SD/20

21^†

68/F

1/−

RSW

STR

58.4

STR

None

SD/18

23^†

Column descriptions (in left-to-right order): Age/Gender (age in years); PATH, WHO grade/multifocal; SUR, surgery; RT, radiotherapy; Gy, gray; EBRT, external beam radiotherapy; SRT, stereotactic radiotherapy; CHEMORx, chemotherapy, number cycles^✫ (best response); #Cy, number of cycles; RESP, response assessment/duration in months; OS, overall survival

Tumor location (in order listed): LF, left frontal; LP, left parietal; LCS, left cavernous sinus; LT, left temporal; RCS, right cavernous sinus; RSW, right sphenoid wing; LSW, left sphenoid wing; LSB, left skull base; CbPA, cerebellopontine angle; RSS, right sphenoid sinus; RCS, cavernous sinus; RF, right frontal; LP, left parietal; RT, right temporal; RP, right parietal; RF, right frontal; Lten, left tentorium; RFP, right frontoparietal; RSW, right sphenoid wing

Other (alphabetically): Bx, biopsy; GTR, gross total resection; HU, hydroxyurea; PD, progressive disease; SD, stable disease; SS, long-acting octreotide acetate (Sandostatin LAR); STR, subtotal resection; TMZ, temozolomide

^✫Bevacizumab plus celecoxib

^†Alive

RECURRENT MENINGIOMA: HIGH-GRADE MENINGIOMA REFRACTORY TO RECURRENT SURGERY AND RADIATION HYDROXYUREA

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Recurrent Meningioma: High-Grade Meningioma Refractory to Recurrent Surgery and Radiation Hydroxyurea

Chamberlain MC. J Neurooncol 2012;107:315–321

Hydroxyurea 1000 mg/m² per day; administer orally, continually for 28 consecutive days, every 4 weeks (total dosage/cycle = 28,000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Efficacy

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Efficacy

Hydroxyurea for Recurrent Meningioma (Adapted from Chamberlain and Johnston)

Sources

Grades 2/3^✫

Prior RT

Response (%)

Median TTP^†

G ≥3 Toxicity (%)

Newton 2000

Newton 2004

17 (4)

SD (88)

20 months

25 (15)

Mason 2002

20 (4)

SD (60)

30 months

Rosenthal 2002

15 (10)

SD (73)

10 months

27 (20)

Hahn 2005

21 (17)

21 (concurrent)

SD (52)

14 months

53 (0)

Loven 2004

12 (4)

SD (8)

13 months

33 (25)

^✫Number with grades 2/3 on pathology review

^†TTP, time to progression

Chamberlain MC, Johnston SK. J Neurooncol 2011;104:765–771

Hahn BM et al. J Neurooncol 2005;74:157–165

Loven D et al. J Neurooncol 2004;67:221–226

Mason WP et al. J Neurosurg 2002;97:341–346

Newton HB et al. Br J Neurosurg 2004;18:495–499

Newton HB et al. J Neurooncol 2000;49:165–170

Rosenthal MA et al. J Clin Neurosci 2002;9:156–158

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

WBC count <2500/mm³, or platelet count <100,000/mm³

Withhold therapy until WBC count is >2500/mm³, and platelet count is >100,000/mm³

Severe anemia

Continue hydroxyurea

Severe gastric distress, such as nausea, vomiting, and anorexia

Withhold therapy until symptoms improve

Toxicity (N = 35)

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Toxicity (N = 35)

Toxicity

Grade 2

Grade 3

Total

Anemia

Constipation

Fatigue

Infection, without neutropenia

Lymphopenia

Nausea

Neutropenia

Thrombophlebitis

Totals

Treatment Monitoring

Complete blood counts and neurologic examination on day 1 of each 28-day cycle
Every 8 weeks and following 2 cycles of hydroxyurea, reevaluate with contrast cranial MR

Patient Characteristics and Individual Efficacy

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Patient Characteristics and Individual Efficacy

Initial Therapy

Salvage Therapy

Hydroxyurea Therapy

Age/Gender

Tumor Location

SUR

SRS

SUR

SRSGy

#Cy

RESP

PFS

86/F

GTR

0.5

75/M

STR

59.4

STR

0.5

70/F

RCS, RSW

STR

0.5

68/F

GTR

STR

56/F

GTR

STR

73/F

RSW

STR

42/M

RT, RF

STR

STR x2

61/F

LtenCbPA

GTR

STR x1

58/F

RSW

STR

80/F

GTR

STR

1.5

52/M

GTR

59.4

GTR

1.5

66/F

RF, RP

STR

1.5

67/F

GTR

STR

1.5

68/M

RCS

51/M

RF, RP

STR

59.4

STR x2

78/F

GTR

63/F

GTR

STR

69/F

GTR

59.4

GTR

66/F

LF, RF

STR

50/M

59.4

40/F

GTR

2.5

63/F

Rten

GTR

59.4

STR

2.5

62/F

RCS

48/F

GTR

STR

63/M

STR

59.4

60/F

LF, LP

3.5

76/F

LF, RF

STR

59.4

3.5

64/F

Rten

GTR

59.4

STR

79/F

GTR

STR

70/F

GTR

59.4

GTR

4.5

34/M

RF, RP

GTR

4.5

38/F

RCS

59.4

82/F

RT, falx, RSW

STR

62/F

LCS, LSW

STR

59.4

47/F

LF, RF

STR

Column descriptions (in left-to-right order): Age/Gender (age in years); SUR, surgery; RT, radiotherapy; Gy, gray; SRT, stereotactic radiotherapy; CHEMORx, chemotherapy, number cycles^✫ (best response); #Cy, number of cycles; RESP, response assessment/duration in months; PFS, progression-free survival (in months)

Tumor location (in order listed): LF, left frontal; RF, right frontal; RCS, cavernous sinus; RSW, right sphenoid wing; RP, right parietal; RT, right temporal; Lten, left tentorium; CbPA, cerebellopontine angle; LT, left temporal; RCS, right cavernous sinus; Rten, right tentorium; LP, left parietal; LCS, left cavernous sinus; LSW, left sphenoid wing

Other (alphabetically): Bx, biopsy; GTR, gross total resection; PD, progressive disease; SD, stable disease; STR, subtotal resection

REGIMEN FOR NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: INDUCTION CHEMOTHERAPY WITH RITUXIMAB, METHOTREXATE, AND TEMOZOLIMIDE, FOLLOWED BY WHOLE-BRAIN RADIOTHERAPY AND POSTIRRADIATION TEMOZOLOMIDE

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Regimen for Newly Diagnosed Primary Central Nervous System Lymphoma: Induction Chemotherapy with Rituximab, Methotrexate, and Temozolimide, Followed by Whole-Brain Radiotherapy and Postirradiation Temozolomide

Glass J et al. J Clin Oncol 2016;34:1620–1625

The regimen consists of a single dose of intravenous rituximab 375 mg/m² followed 3 days later by initiation of high-dose methotrexate 3.5 g/m² given every 2 weeks for 5 doses (during weeks 1, 3, 5, 7, and 9) and two 5-day courses of temozolomide 100 mg/m²/day (during weeks 4 and 8). Twice-daily whole-brain radiation therapy is given for a total of 30 fractions (during weeks 11, 12, and 13), followed lastly by ten 5-day courses of single-agent temozolomide maintenance, initiated at 150 mg/m²/day with the first course and then escalated to 200 mg/m²/day for remaining courses, repeated every 4 weeks (during weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50)

Premedications for Rituximab:

Acetaminophen 650–1000 mg; administer orally 30–60 minutes before starting rituximab, plus

Diphenhydramine 25–50 mg; administer orally or intravenously 30–60 minutes before starting rituximab

Rituximab 375 mg/m²; administer intravenously in 0.9% sodium chloride (0.9% NS) or 5% dextrose injection (D5W) diluted to a concentration within the range 1–4 mg/mL once, 3 days prior to the first (week 1) dose of methotrexate (total dosage = 375 mg/m²)

Notes on rituximab administration:

Administer initially at a rate of 50 mg/h. If hypersensitivity or infusion reactions do not occur during the first 30 minutes, increase the rate by 50 mg/h every 30 minutes as tolerated to a maximum rate of 400 mg/h
Interrupt rituximab administration for fever, chills, edema, congestion of the head and neck mucosa, hypertension, and other serious adverse events. Resume rituximab administration after adverse events abate

Hydration before, during, and after each methotrexate administration:

Before each methotrexate administration:

5% D5W or 5% dextrose/0.45% sodium chloride injection (D5W/0.45% NS) with 50–100 mEq sodium bicarbonate injection/L; administer intravenously at 100–150 mL/h

Adjust infusion rate to achieve and maintain a urine output ≥100 mL/h for ≥4 hours before starting methotrexate
Adjust sodium bicarbonate content to produce a urine pH within the range ≥7.0 to ≤8.0 before starting methotrexate

During each methotrexate administration:

No additional hydration (see below)

After each methotrexate administration:

D5W or D5W/0.45% NS with 50–100 mEq sodium bicarbonate injection/L; administer intravenously at 100–150 mL/h until serum methotrexate concentration <0.1 μmol/L

Adjust infusion rate to maintain urine output ≥100 mL/h
Adjust sodium bicarbonate content to maintain urine pH ≥7.0 to ≤8.0

Methotrexate 3500 mg/m² in 500 mL D5W or 0.45% NS injection, with 50–100 mEq sodium bicarbonate per dose; administer intravenously over 4 hours, every 14 days for 5 doses during weeks 1, 3, 5, 7, and 9 (total dosage every 14 days = 3500 mg/m²)

