Chapter 25: Melanoma

Ahmad A. Tarhini; Amanda L. Gillespie-Twardy; John M. Kirkwood

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

76,100 (male: 43,890; female: 32,210. Estimated new cases for 2014 in the United States)

Stage at Presentation

Stage 0:

49.3%

21.1 per 100,000 male and female per year (27.4 per 100,000 male 16.7 per 100,000 female)

Stage I:

36.3%

Stage II:

7.3%

Deaths:

Estimated 9,710 in 2014 (male: 6,470; female: 3,240)

Stage III:

3.7%

Median age:

61 years

Stage IV:

3.4%

Male to female ratio:

1.5:1

Koh HK. N Engl J Med 1991;325:171–182

National Cancer Institute, Surveillance, Epidemiology and End Results (SEER) Program

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

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Work-up

Stage IB

Stage II

Chest x-ray (optional), LDH

Further imaging as clinically indicated for stage IIB, IIC patients (CT scan ± PET/MRI)

Stage IIIA

Chest x-ray, LDH. Further imaging if clinically indicated (CT scan ± PET, and/or MRI)

Stage IIIB

Stage IIIC

FNA preferred, if feasible, otherwise lymph node biopsy

Chest x-ray, LDH, pelvic CT and if inguinofemoral nodes positive Further imaging if clinically indicated (CT scan ± PET, or MRI)

Stage IV

FNA preferred, if feasible, otherwise lymph node biopsy

Chest x-ray and/or chest CT, LDH; consider abdomen/pelvic CT, head MRI and/or PET

Further imaging if clinically indicated

Notes:

1. Consider sentinel lymph node biopsy (SLNB) for stage IA with adverse features (positive deep margins, lymphovascular invasion, mitotic rate ≥1 mm²)

2. Encourage SLNB for stage IB and II

3. Discuss the impact of SLNB as an important staging tool and that the impact on survival is still unclear

Five-Year Relative Survival

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Five-Year Relative Survival

Stage I:

91–99%

Stage II:

56–77%

Stage III:

27–59%^✫

Stage IV:

18%

^✫Rates are not available for stage IIIA patients (with microscopic lymph node involvement) because patients have at most 4 years of follow-up

Gimotty PA et al. A population-based validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2005;23:8065–8075

NCI, Surveillance, Epidemiology and End Results (SEER) Program

Pathology

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Pathology

Melanoma types

1. Superficial spreading melanoma

60–70%

2. Nodular melanoma

15–30%

3. Lentigo maligna melanoma

4. Acral lentiginous melanoma

2–8%

Lotze MT, Dollard RM, Kirkwood JM, Flickinger JC. Cutaneous melanoma. In: DeVita VT et al.: Cancer: Principles & Practice of Oncology, 6th ed. Lippincott Williams & Wilkins, 2001

Staging

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Staging

Primary Tumor (T)

Classification

Thickness (mm)

Ulceration Status/Mitoses

Tis

≤1.00

a. Without ulceration and mitosis <1/mm²

b. With ulceration or mitoses ≥1/mm²

1.01–2.00

a. Without ulceration

b. With ulceration

2.01–4.00

a. Without ulceration

b. With ulceration

>4.00

a. Without ulceration

b. With ulceration

NA, Not applicable

Staging

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Staging

Distant Metastases (M)

Site

Serum LDH

No distant metastases

M1a

Distant skin, subcutaneous, or nodal metastases

Normal

M1b

Lung metastases

Normal

M1c

All other visceral metastases

Any distant metastasis

Normal

Elevated

LDH, Lactate dehydrogenase; NA, not applicable

Balch CM et al. J Clin Oncol 2009;27:6199–6206

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010

Staging

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Staging

Regional Lymph Nodes (N)

Number of Metastatic Nodes

Nodal Metastatic Burden

a. Micrometastasis^✫

b. Macrometastasis^†

2–3

a. Micrometastasis^✫

b. Macrometastasis^†

c. In transit metastases/satellites without metastatic nodes

≥4 metastatic nodes, or

Matted nodes, or

In transit metastases/satellites with metastatic nodes

NA, Not applicable

^✫Micrometastases are diagnosed after sentinel lymph node biopsy

^†Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically

Staging

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Staging

Anatomic Stage Grouping for Cutaneous Melanoma

Clinical Staging

Tis

T1a

T1b

T2a

IIA

T2b

T3a

IIB

T3b

T4a

IIC

T4b

III

Any T

N >N0

Any T

Any N

Note: Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases

Staging

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Staging

Anatomic Stage Grouping for Cutaneous Melanoma

Pathologic Staging

Tis

T1a

T1b

T2a

IIA

T2b

T3a

IIB

T3b

T4a

IIC

T4b

IIIA

T1–4a

N1a

T1–4a

N2a

IIIB

T1–4b

N1a

T1–4b

N2a

T1–4a

N1b

T1–4a

N2b

T1–4a

N2c

IIIC

T1–4b

N1b

T1–4b

N2b

T1–4b

N2c

Any T

Any N

Note: Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial (ie, sentinel node biopsy) or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes

Expert Opinion

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Tumor Thickness

Recommended Margins^✫

In situ

0.5 cm

≤1.0 mm

1.0 cm

1.01-2.0 mm

1-2 cm

2.01-4.0 mm

2.0 cm

>4.0 mm

2.0 cm

^✫The recommended surgical margin in the treatment of melanoma depends on the tumor thickness