Notes:
- Add sodium bicarbonate in amounts sufficient to produce a bicarbonate concentration equivalent to fluid used for the same volume of hydration fluid given over a 4-hour period
- No methotrexate dose reduction is necessary for patients with a creatinine clearance ≥50 mL/min
- Methotrexate should not be administered if creatinine clearance is <50 mL/min
- Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, sulfonamides, penicillins, probenecid, and proton pump inhibitors during methotrexate therapy
- Preservative-free formulations of methotrexate injection should be used for high-dose therapy

Leucovorin calcium 25 mg per dose; administer orally or intravenously in 25–250 mL 0.9% NS or D5W over 15–30 minutes every 6 hours, starting 24 hours after each methotrexate administration began, and continue until serum methotrexate concentration <0.1 μmol/L, repeated every 14 days for 5 courses during weeks 1, 3, 5, 7, and 9

When serum methotrexate concentrations are ≤0.1 μmol/L, discontinue intravenous hydration and intravenous leucovorin, then:

Give leucovorin calcium 25 mg; administer orally every 6 hours for 2 days (8 doses), and
Continue hydration orally with >1500 mL/m² (>50 fluid ounces/m²) for 3 days after intravenous hydration is discontinued

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Leucovorin Rescue Guidelines

Clinical Situation

Serum Methotrexate Concentration^✫

Leucovorin Dosage, Schedule, and Duration

Normal methotrexate elimination

• ≤10 μmol/L at 24 hours, or

• ≤1 μmol/L at 48 hours, or

• ≤0.1 μmol/L at 72 hours

• Give leucovorin calcium 25 mg intravenously every 6 hours until serum methotrexate concentrations are <0.1 μmol/L (<1 × 10⁻⁷ mol/L, or <100 nmol/L), then give leucovorin calcium 25 mg orally every 6 hours for 2 days (8 doses)

Delayed/late methotrexate elimination

• ≥10 μmol/L at 24 hours, or

• ≥1 μmol/L at 48 hours, or

• ≥0.1 μmol/L at 72 hours, or

• ≥0.05 μmol/L at 96 hours, or

• ≥100% increase in serum creatinine concentration at 24 hours after methotrexate administration

• Give leucovorin calcium 100 mg/m² intravenously every 3 hours

• When serum methotrexate concentration results are <0.1 μmol/L, the leucovorin dosage may be decreased to 10 mg/m² intravenously given every 3 hours until the serum methotrexate concentration is <0.05 μmol/L or undetectable

• Consider administration of glucarpidase (if methotrexate concentration is >1 μmol/L in the setting of acute kidney injury)

^✫After methotrexate administration is begun

Methotrexate concentration conversions: 1 μmol/L = 10⁻⁶ mol/L = 1000 nmol/L

Temozolomide 100 mg/m²/day; administer orally once daily for 5 consecutive days, on an empty stomach with water at bedtime, every 4 weeks for 2 cycles during weeks 4 and 8 (total dosage/4-week course = 500 mg/m²)

Note: Patients who vomit after taking temozolomide should be instructed to take their next dose at the next regularly scheduled time

Whole-brain radiation therapy twice daily at 1.2 Gy/fraction for 5 days/week for a total of 30 fractions during weeks 11, 12, and 13 (total dosage = 36 Gy)

Temozolomide; administer orally once daily for 5 consecutive days, on an empty stomach with water at bedtime, every 4 weeks, for 10 cycles during weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50, as follows:

Week 14: administer 150 mg/m²/day (total dosage/4-week course during week 14 = 750 mg/m²)
Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50: administer 200 mg/m²/day (total dosage/4-week course = 1000 mg/m²)
Note: Patients who vomit after taking temozolomide should be instructed to take their next dose at the next regularly scheduled time

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with methotrexate or temozolomide is MODERATE

Emetogenic potential on day with rituximab is MINIMIAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—not indicated
Antiviral— antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

This phase 1/2 trial (Radiation Therapy Oncology Group [RTOG] 0227) involved 53 patients with newly diagnosed primary central nervous system lymphoma (PCNSL). Of the enrolled patients, 12 took part in both the phase 1 and phase 2 portions of the trial and the remainder were enrolled in only the phase 2 portion. All patients received the following chemotherapy regimen: rituximab (375 mg/m²) 3 days before the first methotrexate dose, methotrexate (3.5 g/m²) in weeks 1, 3, 5, 7, and 9, and temozolomide in weeks 4 and 8 (the temozolomide dose in the phase 1 portion patients was initially 100 g/m², with dose escalations to 150 and 200 g/m²; in the phase 2 portion patients, temozolomide was administered at the maximum tolerated dose of 100 mg/m²). Each methotrexate dose was preceded by urine alkalinization with intravenous sodium bicarbonate and followed (after 24 hours) by intravenous administration of leucovorin (25 mg every 6 hours) until the patient’s methotrexate level (measured daily) was ≤ 0.1 µmol/L. In weeks 11–13, patients received twice-daily 1.2 Gy fractions of whole-brain radiotherapy (total of 36 Gy). In weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50, patients received temozolomide (200 mg/m² daily, although in week 14 a daily dose of 150 mg/m² was allowed) for 5 days.

Efficacy (N = 53)

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Efficacy (N = 53)

2-year overall survival

80.8%

Estimated median overall survival

7.5 years

2-year progression-free survival

63.6%

Estimated median progression-free survival

5.4 years

Note: Of the 53 patients initially treated, 45 completed the initial chemotherapy and 42 received the whole-brain radiotherapy. After completion of the initial chemotherapy, 35 patients were assessable for radiographic response. Median follow-up time for eligible living patients was 3.6 years

Therapy Monitoring

Prior to rituximab administration: Hepatitis B surface antigen, hepatitis B core antibody (total antibody, or IgG only)
Prior to the first dose of methotrexate: 24-hour urine collection for creatinine clearance, serum creatinine
Prior to each dose of methotrexate: CBC with differential, platelet count, BUN, serum creatinine, estimated creatinine clearance (Cockroft-Gault method), AST, ALT, total bilirubin, electrolytes, serum bicarbonate, urine output, urine pH, review medication list for potential drug-drug interactions, urine hCG (women of childbearing potential only)
Following each dose of methotrexate, until methotrexate concentration is <0.1 µmol/L:
- ✓Daily: methotrexate concentration (draw first sample 24 hours after start of methotrexate infusion and repeat every 24 hours), CBC with differential, platelet count, BUN, serum creatinine, AST, ALT, total bilirubin, weight, fluid balance
- ✓At least every 8 hours during methotrexate administration: Urine pH
Prior to each course of temozolomide: CBC with differential, platelet count, AST, ALT, total bilirubin, urine hCG (women of childbearing potential only)
During first cycle and in any cycle after a dose adjustment, weekly CBC with differential and platelet count to assess dose
Response assessment: At the completion of initial rituximab, methotrexate, temozolomide chemotherapy, after completion of radiation therapy, every 2 months during postradiation temozolomide, at completion of temozolomide, every 3 months from the end of treatment until 2 years since the start of treatment, every 6 months for 3 to 5 years

Treatment Modifications

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Treatment Modifications

PRERADIATION [Methotrexate, Rituximab, and Temozolomide]

Methotrexate, Rituximab, and Temozolomide—Hematologic Toxicity

ANC <1000/mm³ or platelet count <70,000/mm³ on weeks 4/8 at start of temozolomide but persisting for <2 weeks

Withhold temozolomide until ANC ≥1000/mm³ and platelet count ≥70,000/mm³. Chemotherapy can then be administered at full dose

ANC <1000/mm³ or platelet count <70,000/mm³ on weeks 4/8 at start of temozolomide but persisting for ≥2 weeks

Withhold treatment until ANC ≥1000/mm³and platelet count >70,000/mm³. Temozolomide can then be administered but at 25% reduced dose. The dose of methotrexate is not reduced for hematologic toxicity

Recurrence of ANC <1000/mm³ or platelet count <70,000/mm³ on weeks 4/8 at start of temozolomide persisting for ≥2 weeks despite a previous dose reduction

Discontinue temozolomide

ANC <1000/mm³ or platelet count <70,000/mm³ at time of methotrexate administration on weeks 1, 3, 5, 7 and 9

Delay administration of methotrexate until ANC ≥1000/mm³and platelet count >70,000/mm³. The dose of methotrexate is not reduced for hematologic toxicity

ANC <1000/mm³ at any time during treatment

Administer filgrastim if deemed to be of value

Methotrexate, Rituximab, and Temozolomide—Nonhematologic Toxicity

Serum bilirubin >1.2 mg/dL at time of methotrexate administration on weeks 1, 3, 5, 7, and 9

Delay administration of methotrexate until recovery

ALT >450 U/L at time of methotrexate administration on weeks 1, 3, 5, 7, and 9

Mucositis with as yet no evidence of healing at time of methotrexate administration on weeks 1, 3, 5, 7, and 9

≥G2 nephrotoxicity from methotrexate (serum creatinine >1.5× baseline value, or >1.5× laboratory ULN)

Obtain 24-hour urine collection for CrCl prior to the next dose of methotrexate. The CrCl must be >50 mL/min per 1.73 m² to receive additional methotrexate

Methotrexate, Rituximab, and Temozolomide— Rituximab Infusion-Related Toxicity

Onset of infusion-related events (fevers, chills, rigors, edema, congestion of the head and neck mucosa, hypotension) during rituximab infusion

1. Interrupt rituximab infusion

2. For fever, chills: Give additional dose of acetaminophen 650 mg orally and diphenhydramine 25–50 mg by intravenous push

3. For rigors: Give meperidine 12.5–25 mg by intravenous push ± promethazine 12.5–25 mg by intravenous infusion in at least 10 mL 0.9% NS or D5W over 5–15 minutes. If after 15–20 minutes the response to a single dose is considered inadequate, the dose may be repeated

4. After symptoms resolve, resume rituximab infusion at a minimum of 50% reduction in the rate at which the event occurred. If no further infusion-related events, increase the rate by 50 mg/h every 30 minutes, as tolerated, up to a maximum rate of 400 mg/h

Dyspnea or wheezing, without allergic findings (urticaria, or tongue or laryngeal edema) during rituximab infusion

1. Interrupt rituximab infusion immediately

2. Give hydrocortisone 100 mg by intravenous push (or glucocorticoid equivalent)

3. Give an additional dose of diphenhydramine 25–50 mg by intravenous push and an H₂-antagonist (ranitidine 50 mg or famotidine 20 mg) by intravenous push

Note: Medications and equipment for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction during rituximab administration (eg, intravenous fluids, epinephrine, antihistamines, glucocorticoids, and oxygen)

POSTRADIATION CHEMOTHERAPY [Temozolomide daily for 5 days every 28 days on weeks 14– 50]

Temozolomide— Hematologic Toxicity

ANC <1000/mm³ or platelet count <70,000/mm³ on day of start of a course of temozolomide but persisting for <2 weeks

Withhold treatment until the ANC ≥1000/mm³ and platelet count >70,000/mm³. Temozolomide can then be administered at full dose

ANC <1000/mm³ or platelet count <70,000/mm³ on day of start of a course of temozolomide but persisting for ≥2 weeks

Withhold treatment until the ANC ≥1000/mm³and platelet count >70,000/mm³. Temozolomide can then be administered but at 25% reduced dose

Recurrence of ANC <1000/mm³ or platelet count <70,000/mm³ on day of start of a course of temozolomide persisting for ≥2 weeks despite a previous dose reduction

Discontinue chemotherapy

ANC <1000/mm³ at any time during treatment

Administer filgrastim if deemed to be of value

Temozolomide— Nonhematologic Toxicity

Continue treatment and maintain dose in subsequent cycle

G2 (1st occurrence)

Interrupt until resolved to ≤G1; administer 100% of original dose in subsequent cycle

G2 (2nd occurrence)

Interrupt until resolved to ≤G1; administer 75–80% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G2 (3rd occurrence)

Interrupt until resolved to ≤G1; administer 50% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G2 (4th occurrence)

Discontinue treatment permanently

G3 (1st occurrence)

Interrupt until resolved to ≤G1; administer 75–80% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G3 (2nd occurrence)

Interrupt until resolved to ≤G1; administer 50% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G3 (3rd occurrence)

Discontinue treatment permanently

G4 (1st occurrence)

Discontinue permanently or if physician deems it to be in the patient’s best interest to continue, interrupt until resolved to ≤G1, then resume therapy with doses ≤50% of that at the time G4 toxicity occurred. Note: Once the dose has been reduced, it should not be increased at a later time

Adverse Events (N = 53)

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Adverse Events (N = 53)

Chemotherapy-Related Toxicities (prior to start of whole-brain radiotherapy; N = 53)

Toxicities Related to Chemotherapy and Acute Radiotherapy (after start of whole-brain radiotherapy; N = 42)

Grade (%)^✫

Grade 3

Grade 4

Grade 3

Grade 4

Hematologic

Metabolic

Hepatic

Neurologic

Constitutional

Gastrointestinal

Pain

Renal/genitourinary

Cardiovascular

Ocular

Auditory/hearing

Coagulation

Dermatologic

Febrile neutropenia

Musculoskeletal

^✫According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 2.0

Note: Grade 3 and 4 toxicities defined as being definitely, probably, or possibly related to phase 2 treatment are included. Hematologic toxicities that occurred during radiotherapy were attributed to prior chemotherapy

REGIMEN FOR RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: HIGH-DOSE CYTARABINE

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Regimen for Recurrent Primary Central Nervous System Lymphoma: High-Dose Cytarabine

Chamberlain MC. J Neurooncol 2016;126:545–550

Cytarabine 3000 mg/m² per dose; administer intravenously in 100–1000 mL 0.9% sodium chloride injection or 5% dextrose injection over 3 hours, every 12 hours for 4 doses (2 doses/day) on days 1 and 2, every 28 days, until disease progression (total dosage/cycle = 12,000 mg/m²)

Note:
- Patients with renal dysfunction and/or elderly patients are at increased risk of high-dose cytarabine-induced cerebellar toxicity; consider initiating treatment at a reduced dose. Dose reduction recommendations vary; one commonly cited reference (Kintzel PE, Dorr RT. Cancer Treat Rev 1995;21:33–64) suggests:
  - Creatinine clearance 46–60 mL/min: Reduce dose to 1800 mg/m² per dose
  - Creatinine clearance 31–45 mL/min: Reduce dose to 1500 mg/m² per dose
  - Creatinine clearance <30 mL/min: Consider use of alternative drug

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg/day, by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL, by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed
Continue daily filgrastim use until ANC ≥5000/mm³ after the leukocyte nadir
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment. Do not administer pegfilgrastim within 14 days before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis during periods of neutropenia
Antifungal—fluconazole is recommended during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Keratitis prophylaxis

Steroid ophthalmic drops (prednisolone 1% or dexamethasone 0.1%); administer 2 drops by intraocular instillation into each eye every 6 hours starting prior to the first cytarabine dose and continuing until 48 hours after high-dose cytarabine is completed

Patient Population Studied

A retrospective review was performed for 14 patients with recurrent primary central nervous system lymphoma (PCNSL) after having failed first-line treatment (high-dose methotrexate plus rituximab) and second-line therapy (first salvage; temozolomide in 5 patients, high-dose methotrexate plus rituximab in 5 patients, and procarbazine plus lomustine plus vincristine in 4 patients). All patients received high-dose cytarabine (3 g/m² over a 3 hour infusion) every 12 hours for 4 treatments and then, 12 hours after the final dose of cytarabine, pegfilgrastim (6 mg).

Efficacy (N = 14)

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Efficacy (N = 14)

Median progression-free survival

3 months

6-month progression-free survival

Median overall survival

12 months

Therapy Monitoring

CBC with differential and platelet counts and comprehensive metabolic panel daily during chemotherapy
Outpatient monitoring post-chemotherapy: CBC with differential, platelets, and comprehensive metabolic panel, 2–3 times weekly until counts recover
Monitor for signs of cerebellar toxicity (nystagmus, dysmetria, and ataxia) before each dose of cytarabine
Patients who receive high-dose cytarabine need to be closely monitored for changes in renal function. Renal dysfunction is highly correlated with an increased risk of cerebellar toxicity
Response assessment: Contrast-enhanced MRI of the brain prior to each cycle of chemotherapy

Treatment Modifications

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Treatment Modifications

HIGH-DOSE CYTARABINE

Adverse Event

Treatment Modification

Fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise, 6–12 hours following drug administration (cytarabine or Ara-C syndrome).

Corticosteroids are beneficial in treating or preventing this syndrome. If the symptoms are deemed treatable, continue therapy with cytarabine and pretreat with corticosteroids

Neurologic (cerebellar) toxicity

Hold cytarabine. Patients who develop CNS symptoms should not receive subsequent high-dose cytarabine.

ANC <1000/mm³ or platelet count <50,000/mm³

Consider suspending or modifying doses/schedule.

Note: ANC and platelet count may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12–24 days. When definite signs of marrow recovery appear, restart therapy

Adverse Events (N = 14)

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Adverse Events (N = 14)

Grade (%)^✫

Grade 1/2

Grade 3

Grade 4

Neutropenia

Anemia

Lymphopenia

Mucositis

Thrombocytopenia

Fatigue

Neutropenic fever

Conjunctivitis

Nausea

Infection without neutropenia

Encephalopathy

^✫According to the National Cancer Institute Common Terminology Criteria for Adverse Events

Note: No treatment-related deaths were recorded and no patient discontinued therapy because of toxicity.

REGIMEN FOR RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: TOPOTECAN

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Regimen for Recurrent Primary Central Nervous System Lymphoma: Topotecan

Voloschin AD et al. J Neurooncol 2008;86:211–215

Topotecan HCl 1.5 mg/m²/day; administer intravenously in 50–250 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 30 minutes, for 5 consecutive days, on days 1 through 5, every 21 days (total dosage/cycle = 7.5 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1–5 is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with 1 of the following:

Filgrastim (G-CSF) 5 mcg/kg/day, by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL, by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed
Continue daily filgrastim use until ANC ≥5000/mm³ after the leukocyte nadir
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment. Do not administer pegfilgrastim within 14 days before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone during periods of neutropenia, or no prophylaxis
Antifungal—consider fluconazole during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

This prospective phase 2 study involved 15 patients with refractory or relapsed primary central nervous system lymphoma (PCNSL). Eligible patients were aged ≥18 years and had a Karnofsky performance status score ≥50. Patients on concurrent treatment with whole-brain irradiation or other intravenous chemotherapies were ineligible. All patients received intravenous topotecan (1.5 mg/m² over a 30-minute infusion) on days 1–5 of each 21-day cycle for up to 10 cycles. Ondansetron was used as prechemotherapy antiemetic therapy.