Prognosis according to stage:
- Stage I: Excellent prognosis with surgical treatment alone and a cure rate of more than 85%
- Stages IIA and IIB: The 3–5-year postsurgical relapse rate in patients with stages IIA and IIB is 20–30% and 40–55%, respectively
- Stage III: Patients with regional lymph node involvement have a 5-year relapse rate of 60–80%
- Stage IV: Continues to be associated with a dismal prognosis with a median survival of 6–9 months
Diagnosis and initial surgical management:
- For patients with a suspicious pigmented lesion, an excisional biopsy is preferred
- When an excisional biopsy is thought inappropriate because of location (eg, face, ear, palm, sole, digit, subungual), a full-thickness incisional biopsy or a punch biopsy rather than a shave is acceptable
- Patients with initial presentation of melanoma T1–4 should be treated by wide excision of the primary. Definitive surgery should include wide excision of the primary and lymphadenectomy. For subungual melanoma, a distal interphalangeal amputation with histologically negative margins constitutes an adequate wide excision
- Consider sentinel lymph node biopsy (SLNB) for stage IA with adverse features (positive deep margins, lymphovascular invasion, mitotic rate ≥1/mm²). Encourage SLNB for stage IB and II. SLNB is an important staging tool, but its effect on survival is still unclear
Adjuvant therapy
- For the adjuvant treatment of malignant melanoma, the current U.S. Food and Drug Administration (FDA) approved regimens are high-dose interferon alfa-2b (HDI), which was approved in 1995, and pegylated interferon alfa-2b, which was recently approved for the treatment of stage III disease based on the EORTC 18991 study
- HDI is the only form of adjuvant therapy that has ever shown a consistent, significant, and durable relapse-free survival benefit in multicenter randomized controlled trials from U.S. Cooperative Groups. Estimated relapse frequency reductions of 24–38% and mortality reductions of 22–32% based on the hazard ratios for patients treated with interferon alfa versus observation, or the GMK vaccine have been demonstrated
- Based on the EORTC 18991 study, pegylated interferon alfa-2b has recurrence-free survival benefits that seem to be confined to the subpopulation of patients with microscopic nodal disease, and therefore, it can be offered to patients who cannot undertake high-dose interferon alfa-2b treatment
Metastatic melanoma
- For metastatic melanoma, survival is estimated at less than 2% at 5 or more years. However, major improvements in patient survival have been demonstrated with recently approved agents (ipilimumab, vemurafenib) and with several agents that are still in development (dabrafenib, PD1/PDL1 inhibitors)
- Single-agent dacarbazine is the only cytotoxic chemotherapy agent approved by the FDA for metastatic melanoma. Response rates range from 20% in early trials to 6.7% in one of the largest recent phase III trials. Median response durations range from 4–6 months. Higher response rates have been achieved with strategies involving combination chemotherapy and autologous bone marrow transplant, but with higher toxicities and no benefit in terms of relapse or survival
  
  Bedikian AY et al. J Clin Oncol 2006;24:4738–4745
  
  Chapman PB et al. J Clin Oncol 1999;17:2745–2751
  
  Kirkwood JM. Cancer Principles and Practice of Oncology, 1993, pp 1–16
- Temozolomide (TMZ) is transformed in vivo to monomethyltriazenoimidazole carboxamide (MTIC), the same active metabolite derived from hepatic metabolism of dacarbazine. Temozolomide crosses the blood–brain barrier and does not require metabolic activation; it undergoes spontaneous chemical degradation to MTIC at physiologic pH. A large randomized trial compared temozolomide with dacarbazine in patients with melanoma after the first presentation of metastatic disease. The median overall survival was 7.7 months with temozolomide and 6.4 months with dacarbazine (HR = 1.18; p = 0.2). The 6-month overall survival rate for temozolomide compared to dacarbazine was 61% versus 51%, respectively (HR = 1.36; p = 0.063). The difference between the treatment groups for overall survival did not reach statistical significance (p = 0.20), the 95% confidence interval for the HR (0.92–1.52) indicated temozolomide was at least equivalent to dacarbazine. Continuous prolonged daily administration of temozolomide has been found to more effectively deplete the activity of the DNA repair enzyme O₆-methylguanine-DNA-methyltransferase (MGMT) (73% after 21 days, with low levels persisting up to day 28). In phase I studies of daily temozolomide use, including a trial in which the drug was administered for 21 days during a 28-day cycle, temozolomide 75 mg/m² per day resulted in a 2.1-fold greater exposure to drug per 28-day period than a 5-day schedule. A recent Phase III trial described temozolomide use on an extended schedule (150 mg/m² per day orally on days 1–7, repeated every 14 days). There was no significant difference in overall survival (HR = 0.99, median 9.13 months [temozolomide] vs. 9.36 months [dacarbazine]), progression-free survival (HR = 0.92, median 2.30 months [temozolomide] vs. 2.17 months [dacarbazine]), or overall response rates (CR/PR) (14% temozolomide vs. 10 % dacarbazine)
  
  Brock CS et al. Cancer Res 1998;58:4363–4367
  
  Middleton MR et al. J Clin Oncol 2000;18:158–166
  
  Patel PM et al. In: Proceedings of the 33rd ESMO Congress; 2008 Sept 12–16; Stockholm, Sweden. (EORTC 18032). Available from: www.esmo.org/fileadmin/media/presentations/977/2132/Media%20briefing%20PATEL.ppt.pdf
- High-dose aldesleukin (high-dose IL-2, HD IL-2) is approved by the U.S. Food and Drug Administration for metastatic melanoma based on a retrospective analysis of 8 phase II trials that demonstrated an objective response rate of 16% with durable responses in approximately 4% of patients. However, the major toxicities associated with this regimen, including a capillary leak syndrome leading to hypotension, renal insufficiency, and hypoxia, has precluded its widespread application. The use of high-dose aldesleukin is currently limited to specialized programs with experienced personnel, and it is generally offered to patients with good performance and excellent organ function
  
  Atkins MB et al. J Clin Oncol 1999;17:2105–2116
- Promising results from a single-arm study of paclitaxel and carboplatin plus sorafenib (PC + SOR) in advanced melanoma has led to further investigation in a randomized phase III trial as second-line treatment. The addition of SOR to PC did not improve PFS or ORR, but overall, PC showed an improvement in the disease control rate (DCR) compared to historical data (DCR 62%; ORR 11%; SD 51%)
- Agarwala SS et al. J Clin Oncol 2007;25(June 20 Suppl) [abstract 8510]
- In 2011, the FDA approved ipilimumab for late-stage (metastatic) melanoma. Ipilimumab (Yervoy; Bristol-Myers Squibb Company, Princeton, NJ) is a monoclonal antibody to cytotoxic T-lymphocyte antigen-4 (CTLA4), which is also known as CD152 (cluster of differentiation 152). CTLA4, a member of the immunoglobulin superfamily, is expressed on the surface of T cells and transmits an inhibitory signal. CTLA4 is similar to CD28, a costimulatory protein that is also present on the surface of T-cells. Both CTLA4 and CD28 bind to CD80 (B7–1) and CD86 (B7–2) on antigen-presenting cells (APCs). Response to an antigen begins when an APC loads a peptide on its major histocompatibility complex (MHC) antigen and presents this to a resting T cell through its T-cell receptor (TCR). The outcome depends in part on the interaction of CD80 and CD86 on the APC with CTLA4 and CD28 on the T-cell surface. An interaction with CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. By targeting CTLA4, ipilimumab reduces inhibitory signals and may augment the immune response. Ipilimumab's safety and effectiveness were established in a single international study of 676 patients. All patients in the study had stopped responding to other FDA approved or commonly used treatments for melanoma. Because of the unusual and severe side effects associated with ipilimumab, it was approved with a Risk Evaluation and Mitigation Strategy to inform healthcare professionals about these serious risks. A medication guide is also provided to patients to inform them about potential side effects
  