Efficacy (N = 15)

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Efficacy (N = 15)

Median overall survival

981 days

Median progression-free survival

60 days

Response rate^✫

40%

^✫Response rate includes complete response (in 20%) and partial response (in 20%)

Therapy Monitoring

Before day 1chemotherapy: CBC with differential, platelet count, LFTs, serum BUN, creatinine, electrolytes, urine hCG (women of childbearing potential only)
Weekly: CBC with differential, platelet count
Day 15: LFTs, serum BUN, and creatinine
Response evaluation: Contrast-enhanced MRI of the brain every 2–3 cycles

Treatment Modifications

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Treatment Modifications

Topotecan

Topotecan starting dose

1.5 mg/m² days 1–5, every 21 days

Topotecan dose level −1

1.25 mg/m² days 1–5, every 21 days

Topotecan dose level −2

1 mg/m² days 1–5, every 21 days

Adverse Event

Treatment Modifications

Day of treatment ANC ≤1000/mm³ or platelets ≤100,000/mm³, or serum creatinine >1.5 mg/dL

Delay topotecan treatment by 1 week until ANC >1000/mm³, platelets >100,000/mm³, and serum creatinine ≤1.5 mg/dL. Consider dose reduction as outlined below in this table, if applicable

Febrile neutropenia (ANC <1000/mm³ with temperature >38°C or >100.4°F), or ANC <1000/mm³ for ≥7 days despite 1 dose reduction; or ANC <500/mm³ at any time

Reduce topotecan dose by 1 level and consider adding filgrastim in subsequent cycles, if applicable and not already used as primary prophylaxis

Platelet nadir <50,000/mm³, or platelets <100,000/mm³for ≥7 days

Reduce topotecan dose by 1 level

G2/3 mucositis or diarrhea

Reduce topotecan dosage by 1 level

G4 mucositis or diarrhea

Reduce topotecan dosage by 1 level or consider discontinuing topotecan

Recurrent mucositis or diarrhea despite dosage reduction or persistence of mucositis/diarrhea >2 weeks beyond scheduled start of next cycle

Discontinue topotecan

Delay of treatment for any toxicity >2 weeks

Other G3/4 nonhematologic toxicity, excluding G3 nausea

Delay topotecan until resolution to ≤G1, then reduce dose by 1 level

Topotecan dose adjustments for renal impairment:
- Creatinine clearance 20–39 mL/min: Reduce to 0.75 mg/m²/dose
- Creatinine clearance <20 mL/min: Insufficient data exist to guide dose reduction
Dose adjustment unlikely to be necessary in patients with hepatic impairment
Patients who are pregnant or who becomes pregnant should be apprised of the potential hazard to the fetus

Adverse Events (N = 15)

No deaths were directly related to treatment toxicity. Five patients discontinued therapy owing to toxicity. G3 and G4 neutropenia were experienced by 40% and 33% of patients, respectively. G3 thrombocytopenia was experienced by 20% of patients; no patients experienced G4 thrombocytopenia. At some point during the treatment, 87% of patients received G-CSF.

REGIMEN FOR RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: PEMETREXED

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Regimen for Recurrent Primary Central Nervous System Lymphoma: Pemetrexed

Raizer JJ et al. Cancer 2012;118:3743–3748

Folic acid 350–1000 mcg daily; administer orally, beginning 1–3 weeks before chemotherapy and continuing throughout treatment with pemetrexed and for 21 days after the last pemetrexed dose, and

Cyanocobalamin (vitamin B₁₂) 1000 mcg; administer intramuscularly every 9 weeks, beginning 1–3 weeks before chemotherapy and continuing throughout treatment with pemetrexed, and

Dexamethasone 4 mg; administer intravenously or orally twice daily for 3 consecutive days, starting the day before each pemetrexed administration to decrease the risk of severe skin rash associated with pemetrexed

Pemetrexed 900 mg/m²; administer intravenously in 100 mL 0.9% sodium chloride injection (0.9% NS) over 10 minutes for 2 doses on day 1 and day 22, repeated every 42 days until disease progression (total dosage/6-week cycle = 1800 mg/m²)

Note: Patients continued pemetrexed until disease progression. If a complete response (CR) was achieved, pemetrexed was discontinued after administration of 1 additional cycle (ie, 2 doses) post-documentation of CR.

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is INTERMEDIATE

Antimicrobial primary prophylaxis to be considered:

Antibacterial—consider a fluoroquinolone during periods of neutropenia, or no prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—consider fluconazole during periods of neutropenia
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Steroid-associated gastritis

Add a proton pump inhibitor or H₂-receptor antagonist during dexamethasone use to prevent gastritis and duodenitis

Patient Population Studied

This study involved 11 patients with refractory or relapsed primary central nervous system lymphoma (PCNSL). Eligible patients were aged >18 years, had a Karnofsky performance status score ≥60, and had to have undertaken at least 1 prior failed chemotherapy regimen. All patients received intravenous pemetrexed (900 mg/m² over a 10-minute infusion) every 3 weeks. From 5 days before the first dose of pemetrexed through to 21 days after the last dose, all patients took folic acid (1 mg daily) and vitamin B₁₂ (1 mg intramuscular injection every 9 weeks) to reduce pemetrexed-related toxicities. Similarly, patients not already taking dexamethasone received oral dexamethasone (4 mg) twice daily on the day before, the day of, and the day after each pemetrexed dose.

Efficacy (N = 11)

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Efficacy (N = 11)

Median progression-free survival

5.7 months

Progression-free survival at 6 months

45%

Progression-free survival at 12 months

27%

Median overall survival

10.1 months

Overall survival at 12 months

45%

Overall response rate^✫

55%

Disease control rate^†

91%

^✫Overall response rate includes patients with either a complete or partial response to treatment. A complete response was observed in 36% of patients

^†Disease control rate includes patients with a complete or partial response to treatment or stable disease

Note: Median follow-up was 10.1 months

Therapy Monitoring

Prior to each dose of pemetrexed: CBC with differential, platelet count, liver function tests, BUN/serum creatinine, electrolytes,
Weekly during treatment: CBC with differential, platelet count
Response assessment: Clinical examination prior to each dose of pemetrexed, contrast-enhanced MRI of brain at baseline and then repeated approximately every 6–9 weeks

Treatment Modifications

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Treatment Modifications

PEMETREXED

Adverse Event

Treatment Modification

Delay cycle until ANC is >1500/mm³ and platelet count >100,000/mm³

ANC nadir <500/mm³ + platelet nadir ≥50,000/mm³

Delay therapy up to 21 days until ANC >1500/mm³ and platelet count >100,000/mm³, then reduce pemetrexed dose by 25% for subsequent cycles

Platelet nadir <50,000/mm³ without bleeding + any ANC nadir

Platelet nadir <50,000/mm³ with bleeding + any ANC nadir

Delay therapy up to 21 days until ANC>1500/mm³ and platelet count >100,000/mm³, then reduce dose by 50% for subsequent cycles

G3 toxicity other than mucositis or elevated transaminases

Delay start of pemetrexed for up to 21 days until ≤G1 or returns to baseline, then reduce dose by 25% for subsequent cycles

G4 toxicity other than mucositis

Any grade diarrhea requiring hospitalization or ≥G3 diarrhea

≥G3 mucositis

Delay start of pemetrexed for up to 21 days until ≤G1 or returns to baseline, then reduce dose by 50% for subsequent cycles

ALT and AST >1.5× ULN in a patient without liver metastasis

Withhold pemetrexed until ALT and AST ≤1.5× ULN

ALT and AST >2.5× ULN in a patient with liver metastasis with alkaline phosphatase >2.5× ULN

Withhold pemetrexed until ALT and AST ≤2.5× ULN and alkaline phosphatase ≤2.5× ULN

Severe hypersensitivity reaction to pemetrexed

Permanently discontinue pemetrexed

Third occurrence of an adverse event requiring a dose reduction

≥G3 neurotoxicity

Creatinine clearance <45 mL/min

Delay pemetrexed until creatinine clearance is ≥45 mL/min

Delays of ≤42 days are permitted for recovery from pemetrexed-related toxicities

Adverse Events (N = 11)

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Adverse Events (N = 11)

Grade (%)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Thrombocytopenia

Leukopenia

Infection

Anemia

Fatigue

Increased ALT or AST

Stomatitis

Cellulitis

Neuropathy

Skin rash

Weight loss

Diarrhea

Fever

Lymphocytosis

Nausea

Notes: Four patients discontinued treatment because of toxicities: 2 owing to pneumonia, 1 owing to cellulitis, and 1 owing to clinical decline in the setting of grade 2 thrombocytopenia. One patient died of unknown cause

REGIMEN FOR RECURRENT GLIOBLASTOMA: LOMUSTINE AND BEVACIZUMAB

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Regimen for Recurrent Glioblastoma: Lomustine and Bevacizumab

Taal W et al. Lancet Oncol 2014;15:943–953

Wick W et al. N Engl J Med 2017;377:1954–1963

Protocol for: Wick W et al. N Engl J Med 2017;377:1954–1963 (https://www.nejm.org/doi/suppl/10.1056/NEJMoa1707358/suppl_file/nejmoa1707358_protocol.pdf)

Bevacizumab 10 mg/kg; administer intravenously in 100 mL 0.9% sodium chloride injection (0.9% NS) on days 1, 15, and 29, every 6 weeks until disease progression (total dosage/6-week cycle = 30 mg/kg), plus:

Note:

Bevacizumab administration duration for the initial dose is 90 minutes. If administration is well tolerated, the administration duration may be decreased stepwise during subsequent administrations to 60 minutes and, finally, to a minimum duration of 30 minutes

Lomustine 90 mg/m²(maximum dose = 160 mg); administer orally as a single dose, without food, on day 1, every 6 weeks, until disease progression (total dosage/6-week cycle = 90 mg/m²; maximum dosage/6-week cycle = 160 mg)

Notes:

In the absence of ≥grade 2 hematologic toxicity, may increase the lomustine dose to 110 mg/m² starting with cycle 2, thus:
- Lomustine 110 mg/m² (maximum dose = 200 mg); administer orally as a single dose, without food, on day 1, every 6 weeks, until disease progression (total dosage/6-week cycle = 110 mg/m²; maximum dosage/6-week cycle = 200 mg)
To reduce the likelihood of a medication error leading to severe myelosuppression, prescribe, dispense, and administer only enough capsules to supply 1 dose of lomustine. Educate patients that only 1 dose of lomustine is to be taken every 6 weeks and only after documentation of adequate hematologic recovery. (ISMP 2014; https://www.ismp.org/resources/oral-chemotherapy-we-simply-must-do-better. Accessed June 20, 2018)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is MODERATE–HIGH

Emetogenic potential on days 15 and 29 is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A multicenter, randomized, phase 3 trial (European Organisation for Research and Treatment of Cancer [EORTC] 26101) involved 437 patients with progressive glioblastoma after standard chemoradiation. Patients were randomly assigned in a 2:1 ratio to lomustine plus bevacizumab or lomustine alone. Patients in the combination therapy group received lomustine (90 mg/m² with maximal dose of 160 mg, but increased to 110 mg/m² with maximal dose of 200 mg if no grade >1 hematologic toxic effects were noted in the first cycle) every 6 weeks plus bevacizumab (10 mg/kg) every 2 weeks. Patients in the monotherapy group received lomustine (110 mg/m²; maximal dose of 200 mg) every 6 weeks.

Efficacy (N = 437)

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Efficacy (N = 437)

Lomustine plus Bevacizumab (N = 288)

Lomustine Alone (N = 149)

Median overall survival

9.1 months

8.6 months

HR 0.95, 95% CI 0.74–1.21; P = 0.65

Median progression-free survival

4.2 months

1.5 months

HR 0.49, 95% CI 0.39–0.61; P <0.001

Objective response rate

41.5%

13.9%

Therapy Monitoring

Prior to each dose of lomustine: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes
Baseline pulmonary function studies with frequent PFTs during treatment
Prior to each dose of bevacizumab: Vital signs, urine dipstick for protein (perform 24-hour urine collection if ≥2+ protein)
Weekly: CBC with differential, platelet count (monitor blood counts weekly for 6 weeks after a dose). Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1–2 weeks. Leukopenia occurs at 5–6 weeks after a dose and persists for 1–2 weeks
Response assessment: Contrast-enhanced MRI of the brain every 6 weeks for 6 months, then every 12 weeks thereafter

Treatment Modification

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Treatment Modification

BEVACIZUMAB DOSE MODIFICATIONS

Adverse Event

Treatment Modification

Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ

Discontinue bevacizumab permanently

Serious bleeding

Wound dehiscence requiring medical intervention

Nephrotic syndrome

Hypertensive crisis or hypertensive encephalopathy or reversible posterior leukoencephalopathy syndrome (RPLS)

Congestive heart failure

Necrotizing fasciitis

Severe arterial or venous thromboembolic events

Discontinue bevacizumab permanently; the safety of reinitiating bevacizumab after a thromboembolic event is resolved is not known

Moderate to severe proteinuria

Patients with a ≥2+ urine dipstick reading should undergo further assessment, eg, a 24-hour urine collection. Suspend bevacizumab administration for ≥2 g of proteinuria/24 h and resume when proteinuria is <2 g/24 h

Severe hypertension not controlled with medical management

Hold bevacizumab pending further evaluation and treatment of hypertension

Mild, clinically insignificant infusion reaction

Decrease the rate of infusion

Clinically significant but not severe infusion reaction

Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution. If decision is made to restart, the infusion may be continued at ≤50% of the rate prior to the reaction and increased in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle

Severe infusion reaction—hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, G3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis)

Stop infusion and administer appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen). Discontinue bevacizumab

Planned elective surgery

Suspended bevacizumab at least 28 days before elective surgery and do not resume for at least 28 days after surgery or until surgical incision is fully healed

Recent hemoptysis

Do not administer bevacizumab

Evidence of rectosigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

LOMUSTINE DOSE MODIFICATIONS

Lomustine dose levels

Dose level +1

110 mg/m² as a single dose; maximum 200 mg

Starting dose

90 mg/m² as a single dose; maximum 160 mg

Dose level -1

75 mg/m²as a single dose; maximum 130 mg

No >G1 neutropenia and no >G1 thrombocytopenia during cycle 1

Increase lomustine to dose level +1 beginning with cycle 2

Day 1 WBC <4000/mm³ or platelets <100,000/mm³

Delay therapy until WBC ≥4000/mm³ and platelets ≥100,000/mm³

WBC nadir during the prior cycle <2000/mm³, or ANC nadir during the prior cycle <1000/mm³, or platelet nadir during the prior cycle <50,000/mm³

Delay therapy until WBC ≥4000/mm³ and platelets ≥100,000/mm³if necessary, then reduce lomustine to dose level -1 in subsequent cycle(s)

≥G3 liver toxicity (AST/ALT >5× ULN) and/or ≥G2 bilirubin (>1.5–3× ULN)

Delay therapy until resolution to ≤G1 (AST/ALT ≤3× ULN; bilirubin ≤1.5× ULN), then reduce lomustine 1 dose level in subsequent cycle(s)

Any G4 nonhematologic toxicity

Discontinue lomustine

≥G2 nonhematologic toxicity that does not recover to ≤G1 within 2 weeks

Any ≥G2 nonhematologic toxicity that recurs at the next cycle to ≥G2

Any pulmonary symptoms, but with PFT showing DLco ≥ predicted value

Continue with same lomustine dose

Any pulmonary symptoms, but with PFT showing <60% of predicted value

Discontinue lomustine

Decreased oxygen saturation at rest (eg, pulse oximeter <88% or Pao₂ ≤55 mm Hg)

Shortness of breath at rest or shortness of breath that limits self-care or ADL

Severe cough limiting self-care or ADL

Cumulative lomustine dosage >1100 mg/m²

Discontinue lomustine due to concerns of developing pulmonary fibrosis

Creatinine clearance 10–50 mL/min

Reduce lomustine dose by 25%

Creatinine clearance <10 mL/min

Reduce lomustine dose by 50–75%

Notes:

• Usually no more than a total of 6–7 cycles (660–770 mg/m²) of lomustine is recommended. Patients receiving >1100 mg/m² cumulative lomustine dosage have a higher risk of developing pulmonary toxicity. Patients with a baseline FVC or DLco <70% are particularly at risk (GLEOSTINE™ [lomustine] capsules; June 2018 product label. NextSource Biotechnology, LLC, Miami, FL)

• Patients who are pregnant or who become pregnant should be apprised of the potential hazard to the fetus from therapy with lomustine

Adverse Events (N = 430)

Grade 3–5^✫ adverse events were recorded in 63.6% of patients assigned to lomustine plus bevacizumab and in 38.1% of patients assigned to lomustine alone. Grade 3–5 adverse events of special interest were pulmonary embolism (in 5% of the combination therapy group), arterial hypertension (in 24% of the combination therapy group and in <1% of the monotherapy group), and hematologic toxic effects (in 54% of the combination therapy group and in 50% of the monotherapy group). Deaths unrelated to the tumor were noted for 5 (2%) patients assigned to combination therapy (2 from myocardial infarctions, 1 from large-intestine perforation, 1 from sepsis, and 1 from intracranial hemorrhage) and 1 patient (<1%) assigned to monotherapy (as a result of lung infection). Treatment-related adverse events occurred in 85.2% and 53.1% of patients assigned to combination therapy and monotherapy, respectively, and treatment-related serious adverse events occurred in 38.5% and 9.5% of patients, respectively.

REGIMEN FOR NEWLY DIAGNOSED ANAPLASTIC OLIGODENDROGLIOMAS AND OLIGOASTROCYTOMAS: PROCARBAZINE, LOMUSTINE, AND VINCRISTINE PLUS RADIATION

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Regimen for Newly Diagnosed Anaplastic Oligodendrogliomas and Oligoastrocytomas: Procarbazine, Lomustine, And Vincristine Plus Radiation

Cairncross G et al. J Clin Oncol 2006;24:2707–2714

Cairncross G et al. J Clin Oncol 2013;31:337–343

Protocol for: Cairncross G et al. J Clin Oncol 2013;31:337–343

Lomustine (CCNU) 130 mg/m²; administer orally as a single dose, without food, on day 1, every 6 weeks, for 4 cycles (total dosage/6-week cycle = 130 mg/m²)

Note: To reduce the likelihood of a medication error leading to severe myelosuppression, prescribe, dispense, and administer only enough capsules to supply 1 dose of lomustine. Educate patients that only 1 dose of lomustine is to be taken every 6 weeks and only after documentation of adequate hematologic recovery. (ISMP 2014. https://www.ismp.org/resources/oral-chemotherapy-we-simply-must-do-better. Accessed June 20, 2018)

Procarbazine 75 mg/m²/day; administer orally once daily for 14 consecutive days on days 8–21, every 6 weeks, for 4 cycles (total dosage/6-week cycle = 1050 mg/m²)

Note: Because procarbazine is a weak monoamine oxidase inhibitor, one should restrict tyramine-containing foods in patients receiving procarbazine

Vincristine 1.4 mg/m² per dose; administer by intravenous infusion over 15 minutes in 50 mL 0.9% sodium chloride injection (0.9% NS) for 2 doses, on days 8 and 29, every 6 weeks, for 4 cycles (total dosage/6-week cycle = 2.8 mg/m²)

Notes:
- The dose of vincristine is not capped in this regimen (Cairncross et al 2006)
- The World Health Organization (WHO) World Alliance for Patient Safety recommends that vincristine preparations include a clear warning label that reads: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” To avoid inadvertent intrathecal injection, which is uniformly fatal, vincristine should never be dispensed in a syringe. Instead, vincristine should be prepared in a small-volume intravenous bag (ie, 50 mL minibag) diluted in a compatible solution. (WHO 2007. http://www.who.int/patientsafety/highlights/PS_alert_115_vincristine.pdf?id=3034. Accessed June 22, 2018)

Begin radiation therapy within 6 weeks of the last dose of chemotherapy:

Radiation therapy once daily at 1.8 Gy/fraction for 5 days/week for a total of 33 fractions (total dosage = 59.4 Gy)

Notes:

The first 28 fractions were delivered to the initial target volume
The last 5 fractions were delivered to the boost volume

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 and days 8–21 is MODERATE–HIGH

Emetogenic potential on day 29 is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

This multicenter, randomized, phase 3 trial (Radiation Therapy Oncology Group [RTOG] 9402) with long-term follow-up involved 291 patients with anaplastic oligodendroglioma or anaplastic oligoastrocytoma. Eligible patients were aged ≥18 years and had a Karnofsky performance status score ≥60. Patients randomly assigned to receive chemotherapy in addition to radiation received 4 cycles of the following regimen every 6 weeks before radiation: oral lomustine (130 mg/m²) on day 1, oral procarbazine (75 mg/m² daily) on days 8–21, and intravenous vincristine (1.4 mg/m²) on days 8 and 29. Radiation was administered within 6 weeks of the last chemotherapy dose in patients assigned to chemotherapy and within 1 week of randomization in all other patients. All patients received 33 fractions of 1.8 Gy radiation, with 1 fraction administered per day, 5 days per week.