  Hodi FS et al. N Engl J Med 2010;363:711–723
- In 2011, the FDA also approved vemurafenib for the treatment of late-stage (metastatic) or unresectable melanoma with the BRAF V600E mutation. Vemurafenib is a potent inhibitor of oncogenic BRAF kinase activity. In the BRIM-3 study, vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. Vemurafenib resulted in a 63% relative reduction in the risk of death and a 74% relative reduction in the risk of either death or disease progression when compared to dacarbazine
  
  Chapman PB et al. N Engl J Med 2011;364:2507–2516
- In 2013 the FDA approved the MEK inhibitor trametinib in combination with the BRAF inhibitor dabrafenib to treat patients with advanced melanoma that is unresectable or metastatic. The FDA had approved both drugs as single agents to treat patients with unresectable or metastatic melanoma. They were approved as a combination therapy for patients with melanoma whose tumors express BRAF V600E and V600K. Trametinib in combination with dabrafenib was the first drug approved for combination treatment of melanoma. The safety and effectiveness of the combination were demonstrated in a clinical trial of 162 participants with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation, most of whom had not received prior therapy. Participants received either the combination or dabrafenib as a single agent. Results showed that 76% of participants treated with the combination had an OR that lasted 10.5 months. In contrast, 54% of participants treated with dabrafenib as a single agent experienced an OR that lasted 5.6 months. One of the serious side effects of dabrafenib—the development of a new squamous cell carcinoma of the skin—was reduced with the combination, consistent with the biology of the effects of these two drugs on the targeted molecular pathway. The incidence of squamous cell carcinoma of the skin in this trial was 7% with the combination compared to 19% with single agent dabrafenib. The FDA approved the combination under the agency's accelerated approval program.
  
  Flaherty et al. N Engl J Med 2012;367:1694–1703
- The programmed death-1 (PD-1) receptor is a T-cell co-inhibitory molecule that binds to PD-1 and PD-2 ligands (PD-L1 and PD-L2) on antigen-presenting cells and suppresses T-cell activation. These ligands are aberrantly expressed in several tumors, including melanoma. Inhibiting the interaction between PD-1 and PD-L1 has been shown to enhance T-cell responses in vitro and mediates preclinical anti-tumor activity. As a result, the anti-PD-1 monoclonal antibody BMS-936558 (also known as MDX-1106 and ONO-4538) and the anti-PD-L1 monoclonal antibody BMS-936559 were developed. In a phase I dose-escalation study, the anti-PD-1 antibody BMS-936558 was administered to 104 patients with advanced melanoma. Twenty-six objective responses were observed in 94 evaluable patients (28%) at doses ranging from 0.1 to 10 mg/kg. At a dose of 3 mg/kg, the response rate was 41% (in 7 of 17 patients). The response was also durable; in 13 of the 26 patients with an objective response, the response lasted for 1 year or more. Stable disease lasting at least 24 weeks was seen in 6 patients (6%). PFS at 24 weeks was 41%. The most common treatment-related adverse events were fatigue, rash, diarrhea, pruritis, decreased appetite, and nausea. Grade 3 or 4 treatment-related adverse events were seen in 14%, and there were 3 drug-related deaths (1%) due to pneumonitis. In a separate phase I study, the anti-PD-L1 antibody BMS-936559 was tested in 55 patients with advanced melanoma. Nine out of 52 patients with melanoma (17%) had an objective response at escalating dose ranges (1 to 10 mg/kg), with 3 patients achieving a complete response. All 9 patients started treatment at least 1 year before the data analysis, and of these patients, 5 had an objective response lasting for at least 1 year. In addition, 14 of 52 patients (27%) had stable disease lasting at least 24 weeks. PFS at 24 weeks was 42%. The most common treatment-related adverse events were fatigue, infusion reactions, diarrhea, arthralgia, rash, nausea, pruritis, and headache. Grade 3 or 4 treatment-related adverse events were seen in 9%
  
  Batus M et al. Am J Clin Dermatol 2013
  
  Brahmer JR et al. N Engl J Med 2012;366:2455–2465
  
  Topalian SL et al. N Engl J Med 2012;366:2443–2454

REGIMEN: INTERFERON ALFA-2B

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Regimen: Interferon ALFA-2B

Kirkwood JM et al. J Clin Oncol 1996;14:7–17 [Trial E1684]

Interferon alfa-2b 20 million units/m² per dose; administer intravenously over 20 minutes in 0.9% sodium chloride injection (0.9% NS), sufficient to produce a solution with an interferon concentration ≥10 million units/100 mL, 5 consecutive days/week for 4 weeks (total dosage/week = 100 million units/m²), then:

Interferon alfa-2b 10 million units/m² per dose; administer subcutaneously 3 days/week for 48 weeks (total dosage/week = 30 million units/m²)

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—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

ECOG 1684 was a study of 143 patients with deep primary (T4) or regionally metastatic (N1) cutaneous melanoma who had no evidence of distant metastatic disease or significant medical or psychiatric comorbidity and who had not previously received systemic adjuvant therapy

Efficacy (N = 143)

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Efficacy (N = 143)

Median relapse-free survival

1.72 years

Overall median survival

3.8 years

5-Year relapse-free survival rate

37%

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

First occurrence of a DLT^✫

Hold dose until resolution, then reduce interferon alfa dosage by 33%

Second occurrence of a DLT^✫

Hold dose until resolution, then decrease interferon alfa dosage by 66%

Third occurrence of a DLT^✫

Discontinue interferon alfa therapy

^✫Definitions of dose-limiting toxicities (DLTs): hematologic DLT, granulocyte count <500/mm³; hepatic DLT, SGPT (ALT) or SGOT (AST) >5 times ULN (upper limit of normal)

Notes:

1. Dose reductions or delays are usually required at least once for 50% of patients during the IV treatment phase and for 48% during the subcutaneous treatment phase

2. Of patients with appropriate dose reductions, 74–90% continue treatment on protocol for 1 year or until relapse

3. Dose delays and reductions as a result of adverse events occur in 28–44% of patients during the induction phase and in 36–52% of patients during the maintenance phase

4. A response to other adverse events is determined largely by the patient and treating physician. Side effects are rarely life-threatening and should not lead to discontinuation if appropriate and proactive supportive care is provided