Efficacy (N = 291)

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Efficacy (N = 291)

Procarbazine, Lomustine, and Vincristine Plus Radiation (N = 148)

Radiation Only

(N = 143)

Median overall survival

4.6 years

4.7 years

HR 0.79, 95% CI 0.60–1.04; P = 0.1

Median progression-free survival

HR 0.68, 95% CI 0.53–0.88; P = 0.003

Note: Median follow-up was 11.3 years. NR, not reported

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Efficacy (N = 291)

For patients with codeleted (1p/19q) tumors (N = 126):

Procarbazine, Lomustine, and Vincristine Plus Radiation (N = 59)

Radiation Only

(N = 67)

Median overall survival

14.7 years

7.3 years

HR 0.59, 95% CI 0.37–0.95; P = 0.03

Median progression-free survival

8.4 years

2.9 years

HR 0.47, 95% CI 0.30–0.72; P < 0.001

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Efficacy (N = 291)

For patients with noncodeleted tumors (N = 137):

Procarbazine, Lomustine, and Vincristine Plus Radiation (N = 76)

Radiation Only

(N = 61)

Median overall survival

2.6 years

2.7 years

HR 0.85, 95% CI 0.58–1.23; P = 0.39

Median progression-free survival

1.2 years

1.0 years

HR 0.81, 95% CI 0.56–1.16; P = 0.24

Therapy Monitoring

Prior to the start of each cycle: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes; consider baseline pulmonary function testing (PFTs) especially in a patient with any pulmonary symptoms
Weekly during PCV chemotherapy: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes. Repeat PFTs if symptoms of potential pulmonary compromise develop. Note, monitor blood counts weekly for 6 weeks after a dose: Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1–2 weeks, while leukopenia occurs at 5–6 weeks after a dose and persists for 1–2 weeks
Response assessment: Perform follow-up MRI or CT scans before each cycle and 4–6 weeks after RT; thereafter, perform scans at increasing intervals, and after 5 years, annually, or as needed

Treatment Modifications

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Treatment Modifications

PROCARBAZINE, LOMUSTINE, AND VINCRISTINE FOLLOWED BY RADIATION

Starting lomustine dose

130 mg/m² as a single dose

Starting procarbazine dose

75 mg/m²/day for 14 consecutive days

Starting vincristine dose

1.4 mg/m² per dose (no maximum dose) ×2 doses days 8 and 29

Adverse Event

Treatment Modifications

Day 1 ANC <1500/mm³ or platelets <100,000/mm³

Delay start of cycle until ANC ≥1500/mm³ and platelets ≥100,000/mm³. Note that day 8 and day 29 vincristine should not be delayed for hematologic toxicity

Nadir ANC ≥500/mm³ and platelet count ≥50,000/mm³

Continue with same dose

Nadir ANC <500/mm³ or platelet count <50,000/mm³

Delay therapy until ANC ≥1500/mm³ and platelets ≥100,000/mm³. Reduce lomustine and procarbazine dosages by 25–50%. Do not reduce vincristine dose

≥G2 nonhematologic toxicity that does not recover to ≤G1 within 2 weeks (>8 weeks between cycles)

Discontinue regimen

Any ≥G2 nonhematologic toxicity that recurs at the next cycle to ≥G2

≥G3 nausea or vomiting, persistent despite maximum antiemetic therapy

Reduce doses of lomustine and/or procarbazine by 25% for G3 or 50% for G4 for all subsequent doses

Other G3/4 nonhematologic toxicities

Delay attributable medication(s) until resolution to ≤G1, then reduce dose of attributable medication(s) by 25% for G3 or 50% for G4 toxicity in subsequent doses. For G4 toxicity, consider permanent discontinuation of therapy

Urticarial rash

Discontinue procarbazine unless attributable to another concomitant medication.

≥G2 liver toxicity (AST/ALT >3× ULN) and/or ≥G2 bilirubin (>1.5–3× ULN)

Delay therapy until resolution to ≤G1 (AST/ALT ≤3× ULN; bilirubin ≤1.5× ULN), then reduce lomustine, procarbazine, and vincristine by 25%

Patient concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily

Adjust vincristine dose

Total serum bilirubin >3 mg/dL: delay vincristine until total bilirubin ≤1.5 mg/dL

Reduce vincristine dose by 50% in all subsequent cycles

Severe abdominal pain or severe jaw pain

Reduce vincristine dose by 50% for all subsequent doses

≥G3 peripheral neuropathy or ≥G3 motor neuropathy

Discontinue vincristine

Painful paresthesia or peripheral weakness

Discontinue vincristine

SIADH

Reduce vincristine dose or discontinue vincristine

Constipation, abdominal cramps, paralytic ileus

Temporarily discontinue vincristine. Treat symptoms. Resume vincristine when normal bowel function restored. Administer a routine prophylactic regimen against constipation

Creatinine clearance 10–50 mL/min

Reduce lomustine dose by 25%

Creatinine clearance <10 mL/min

Reduce lomustine dose by 50–75%

Any pulmonary symptoms, but with PFT showing DLco ≥ the predicted value

Continue with same lomustine dose

Any pulmonary symptoms, but with PFT showing <60% of the predicted value

Discontinue lomustine

Decreased oxygen saturation at rest (eg, pulse oximeter <88% or Pao₂ ≤55 mm Hg)

Shortness of breath at rest or shortness of breath that limits self-care or ADLs

Severe cough-limiting self-care or ADLs

Cumulative lomustine dosage >1100 mg/m²

Discontinue lomustine due to concerns of developing pulmonary fibrosis

Note: Usually no more than a total of 4 cycles (520 mg/m²) of lomustine is recommended in this regimen. Patients receiving >1100 mg/m² cumulative lomustine dosage have a higher risk of developing pulmonary toxicity. Patients with a baseline FVC or DLco <70% are particularly at risk (GLEOSTINE™ [lomustine] capsules; June 2018 product label. NextSource Biotechnology, LLC, Miami, FL)

Adverse Events

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Adverse Events

Procarbazine, Lomustine, and Vincristine Plus Radiation

Radiation Only

Grade 3/4 Toxicities (%)^✫

During Chemotherapy (N = 146)

Within 90 days of Starting Radiation (N = 141)

Within 90 days of Starting Radiation (N = 131)

Any hematologic

Neutropenia

Thrombocytopenia

Any neurologic

Any gastrointestinal

Nausea or vomiting

Peripheral neuropathy

Other neurologic

Anemia

Pulmonary

Dermatologic

Hepatic

Autonomic neuropathy

Other gastrointestinal

Fever^†

Ototoxicity

Cognitive change

Affective disturbance

^✫According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 1

^†Fatal in one patient

Notes: Grade 3/4 toxicities reported in the short-term follow-up manuscript are shown. Serious late toxicities were uncommon. The long-term follow-up manuscript reported 2 early deaths that were attributed to chemotherapy-induced neutropenia.

REGIMEN FOR NEWLY DIAGNOSED ANAPLASTIC OLIGODENDROGLIOMAS AND OLIGOASTROCYTOMAS: RADIATION PLUS PROCARBAZINE, LOMUSTINE, AND VINCRISTINE

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Regimen for Newly Diagnosed Anaplastic Oligodendrogliomas and Oligoastrocytomas: Radiation Plus Procarbazine, Lomustine, and Vincristine

van den Bent MJ et al. J Clin Oncol 2006;24:2715–2722

van den Bent MJ et al J Clin Oncol 2013;31:344–350

van den Bent MJ et al. Neurology 1998;51:1140–1145

Radiation therapy once daily at 1.8 Gy/fraction for 5 days/week for a total of 33 fractions (total dosage = 59.4 Gy), followed by:

Notes:

The first 25 fractions were delivered to the initial target volume
The last 8 fractions were delivered to the boost volume

Begin chemotherapy within 4 weeks of the end of radiation therapy:

Lomustine (CCNU) 110 mg/m²; administer orally as a single dose, without food, on day 1, every 6 weeks, for 6 cycles (total dosage/6-week cycle = 110 mg/m²)

Note: To reduce the likelihood of a medication error leading to severe myelosuppression, prescribe, dispense, and administer only enough capsules to supply 1 dose of lomustine. Educate patients that only 1 dose of lomustine is to be taken every 6 weeks and only after documentation of adequate hematologic recovery. (ISMP 2014. https://www.ismp.org/resources/oral-chemotherapy-we-simply-must-do-better. Accessed June 20, 2018)

Procarbazine 60 mg/m² per day; administer orally once daily for 14 consecutive days on days 8–21, every 6 weeks, for 6 cycles (total dosage/6-week cycle = 840 mg/m²)

Note: Because procarbazine is a weak monoamine oxidase inhibitor, one should restrict tyramine-containing foods in patients receiving procarbazine

Vincristine 1.4 mg/m² per dose (maximum single dose = 2 mg); administer by intravenous infusion over 15 minutes in 50 mL 0.9% sodium chloride injection (0.9% NS) for 2 doses, on days 8 and 29, every 6 weeks, for 6 cycles (total dosage/6-week cycle = 2.8 mg/m², but not >4 mg/6-week cycle)