Kirkwood JM et al. J Clin Oncol 2002;20:3703–3718

Three U.S. national cooperative group studies have evaluated the benefit of HDI as an adjuvant for high-risk melanoma. All demonstrate significant and durable reduction in the frequency of relapse, while the first and third trials demonstrated significant improvement in the fraction of patients surviving compared to observation (E1684) or to GMK that was a promising vaccine in 1994. E1684 showed a median relapse-free survival (RFS) of 1.72 years for HDI versus 0.98 year with observation (P1 = 0.0023), and a median OS of 3.82 versus 2.78 years (P1 = 0.0237), respectively. E1694 was closed early, based on analysis demonstrating significantly increased mortality and relapse risk for patients who did not receive HDI. E1690 was inconsistent in that mortality benefit did not track with RFS benefit as it did in the E1684 and E1694 trials, but was unique in that it began before FDA approval of HDI, but was completed after FDA approval of HDI for treatment of high-risk melanoma. Not surprisingly, patients who were assigned observation in this trial, where no nodal staging by either elective or sentinel lymph node surgery was required, were associated with systematic crossover from observation to posttrial treatment at nodal relapse with HDI. This may explain why this trial showed RFS, but not OS differences that were observed in the prior and subsequent U.S. Cooperative Group trials. The analysis of each of the foregoing studies has been updated to April 2001, representing a median follow-up of 12.6 years for E1684, where significant clinical benefit of HDI versus observation is evident with respect to RFS (HR = 1.38; P2 = 0.02). Improvement of OS with HDI over observation remains, with diminished magnitude, at this most recent update (HR = 1.22; P2 = 0.18). The changes observed with late reanalysis of this study do not detract from the meaning of the mature observation published at a median follow-up of 6.9 years—considerably longer than many other trial reports. It raises interesting questions regarding competing causes of mortality, because the differences in RFS for the HDI group remain stable out to more than 15 years—and may be a result of deaths from vascular or other events, among the treatment cohort now well into the eighth decade of life (median age now >70 years). In E1694, at a median follow-up of 2.1 years, HDI continued to demonstrate superiority to the GMK in terms of both RFS (HR = 1.33; P2 = 0.006) and OS (HR = 1.32; P2 = 0.04).

Toxicity (N = 143)

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Toxicity (N = 143)

% G1/2

% G3/4

Constitutional^✫

Myelosuppression

Neutropenia

Neurologic

Depression

Hepatotoxicity

^✫Fever, chills, fatigue, malaise, diaphoresis

Notes:

1. Other adverse effects of IFN alfa-2b: anorexia, weight loss, alopecia, transient mild rash-like erythema, exacerbation of psoriasis, erythema or induration at the site of injection, impaired cognitive function, alternating episodes of manic depression

2. Rare adverse effects of IFN alfa-2b: rhabdomyolysis, delirium, cutaneous necrosis at the site of injection

3. Thyroid dysfunction (hypothyroidism or hyperthyroidism) occurs in 8-20% of patients

Kirkwood JM et al. J Clin Oncol 1996;14:7–17

Kirkwood JM et al. J Clin Oncol 2002;20:3703–3718

Therapy Monitoring

WBC, LFTs, electrolytes, and mineral panel: Weekly during induction, monthly during maintenance therapy for at least 3 months, then no less frequently than every 3 months in patients who are stable with no new complaints
Other standard tests (eg, serum electrolytes, thyroid-stimulating hormone [TSH] creatine kinase [CK] levels): Recommended at baseline and at least every 3 months during treatment

Note

Developed as an adjuvant regimen

REGIMEN: PEGYLATED INTERFERON ALFA-2B

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Regimen: Pegylated Interferon ALFA-2B

Eggermont AMM et al. J Clin Oncol 2012;30:3810–3818

Eggermont AMM et al. Lancet 2008;372:117–126

Premedication:

Acetaminophen 650–1000 mg; administer orally 30 minutes before the first dose and as needed prior to subsequent doses of peginterferon alfa-2b

Peginterferon alfa-2b 6 mcg/kg per dose; administer subcutaneously, once weekly for 8 consecutive weeks (induction phase; total dosage/week = 6 mcg/kg), and then:

Peginterferon alfa-2b 3 mcg/kg per dose; administer subcutaneously, once weekly for 5 years (maintenance phase; total dosage/week = 3 mcg/kg)

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 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

Absolute neutrophil count (ANC) <500/mm³, platelet count <50,000/mm³, ECOG PS ≥2, or nonhematologic toxicity G ≥3

Hold dose until ANC ≥500/mm³, platelet count ≥50,000/mm³, ECOG PS 0-1, and nonhematologic toxicity G ≤1. Then, resume at a reduced dose (see below)

Persistent or worsening severe neuropsychiatric disorders, G4 nonhematologic toxicity, inability to tolerate a dose of 1 mcg/kg per week, or new or worsening retinopathy

Permanently discontinue treatment

ECOG PS, Eastern Cooperative Oncology Group Performance Status

Starting Dose

Dose Modification

6 mcg/kg per week

For doses 1 to 8

First modification: 3 mcg/kg per week

Second modification: 2 mcg/kg per week

Third modification: 1 mcg/kg per week

Permanently discontinue peginterferon if patient is unable to tolerate 1 mcg/kg per week

3 mcg/kg per week

For doses 9 to 260

First modification: 2 mcg/kg per week

Second modification: 1 mcg/kg per week

Permanently discontinue peginterferon if patient is unable to tolerate 1 mcg/kg per week

Toxicity (N = 608)

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Toxicity (N = 608)

% All Grades

% G3

% G4

Any

Fatigue

Liver abnormalities

Pyrexia

Headache

Myalgia

Depression

Patient Population Studied

Included in the study were 627 patients with histologically confirmed stage III melanoma (Tx N1-2 M0) whose primary cutaneous melanoma was completely excised with adequate surgical margins and complete regional lymphadenectomy. Patients with ocular or mucous membrane melanoma, evidence of distant metastasis or in-transit metastasis, prior malignancy within the past 5 years, autoimmune disease, uncontrolled infections, cardiovascular disease, liver or renal disease, use of systemic corticosteroids, and previous use of systemic therapy for melanoma were excluded