Note: The World Health Organization (WHO) World Alliance for Patient Safety recommends that vincristine preparations include a clear warning label that reads: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” To avoid inadvertent intrathecal injection, which is uniformly fatal, vincristine should never be dispensed in a syringe. Instead, vincristine should be prepared in a small-volume intravenous bag (ie, 50 mL minibag) diluted in a compatible solution. (WHO 2007. http://www.who.int/patientsafety/highlights/PS_alert_115_vincristine.pdf?id=3034. Accessed June 22, 2018)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 and days 8–21 is MODERATE–HIGH

Emetogenic potential on day 29 is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

This multicenter, randomized, phase 3 trial (European Organisation for Research and Treatment [EORTC] 26951) with long-term follow-up involved 368 patients with newly diagnosed anaplastic oligodendroglioma or mixed anaplastic oligoastrocytoma with ≥25% oligodendroglial content. Eligible patients were aged 16–70 years and had an Eastern Cooperative Oncology Group (ECOG) performance status score ≤2. Patients who had undergone prior chemotherapy or radiation therapy to the skull were not eligible. All patients received 33 fractions of 1.8 Gy radiation, with 1 fraction administered per day, 5 days per week. Within 4 weeks after the end of radiation therapy, patients randomly assigned to receive chemotherapy in addition to radiation received 6 cycles of the following regimen every 6 weeks: oral lomustine (110 mg/m²) on day 1, oral procarbazine (60 mg/m² daily) on days 8–21, and intravenous vincristine (1.4 mg/m²; maximal dose of 2 mg) on days 8 and 29.

Efficacy (N = 368)

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Efficacy (N = 368)

Radiation Plus Procarbazine, Lomustine, and Vincristine (N = 185)

Radiation Only

(N = 183)

Median overall survival

42.3 months

30.6 months

HR 0.75, 95% CI 0.60–0.95; P = 0.018

Median progression-free survival

24.3 months

13.2 months

HR 0.66, 95% CI 0.52–0.83; P = 0.0003

Note: Median follow-up was 140 months. NR, not reported.

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Efficacy (N = 368)

For patients with codeleted (1p/19q) tumors (N = 80):

Radiation Plus Procarbazine, Lomustine, and Vincristine (N = 43)

Radiation Only

(N = 37)

Median overall survival

Not reached

112 months

HR 0.56, 95% CI 0.31–1.03; P = 0.059

Median progression-free survival

157 months

50 months

HR 0.42, 95% CI 0.24–0.74; P = 0.002

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Efficacy (N = 368)

For patients with noncodeleted tumors (N = 236):

Radiation Plus Procarbazine, Lomustine, and Vincristine (N = 114)

Radiation Only

(N = 122)

Median overall survival

25 months

21 months

HR 0.83, 95% CI 0.62–1.10; P = 0.185

Median progression-free survival

15 months

9 months

HR 0.73, 95% CI 0.56–0.97; P = 0.026

Therapy Monitoring

Prior to the start of each cycle: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes; consider baseline pulmonary function testing (PFTs) especially in a patient with any pulmonary symptoms
Weekly during PCV chemotherapy: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes. Repeat PFTs if symptoms of potential pulmonary compromise develop. Note, monitor blood counts weekly for 6 weeks after a dose: Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1–2 weeks, while leukopenia occurs at 5–6 weeks after a dose and persists for 1–2 weeks
Response assessment: Contrast-enhanced MRI of the brain after completion of radiation therapy, prior to cycle 3, prior to cycle 5, 4 months after completion of PCV chemotherapy, then every 6 months for 2 years, then yearly

Treatment Modifications

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Treatment Modifications

RADIATION FOLLOWED BY PROCARBAZINE, LOMUSTINE, AND VINCRISTINE

Starting lomustine dose

110 mg/m² as a single dose

Starting procarbazine dose

60 mg/m²/day for 14 consecutive days

Starting vincristine dose

1.4 mg/m² per dose (maximum = 2 mg) ×2 doses days 8 and 29

Adverse Event

Treatment Modifications

Day 1 ANC <1500/mm³ or platelets <100,000/mm³

Delay start of cycle until ANC ≥1500/mm³ and platelets ≥100,000/mm³. Note that day 8 and day 29 vincristine should not be delayed for hematologic toxicity

Nadir ANC ≥500/mm³ and platelet count ≥50,000/mm³

Continue with same dose

Nadir ANC <500/mm³ or platelet count <50,000/mm³

Delay therapy until ANC ≥1500/mm³ and platelets ≥100,000/mm³. Reduce lomustine and procarbazine dosages by 25–50%. Do not reduce vincristine dose

≥G2 nonhematologic toxicity that does not recover to ≤G1 within 2 weeks (>8 weeks between cycles)

Discontinue regimen

Any ≥G2 nonhematologic toxicity that recurs at the next cycle to ≥G2

≥G3 nausea or vomiting, persistent despite maximum antiemetic therapy

Reduce doses of lomustine and/or procarbazine by 25% for G3 or 50% for G4 for all subsequent doses

Other G3/4 nonhematologic toxicities

Urticarial rash

Discontinue procarbazine unless attributable to another concomitant medication

≥G2 liver toxicity (AST/ALT >3× ULN) and/or ≥G2 bilirubin (>1.5–3× ULN)

Delay therapy until resolution to ≤G1 (AST/ALT ≤3× ULN; bilirubin ≤1.5× ULN), then reduce lomustine, procarbazine, and vincristine by 25%

Patient concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily

Adjust vincristine dose

Total serum bilirubin >3 mg/dL

Delay vincristine until total bilirubin ≤1.5 mg/dL

Reduce vincristine dose by 50% in all subsequent cycles

Severe abdominal pain or severe jaw pain

Reduce vincristine dose by 50% for all subsequent doses

≥G3 peripheral neuropathy or ≥G3 motor neuropathy

Discontinue vincristine

Painful paresthesia or peripheral weakness

Discontinue vincristine

SIADH

Reduce vincristine dose or discontinue vincristine

Constipation, abdominal cramps, paralytic ileus

Temporarily discontinue vincristine. Treat symptoms. Resume vincristine when normal bowel function restored. Administer a routine prophylactic regimen against constipation

Creatinine clearance 10–50 mL/min

Reduce lomustine dose by 25%

Creatinine clearance <10 mL/min

Reduce lomustine dose by 50–75%

Any pulmonary symptoms, but with PFT showing DLco ≥ the predicted value

Continue with same lomustine dose

Any pulmonary symptoms, but with PFT showing <60% of the predicted value

Discontinue lomustine

Decreased oxygen saturation at rest (eg, pulse oximeter <88% or Pao₂ ≤55 mm Hg)

Shortness of breath at rest or shortness of breath that limits self-care or ADLs

Severe cough-limiting self-care or ADLs

Cumulative lomustine dosage >1100 mg/m²

Discontinue lomustine due to concerns of developing pulmonary fibrosis

Notes:

• Usually no more than a total of 6 cycles (660 mg/m²) of lomustine is recommended in this regimen. Patients receiving >1100 mg/m² cumulative lomustine dosage have a higher risk of developing pulmonary toxicity. Patients with a baseline FVC or DLco <70% are particularly at risk (GLEOSTINE™ [lomustine] capsules; June 2018 product label. NextSource Biotechnology, LLC, Miami, FL)

• Patients who are pregnant or who become pregnant should be apprised of the potential hazard to the fetus from therapy with lomustine, procarbazine, and vincristine

Adverse Events (N = 161)

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Adverse Events (N = 161)

Grade (%)

Grade 3

Grade 4

Any hematologic

Neutrophils

White blood cell count

Platelets

Hemoglobin

Vomiting

Nausea

Polyneuropathy

Allergic skin reactions

Notes: Grade 3/4 toxicities reported for the patients who started chemotherapy in the short-term follow-up manuscript are shown. Chemotherapy was prematurely discontinued in 33% of patients owing to hematologic toxicity and in an additional 5% of patients as a result of nonhematologic toxicity

REGIMEN FOR NEWLY DIAGNOSED LOW-GRADE GLIOMAS: RADIATION PLUS PROCARBAZINE, LOMUSTINE, AND VINCRISTINE

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Regimen for Newly Diagnosed Low-Grade Gliomas: Radiation Plus Procarbazine, Lomustine, and Vincristine

Buckner JC et al. N Engl J Med 2016;374:1344–1355

Protocol for: Buckner JC et al. N Engl J Med 2016;374:1344–1355

Radiation therapy once daily at 1.8 Gy/fraction for 5 days/week for a total of 30 fractions (total dosage = 54 Gy), followed by:

Begin chemotherapy after completion of radiation therapy:

Lomustine (CCNU) 110 mg/m²; administer orally as a single dose, without food, on day 1, every 8 weeks, for 6 cycles (total dosage/8-week cycle = 110 mg/m²)

Note: To reduce the likelihood of a medication error leading to severe myelosuppression, prescribe, dispense, and administer only enough capsules to supply 1 dose of lomustine. Educate patients that only 1 dose of lomustine is to be taken every 8 weeks and only after documentation of adequate hematologic recovery. (ISMP 2014. https://www.ismp.org/resources/oral-chemotherapy-we-simply-must-do-better. Accessed June 20, 2018)

Procarbazine 60 mg/m²/ day; administer orally once daily for 14 consecutive days on days 8–21, every 8 weeks, for 6 cycles (total dosage/8-week cycle = 840 mg/m²)

Note: Because procarbazine is a weak monoamine oxidase inhibitor, one should restrict tyramine-containing foods in patients receiving procarbazine

Vincristine 1.4 mg/m² per dose (maximum single dose = 2 mg); administer by intravenous infusion over 15 minutes in 50 mL 0.9% sodium chloride injection (0.9% NS) for 2 doses, on days 8 and 29, every 8 weeks, for 6 cycles (total dosage/8-week cycle = 2.8 mg/m², but not >4 mg/6-week cycle)

Note: The World Health Organization (WHO) World Alliance for Patient Safety recommends that vincristine preparations include a clear warning label that reads: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” To avoid inadvertent intrathecal injection, which is uniformly fatal, vincristine should never be dispensed in a syringe. Instead, vincristine should be prepared in a small-volume intravenous bag (ie, 50 mL minibag) diluted in a compatible solution. (WHO 2007. http://www.who.int/patientsafety/highlights/PS_alert_115_vincristine.pdf?id=3034. Accessed June 22, 2018)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 and days 8–21 is MODERATE–HIGH

Emetogenic potential on day 29 is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

This multicenter, randomized, phase 3 trial (Radiation Therapy Oncology Group [RTOG] 9802) with long-term follow-up involved 251 patients with histologically confirmed grade 2 astrocytoma, oligodendroglioma, or oligoastrocytoma. Eligible patients had a Karnofsky performance status score ≥60, a neurologic function score ≤3, and had undergone a subtotal resection or biopsy if aged 18–39 years or a biopsy or resection of any of the tumor if aged ≥40 years. Patients who had previously received radiation therapy to the brain or head and neck region, or had received prior chemotherapy for any reason, were not eligible. All patients received 30 fractions of 1.8 Gy radiation (prescribed to the isocenter) over 6 weeks. Patients randomly assigned to also receive chemotherapy subsequently received 6 cycles of the following 8-week regimen: oral lomustine (110 mg/m² of body surface area) on day 1, oral procarbazine (60 mg/m² daily) on days 8–21, and intravenous vincristine (1.4 mg/m²; maximal dose of 2 mg) on days 8 and 29.

Efficacy (N = 251)

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Efficacy (N = 251)

Radiation Plus Procarbazine, Lomustine, and Vincristine (N = 125)

Radiation Only

(N = 126)

Median progression-free survival

10.4 years (95% CI 6.1–not reached)

4.0 years (95% CI 3.1–5.5)

HR 0.50; P <0.001

Median overall survival

13.3 years (95% CI 10.6–not reached)

7.8 years (95% CI 6.1–9.8)

HR 0.59; P = 0.003

Note: Median follow-up was 11.9 years

Therapy Monitoring

Prior to the start of each cycle: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes; consider baseline pulmonary function testing (PFTs) especially in a patients with any pulmonary symptoms
Weekly during PCV chemotherapy: CBC with differential, platelet count, LFTs, BUN, creatinine, electrolytes. Repeat PFTs if symptoms of potential pulmonary compromise develop. Note, monitor blood counts weekly for 6 weeks after a dose: Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1–2 weeks, while leukopenia occurs at 5–6 weeks after a dose and persists for 1–2 weeks
Response assessment: Contrast-enhanced MRI of the brain after completion of radiation therapy, prior to cycle 3, prior to cycle 5, 4 months after completion of PCV chemotherapy, then every 6 months for 2 years, then yearly

Treatment Modifications

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Treatment Modifications

RADIATION FOLLOWED BY PROCARBAZINE, LOMUSTINE, AND VINCRISTINE

Starting lomustine dose

110 mg/m² as a single dose

Starting procarbazine dose

60 mg/m²/day for 14 consecutive days

Starting vincristine dose

1.4 mg/m² per dose (maximum = 2 mg) ×2 doses days 8 and 29

Adverse Event

Treatment Modifications

Day 1 ANC <1500/mm³ or platelets <100,000/mm³

Delay start of cycle until ANC ≥1500/mm³ and platelets ≥100,000/mm³. Note that day 8 and day 29 vincristine should not be delayed for hematologic toxicity

Nadir ANC ≥500/mm³ and platelet count ≥50,000/mm³

Continue with same dose

Nadir ANC <500/mm³ or platelet count <50,000/mm³

Delay therapy until ANC ≥1500/mm³ and platelets ≥100,000/mm³. Reduce lomustine and procarbazine dosages by 25–50%. Do not reduce vincristine dose

≥G2 nonhematologic toxicity that does not recover to ≤G1 within 2 weeks (>8 weeks between cycles)

Discontinue regimen

Any ≥G2 nonhematologic toxicity that recurs at the next cycle to ≥G2

≥G3 nausea or vomiting, persistent despite maximum antiemetic therapy

Reduce doses of lomustine and/or procarbazine by 25% for G3 or 50% for G4 for all subsequent doses

Other G3/4 nonhematologic toxicities

Urticarial rash

Discontinue procarbazine unless attributable to another concomitant medication.

≥G2 liver toxicity (AST/ALT >3× ULN) and/or ≥G2 bilirubin (>1.5–3× ULN)

Delay therapy until resolution to ≤G1 (AST/ALT ≤3× ULN; bilirubin ≤1.5× ULN), then reduce lomustine, procarbazine, and vincristine by 25%

Patient concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily

Adjust vincristine dose

Total serum bilirubin >3 mg/dL: delay vincristine until total bilirubin ≤1.5 mg/dL

Reduce vincristine dose by 50% in all subsequent cycles

Severe abdominal pain or severe jaw pain

Reduce vincristine dose by 50% for all subsequent doses

≥G3 peripheral neuropathy or ≥G3 motor neuropathy

Discontinue vincristine

Painful paresthesia or peripheral weakness

Discontinue vincristine

SIADH

Reduce vincristine dose or discontinue vincristine

Constipation, abdominal cramps, paralytic ileus

Temporarily discontinue vincristine. Treat symptoms. Resume vincristine when normal bowel function restored. Administer a routine prophylactic regimen against constipation

Creatinine clearance 10–50 mL/min

Reduce lomustine dose by 25%

Creatinine clearance <10 mL/min

Reduce lomustine dose by 50–75%

Any pulmonary symptoms, but with PFT showing DLco ≥ the predicted value

Continue with same lomustine dose

Any pulmonary symptoms, but with PFT showing <60% of the predicted value

Discontinue lomustine

Decreased oxygen saturation at rest (eg, pulse oximeter <88% or Pao₂ ≤55 mm Hg)

Shortness of breath at rest or shortness of breath that limits self-care or ADLs

Severe cough limiting self-care or ADLs

Cumulative lomustine dosage >1100 mg/m²

Discontinue lomustine due to concerns of developing pulmonary fibrosis

Notes:

• Patients who are pregnant or who become pregnant should be apprised of the potential hazard to the fetus from therapy with lomustine, procarbazine, and vincristine

Chapter 5: Brain Cancer

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INTRODUCTION

Expert Opinion

REGIMEN: TEMOZOLOMIDE

REGIMEN: TEMOZOLOMIDE WITH RADIATION THERAPY

REGIMEN: CARMUSTINE (BCNU)

REGIMEN: LOMUSTINE (CCNU)

REGIMEN: CARBOPLATIN

REGIMEN: PROCARBAZINE, LOMUSTINE (CCNU), VINCRISTINE (PCV)

REGIMEN: ADJUVANT PROCARBAZINE, LOMUSTINE (CCNU), AND VINCRISTINE (PCV) NEWLY DIAGNOSED ANAPLASTIC OLIGODENDROGLIOMA

REGIMEN: HIGH-DOSE TAMOXIFEN

REGIMEN: ERLOTINIB (TARCEVA)

REGIMEN: BEVACIZUMAB (AVASTIN) ± IRINOTECAN

REGIMEN: HIGH-DOSE METHOTREXATE FOR PRIMARY CNS LYMPHOMA

CNS LYMPHOMA REGIMEN: RITUXIMAB, METHOTREXATE, PROCARBAZINE, AND VINCRISTINE FOLLOWED BY CONSOLIDATION, REDUCED-DOSE WHOLE-BRAIN RADIOTHERAPY, AND CYTARABINE (R-MPV → RT + C) NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA

REGIMEN: HIGH-DOSE METHOTREXATE AND RITUXIMAB WITH DEFERRED RADIOTHERAPY NEWLY DIAGNOSED PRIMARY B-CELL CNS LYMPHOMA

RECURRENT MENINGIOMA: LONG-ACTING OCTREOTIDE ACETATE

RECURRENT MENINGIOMA: INTERFERON ALFA

RECURRENT MENINGIOMA: HIGH-GRADE MENINGIOMA REFRACTORY TO RECURRENT SURGERY AND RADIATION HYDROXYUREA

REGIMEN FOR NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: INDUCTION CHEMOTHERAPY WITH RITUXIMAB, METHOTREXATE, AND TEMOZOLIMIDE, FOLLOWED BY WHOLE-BRAIN RADIOTHERAPY AND POSTIRRADIATION TEMOZOLOMIDE

REGIMEN FOR RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: HIGH-DOSE CYTARABINE

REGIMEN FOR RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: TOPOTECAN

REGIMEN FOR RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: PEMETREXED

REGIMEN FOR RECURRENT GLIOBLASTOMA: LOMUSTINE AND BEVACIZUMAB

REGIMEN FOR NEWLY DIAGNOSED ANAPLASTIC OLIGODENDROGLIOMAS AND OLIGOASTROCYTOMAS: PROCARBAZINE, LOMUSTINE, AND VINCRISTINE PLUS RADIATION

REGIMEN FOR NEWLY DIAGNOSED ANAPLASTIC OLIGODENDROGLIOMAS AND OLIGOASTROCYTOMAS: RADIATION PLUS PROCARBAZINE, LOMUSTINE, AND VINCRISTINE

REGIMEN FOR NEWLY DIAGNOSED LOW-GRADE GLIOMAS: RADIATION PLUS PROCARBAZINE, LOMUSTINE, AND VINCRISTINE