Efficacy

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Efficacy

Recurrence-Free Survival

Distant Metastasis-Free Survival

Overall Survival

3.8 Years

7.6 Years

3.8 Years

7.6 Years

3.8 Years

7.6 Years

Number of events

328

384

304

370

262

332

Rate of recurrence-free survival

45.6%

39.1%

48.2%

41.7%

56.8%

47.8%

Median time to event

months

years

months

years

Hazard ratio

0.82

0.87

0.88

0.93

0.98

0.96

p Value

0.01

0.055

0.11

0.33

0.78

0.57

NR, Not reported

Therapy Monitoring

Every 3 months for 3 years and then every 6 months for 2 years: CBC with differential, LFTs, basic metabolic panel, LDH, physical examination, chest x-ray, and CT scans

REGIMEN: DACARBAZINE (DTIC)

Listen

Regimen: Dacarbazine (DTIC)

Middleton MR et al. J Clin Oncol 2000;18:158–166

Dacarbazine 250 mg/m² (initial dosage) per day; administer intravenously in 50–250 mL of either 5% dextrose injection (D5W) or 0.9% sodium chloride injection (0.9% NS) over 30 minutes for 5 consecutive days on days 1–5, every 21 days (total dosage/cycle = 1250 mg/m²)

Alternative regimen:

Eggermont AMM, Kirkwood JM. Eur J Cancer 2004;40:1825–1836

Dacarbazine 1000 mg/m²; administer intravenously in 50–250 mL D5W or 0.9% NS over 30 minutes on day 1, every 28 days, for 2 cycles (total dosage/cycle = 1000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days of chemotherapy is 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

Patient Population Studied

A study of 136 patients with histologically confirmed incurable or unresectable advanced metastatic melanoma. Patients with nonmeasurable disease, ocular melanoma, or CNS metastases were excluded

Efficacy (N = 136)

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Efficacy (N = 136)

Complete response

2.9%

Partial response

10.3%

Stable disease

17.7%

Progressive disease

69.1%

Median overall survival

6.4 months

Toxicity (N = 136)

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Toxicity (N = 136)

% All Grades

% G3

% G4

Hematologic

Anemia

Neutropenia

Thrombocytopenia

Nonhematologic

Asthenia

Fatigue

Fever

Headache

Pain

Anorexia

Constipation

Nausea

Vomiting

Somnolence

Treatment Modifications

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Treatment Modifications

Retreatment allowed if ANC ≥1500/mm³ and platelet count ≥100,000/mm³

Adverse Event

Dose Modification

Retreatment delayed by ≥2 weeks

Reduce dacarbazine dosage by 25%

G3/4 nonhematologic toxicity

Reduce dacarbazine dosage by 50%

>2 Dosage reductions

Discontinue therapy

Therapy Monitoring

Before each cycle: CBC with differential, LFTs, mineral panel, and electrolytes
Response evaluation every 2 cycles: PE, chest x-ray, and CT scans

REGIMEN: TEMOZOLOMIDE

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Regimen: Temozolomide

Middleton MR et al. J Clin Oncol 2000;18:158–166

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

Alternative regimens:

Brock CS et al. Cancer Res 1998;58:4363–4367

Temozolomide 75 mg/m² per day; administer orally for 21 consecutive days, every 28 days, for 2 cycles, followed by reevaluation of index measurable disease (total dosage/week = 525 mg/m²; total dosage/28-day cycle = 1575 mg/m²)

Patel PM et al. EORTC 18032 [poster]. In: 33rd Annual ESMO Congress. Stockholm, Sweden; 2008

Temozolomide 150 mg/m² per day; administer orally for 7 consecutive days, on days 1–7, every 14 days (“7 days on/7 days off”; total dosage/14-day cycle = 1050 mg/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—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 study of 144 patients with histologically confirmed incurable or unresectable advanced metastatic melanoma. Patients with nonmeasurable disease, ocular melanoma, or CNS metastases were excluded

Efficacy (N = 144)

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Efficacy (N = 144)

Complete response

2.8%

Partial response

11.8%

Stable disease

19.4%

Progressive disease

66%

Median overall survival

7.7 months

Toxicity (N = 144)

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Toxicity (N = 144)

% All Grades

% G3

% G4

Asthenia

Fatigue

Fever

Headache

Pain

Anorexia

Constipation

Nausea

Vomiting

Somnolence

Anemia

Neutropenia

Thrombocytopenia

Treatment Modifications

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Treatment Modifications

Retreatment allowed if ANC ≥1500/mm³ and platelet count ≥100,000/mm³

Adverse Event

Dose Modification

Retreatment delayed by ≥2 weeks

Reduce temozolomide dosage by 25%

G3/4 hematologic toxicity

Reduce temozolomide dosage by 25%

G3/4 nonhematologic toxicity

Reduce temozolomide dosage by 50%

>2 Dosage reductions

Discontinue therapy

Therapy Monitoring

Before each cycle: CBC with differential, LFTs, mineral panel, and electrolytes
Response evaluation every 2 cycles: PE, chest x-ray, and CT scans

ADVANCED DISEASE REGIMEN: CARBOPLATIN + PACLITAXEL

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Advanced Disease Regimen: Carboplatin + Paclitaxel

Hauschild A et al. J Clin Oncol 2009;27:2823–2830

Premedications:

Dexamethasone 20 mg per dose; administered orally or intravenously for 2 doses: the first dose between 12 and 14 hours before starting paclitaxel, and a second dose 6–7 hours before starting paclitaxel

Diphenhydramine 50 mg; administer intravenously per push 30 minutes before starting paclitaxel

Ranitidine 50 mg; administer intravenously in 25–100 mL of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 15–30 minutes, 30–60 minutes before starting paclitaxel

Cycles 1 through 4

Paclitaxel 225 mg/m²; administer intravenously, diluted in 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) to a concentration between 0.3 and 1.2 mg/mL, over 3 hours before carboplatin on day 1, every 21 days cycle (total dosage/cycle = 225 mg/m²)

Carboplatin AUC = 6 mg/mL · min^✫; administer intravenously, diluted in 0.9% NS or D5W to a concentration >0.5 mg/mL, over 30 minutes on day 1 every 21 days (total dose/cycle calculated to produce an AUC = 6 mg/mL · min^✫)

Cycles 5 through 10

Paclitaxel 175 mg/m²; administer intravenously, diluted in 0.9% NS or D5W to a concentration between 0.3 and 1.2 mg/mL, over 3 hours on day 1, every 21 days (total dosage/cycle = 175 mg/m²)

Carboplatin AUC = 5 mg/mL · min^✫; administer intravenously, diluted in 0.9% NS or D5W to a concentration >0.5 mg/mL, over 30 minutes on day 1, every 21 days (total dose/cycle calculated to produce an AUC = 5 mg/mL · min^✫)

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

Note: 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. The FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value. No greater estimated GFR values should be used [online] May 23, 2013. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm [accessed February 26, 2014]

Notes:

If paclitaxel is discontinued because of hypersensitivity, carboplatin may be continued
If carboplatin is discontinued because of hypersensitivity, tinnitus, or hearing loss, paclitaxel may be continued
After 4 cycles of chemotherapy, the dose of both chemotherapy agents will be reduced to carboplatin AUC of = 5 mg/mL · min and paclitaxel 175 mg/m². Patients who had a dose reduction during the first 4 chemotherapy cycles will continue at reduced doses. There is no additional dose reduction at cycle 5; a second dose reduction would be triggered by an occurrence of toxicity
In the absence of unacceptable toxicity, patients may continue to receive chemotherapy until disease progression. After completing 10 cycles of chemotherapy, carboplatin and paclitaxel may be discontinued at the discretion of a treating physician

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH with potential for delayed symptoms

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 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

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

See Chapter 47 for more information

Dose Modifications

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Dose Modifications

Adverse Event

Dose Modification

If carboplatin target dose is an AUC = 6 mg/mL · min and paclitaxel dose is 225 mg/m² and one of the following occurs:

• G4 neutropenia (ANC <500/mm³) lasting >7 days

• G4 neutropenia (ANC <500/mm³) with fever (≥38°C [≥100.5°F])

• G4 thrombocytopenia (<25,000/mm³)

• Lack of ANC or platelet count recovery to pretreatment levels by day 28 of each cycle

• Any G3/4 nonhematologic toxicity (including neuropathy) attributed to carboplatin or paclitaxel, with the exception of G4 hypersensitivity reactions

Reduce carboplatin dose to AUC = 5 mg/mL · min and paclitaxel dose to 175 mg/m² on the same administration schedule

Note: This dose reduction is permanent. Do not increase doses during subsequent cycles

If carboplatin target dose is an AUC = 5 mg/mL · min and paclitaxel dose is 175 mg/m² and one of the following occurs:

• G4 neutropenia (ANC <500/mm³) lasting >7 days

• G4 neutropenia (ANC <500/mm³) with fever (≥38°C [≥100.5°F])

• G4 thrombocytopenia (<25,000/mm³)

• Lack of ANC or platelet count recovery to pretreatment levels by day 28 of each cycle

• Any G3/4 nonhematologic toxicity (including neuropathy) attributed to carboplatin or paclitaxel, with the exception of G4 hypersensitivity reaction

Reduce carboplatin dose to AUC = 4 mg/mL · min and paclitaxel dose to 125 mg/m² on the same administration schedule

Note: This dose reduction is permanent. Do not increase doses during subsequent cycles

Note: If any of the criteria for dose reduction are met after this second dose reduction, discontinue carboplatin and paclitaxel

G4 hypersensitivity reactions to either paclitaxel or carboplatin

Discontinue the agent responsible for the hypersensitivity reaction

Note: Continue the remaining chemotherapy agent at the same dose and administration schedule, in the absence of the discontinued agent

Toxicity (N = 134)

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Toxicity (N = 134)

Adverse Event

% G3

% G4

Any event

31%

39%

Hematologic events

25%

34%

Neutrophils

13%

32%

Platelets

Hemoglobin

12%

Infection

11%

Febrile neutropenia

Constitutional symptoms

11%

Fatigue

Gastrointestinal

12%

Diarrhea

Metabolic/laboratory

Lipase

Neurology

19%

Neuropathy, sensory

13%

Pain

16%

Patient Population Studied

A study of 270 patients with unresectable stages III/IV melanoma with disease progression on a dacarbazine- or temozolomide-containing regimen. Prior adjuvant immunotherapy was allowed. Patients with active brain metastases were excluded

Efficacy (N = 135)

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Efficacy (N = 135)

Response

N (%)

15 (11%)

69 (51%)

48 (36%)

Not evaluated

3 (2%)

Median PFS

17.9 weeks

Median OS

42.0 weeks

Therapy Monitoring

Before each cycle: CBC with differential, serum sodium, potassium, BUN, creatinine, glucose, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, LDH, albumin, amylase, lipase
Response evaluation: Every 2 cycles

ADVANCED/UNRESECTABLE MELANOMA REGIMEN: IPILIMUMAB

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Advanced/Unresectable Melanoma Regimen: Ipilimumab

Hodi FS et al. N Engl J Med 2010;363:711–723

Ipilimumab 3 mg; administer intravenously, diluted in 0.9% sodium chloride injection or 5% dextrose injection to a concentration between 1 and 2 mg/mL, over 90 minutes, once every 3 weeks, for a total of 4 doses (total dosage/3-week cycle = 3 mg/kg)

Note: Adverse events associated with the administration of ipilimumab consist primarily of reactions that are immune in nature. Almost all immune-related adverse events can be managed with supportive care or corticosteroids. Corticosteroids do not appear to adversely affect patients who had an immune-related adverse event or alter objective antitumor responses. Glucocorticoids do not appear to alter the activity of activated CD8+ cells, and, therefore, may explain this unique characteristic of CTLA4 inhibition. Rash and colitis are reported most often during early use, whereas hypophysitis is reported with later doses. Ipilimumab immune-related adverse events are dose-dependent in incidence, and occurred more frequently after 10-mg/kg doses than with lower dosages

Patient Population Studied

Patients with a diagnosis of unresectable stage III or IV melanoma who had previously received therapy, including one or more of the following: dacarbazine, temozolomide, fotemustine, carboplatin, or aldesleukin. Other inclusion criteria were: Eastern Cooperative Oncology Group performance status of 0 or 1, and positive status for HLA-A^✫0201. Exclusion criteria included long-term use of systemic corticosteroids

Dose Modifications

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Dose Modifications

Adverse Event

Dose Modification

Note: Among almost 3000 patients treated with ipilimumab, approximately 60% reported an adverse immune-related event; however, only 15% reported a serious adverse immune-related event

Dermatologic Immune-Related Adverse Event

Transient G1/2 skin rash

Continue therapy and treat symptoms with antihistamines or similar

G1/2 skin rash persisting >1–2 weeks

Administer topical or systemic corticosteroids

G3/4 skin rash

Administer intravenous corticosteroids until control is achieved

Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration; or necrotic, bullous, or hemorrhagic manifestations; or erythema Multiforme

Permanently discontinue ipilimumab. Administer systemic glucocorticoid at a dose equivalent to 1–2 mg/kg per day of prednisone. When dermatitis is controlled, corticosteroid dose tapering toward discontinuation should occur over a period of at least 1 month

Nondermatologic Immune-Related Adverse Events

Nondermatologic G1 toxicities

Continue therapy and treat symptoms

G2 enterocolitis

Withhold scheduled ipilimumab doses; administer antidiarrheal treatment and, if symptoms persist for >1 week, initiate systemic glucocorticoid at a dose equivalent to 0.5 mg/kg per day prednisone. If toxicities resolve to G ≤1, and if patient is receiving >7.5 mg prednisone per day or another glucocorticoid at an equivalent daily dose, resume ipilimumab at a dose of 3 mg/kg every 3 weeks until all 4 planned ipilimumab doses are administered, or 16 weeks after the first dose was given have elapsed, whichever occurs earlier. If toxicity does not improve to G ≤1, discontinue treatment permanently

G2 hepatotoxicity: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3–5 times the ULN, or total bilirubin >1.5–3 times the ULN, or alkaline phosphatase >2.5–5 times the ULN

Withhold scheduled ipilimumab doses until toxicity improves to G ≤1. If toxicities resolve to G ≤1, and if patient is receiving >7.5 mg prednisone per day or another glucocorticoid at an equivalent daily dose, resume ipilimumab at a dose of 3 mg/kg every 3 weeks until all 4 planned ipilimumab doses are administered, or 16 weeks after the first dose was given have elapsed, whichever occurs earlier. If toxicity does not improve to G ≤1, discontinue treatment permanently

G2 neuropathy (not interfering with daily activities)

G2 immune-mediated adverse reaction other than enterocolitis or symptomatic endocrinopathy

G2 immune-mediated endocrinopathies

Withhold scheduled dose of ipilimumab until toxicity improves to G ≤1. If toxicities resolve to G ≤1, and if patient is receiving less than 7.5 mg prednisone or equivalent per day, resume ipilimumab at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose have elapsed, whichever occurs earlier. If toxicity does not improve to G ≤1, discontinue treatment permanently. Initiate appropriate hormone replacement therapy

G2 immune-mediated ocular disease

Withhold scheduled dose of ipilimumab. If toxicities resolve to G ≤1, and if patient is receiving less than 7.5 mg prednisone or equivalent per day, resume ipilimumab at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose have elapsed, whichever occurs earlier. If toxicity does not improve to G≤1, discontinue treatment permanently. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis

Persistent G2 immune-mediated adverse reaction, or symptomatic endocrinopathy, or inability to reduce corticosteroid dose to 7.5 mg prednisone per day, or another glucocorticoid at an equivalent daily dose

Permanently discontinue ipilimumab

Failure to complete full treatment course within 16 weeks after administration of first dose of ipilimumab

G3/4 immune-mediated colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline); or stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, or gastrointestinal perforation

Permanently discontinue ipilimumab and initiate systemic corticosteroids at a dose of 1–2 mg/kg of prednisone per day or another glucocorticoid at an equivalent daily dose. Upon improvement to G ≤1, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients

G3/4 hepatotoxicity: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the ULN, or total bilirubin >3 times the ULN, or alkaline phosphatase >5 times the ULN

Permanently discontinue ipilimumab and administer systemic corticosteroids at a dose of 1–2 mg/kg of prednisone per day or another glucocorticoid at an equivalent daily dose. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. During clinical development, mycophenolate treatment was administered to patients who had persistent severe hepatitis despite high-dose corticosteroids

G3/4 motor or sensory neuropathy (interfering with daily activities), Guillain-Barré syndrome, or myasthenia gravis

Permanently discontinue ipilimumab. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1–2 mg/kg of prednisone per day or another glucocorticoid at an equivalent daily dose for severe neuropathies

G3/4 immune-mediated endocrinopathy

Permanently discontinue ipilimumab. Initiate systemic corticosteroids at a dose of 1–2 mg/kg of prednisone per day or another glucocorticoid at an equivalent daily dose, and initiate appropriate hormone replacement therapy

G3/4 immune-mediated ocular disease or disease that is unresponsive to topical immunosuppressive therapy (conjunctivitis, blepharitis, episcleritis, scleritis)

Permanently discontinue ipilimumab

G3/4 immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, noninfectious myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, leukocytoclastic vasculitis, or arthritis)

ULN, Upper limit of normal

Efficacy (N = 137)

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Efficacy (N = 137)

Median overall survival

10.1 months (95% CI, 8.0–13.8)

Rate of overall survival at 12 months

45.6%

Rate of overall survival at 18 months

33.2%

Rate of overall survival at 24 months

23.5%

Objective response^✫,†

10.9%

Complete response^†

1.5%

Partial response^†

9.5%

Stable disease^†

17.5%

Reinduction (n = 8)

Complete response

12.5% (1/8)

Partial response

25% (2/8)

Stable disease

37.5% (3/8)

^✫Responses to ipilimumab continued to improve beyond week 24: 2 patients with SD improved to a PR, and 3 patients with a PR improved to a CR. Among 31 patients given reinduction therapy with ipilimumab, 21 patients achieved a CR, PR, or SD

^†Duration of response: 60.0% maintained an objective response for at least 2 years (26.5–44 months, ongoing)

Toxicity (N = 131)

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Toxicity (N = 131)

Adverse Event

Total % (All Grades)

% G3

% G4

Any event

96.9

37.4

8.4

Any drug-related event

80.2

19.1

3.8

Gastrointestinal disorders

Diarrhea

32.8

5.3

Nausea

35.1

2.3

Constipation

20.6

2.3

Vomiting

23.7

2.3

Abdominal pain

15.3

1.5

Other

Fatigue

42.0

6.9

Decrease appetite

26.7

1.5

Pyrexia

12.2

Headache

14.5

2.3

Cough

16.0

Dyspnea

14.5

3.1

0.8

Anemia

11.5

3.1

Any immune-related event

Any immune-related event

61.1

12.2

2.3

Dermatologic

43.5

1.5

Pruritus

24.4

Rash

19.1

0.8

Vitiligo

2.3

Gastrointestinal

29.0

7.6

Diarrhea

27.5

4.6

Colitis

7.6

5.3

Endocrine

7.6

2.3

1.5

Hypothyroidism

1.5

Hypopituitarism

2.3

0.8

Hypophysitis

1.5

Adrenal insufficiency

1.5

Long-term adverse effects in survivors for >2 years (N = 94)

Injection-site reactions

17%

Vitiligo

12.8%

Proctocolitis with rectal pain

4.3%

Endocrine immune-related adverse event^✫

8.5%

^✫Required hormone-replacement therapy

Toxicity—General Notes:

All immune-related events occurred during the induction and reinduction periods
Median time to the resolution of immune-related adverse events of G2–4 was 4.9 weeks (95% CI, 3.1–6.4)
After administration of corticosteroids, median time to resolution of diarrhea G ≥2 was 2.3 weeks for 14 of 15 patients
In addition to corticosteroids, 4 patients received infliximab (antitumor necrosis factor-α antibody) for diarrhea G ≥3 or colitis
Ongoing events in 94 persons who survived ≥2 years included rash, pruritus, diarrhea, anorexia, and fatigue, generally G1/2 (5–15% of patients) and G3 leukocytosis (1 patient)
There were 14 deaths related to the study drugs (2.1%), of which 7 were associated with immune-related adverse events

Toxicity—Specific Notes:

Skin:

Rash is the most common immune related toxicity associated with ipilimumab (incidence ≈20%)
Median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks (range: days to 17.3 weeks after initiation)

Gastrointestinal:

Most common serious adverse event affects the lower gastrointestinal tract and manifests as diarrhea and/or intestinal bleeding
Serious lower intestinal toxicity was reported in ≈13% of patients treated at 10 mg ipilimumab/kg of body weight
Onset of diarrhea occurred within first 12 weeks after starting treatment, and was generally reversible

Hepatic:

Immune-related hepatotoxicity consists of elevated LFTs and immune hepatitis
Patients with right upper quadrant pain, nausea, or vomiting should have LFTs evaluated immediately, although hepatotoxicity can occur in the absence of symptoms
In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution

Endocrine:

Most patients with hypophysitis/hypopituitarism present with headache; however, visual disturbances, fatigue, confusion, and impotency are common symptoms
Median time to onset of moderate-to-severe immune-mediated endocrinopathy was 11 weeks (range: days to 19.3 weeks after initiation)
Of 21 patients with moderate to life-threatening endocrinopathy, 17 required long-term hormone replacement therapy, most commonly adrenal (n = 10) and thyroid (n = 13) replacement

Neurologic:

Myasthenia gravis and cases of Guillain-Barré syndrome have been reported in association with ipilimumab use
Monitor for symptoms of motor and sensory neuropathy

Therapy Monitoring

Monitor liver function tests (LFTs), thyroid function tests (TFTs) and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms
Monitor patients for signs and symptoms of enterocolitis (diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and bowel perforation
Monitor patients for signs and symptoms of dermatitis
Monitor for symptoms of motor or sensory neuropathy
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency, and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms that may resemble other causes such as brain metastasis or underlying disease
Imaging studies (enlargement of the pituitary gland) may be considered in the diagnosis of hypophysitis
Endoscopy may be considered for persistent or severe gastrointestinal symptoms

ADVANCED/UNRESECTABLE MELANOMA REGIMEN: VEMURAFENIB

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Advanced/Unresectable Melanoma Regimen: Vemurafenib

Chapman PB et al. N Engl J Med 2011;364:2507–2516

Vemurafenib 960 mg/dose; administer orally, twice daily without regard to food, continually (total dose/week = 13,440 mg)

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—not indicated
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

Adverse Event

Dose Modification

G1 or G2 (tolerable)

None; maintain dose at 960 mg twice daily

G2 (intolerable) or G3

Hold dose until G ≤1, then resume vemurafenib at 720 mg twice daily. If the adverse event recurs, hold dose until G ≤1, then further reduce the vemurafenib dose to 480 mg twice daily. If the adverse event occurs a third time, permanently discontinue vemurafenib

Discontinue permanently or hold dose until G ≤1 and then resume vemurafenib at 480 mg twice daily. If the adverse event recurs, discontinue permanently

Cutaneous squamous cell carcinoma

None; maintain dose at 960 mg twice daily; resect lesion

Patient Population Studied

The study evaluated 337 patients with unresectable, previously untreated stage IIIC or stage IV melanoma that tested positive for the BRAF V600E mutation. Patients were excluded if they had a history of cancer within the past 5 years (except basal or squamous cell carcinoma of the skin or carcinoma of the cervix), metastases to the central nervous system (unless such metastases were definitively treated more than 3 months previously with no progression and no requirement for continued glucocorticoid therapy), or if they were on any other concomitant anticancer therapy

Therapy Monitoring

At baseline: Contrast CT or MRI of the brain, chest, abdomen, pelvis, and other anatomical regions as clinically indicated; physical and dermatologic examination; electrocardiography; CBC with differential; LFTs; basic metabolic panel; and LDH
Every 3 weeks: Physical examination, CBC with differential, LFTs, basic metabolic panel, and LDH
Every 6 weeks: Electrocardiography
Tumor assessments are performed at baseline, at weeks 6 and 12, and every 9 weeks thereafter

Therapy Modifications

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Therapy Modifications

Dose Levels

Vemurafenib Dose

Initial dose

960 mg twice daily

First dose reduction

720 mg twice daily

Second dose reduction

480 mg twice daily

Efficacy

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Efficacy

Overall Survival (N = 336)

Hazard ratio

p Value

6 months OS

0.37

<0.001

84%

Progression-Free Survival (N = 275)

Hazard ratio

p Value

Median PFS

0.26

<0.001

5.3 months

Tumor Response (N = 219)

Complete response

Partial response

Median time to response

2 (1%)

104 (47%)

1.45 months

Toxicity (N = 336)

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Toxicity (N = 336)

% G2

% G3

% G4

Arthralgia

Rash

Fatigue

Cutaneous squamous cell carcinoma

Keratoacanthoma

Nausea

Alopecia

Pruritis

Hyperkeratosis

Diarrhea

Headache

Vomiting

Neutropenia

ADVANCED/UNRESECTABLE MELANOMA REGIMEN: DABRAFENIB + TRAMETINIB

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Advanced/Unresectable Melanoma Regimen: Dabrafenib + Trametinib

Flaherty et al. N Engl J Med 2012;367:1694–1703

Dabrafenib 150 mg; administer orally twice daily at least 1 hour before or 2 hours after a meal

Trametinib 2 mg; administer orally once daily at least 1 hour before or 2 hours after a meal

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—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

Patients with histologically confirmed metastatic melanoma with either BRAF V600E or BRAF V600K mutations were eligible for inclusion. Eligible patients had measurable disease, an ECOG PS of 0 or 1. Patients with treated brain metastases and at least a 3-month history of stable disease were allowed to enroll. Patients were randomly assigned to receive 150 mg of dabrafenib twice daily plus once-daily trametinib at a dose of either 1 mg (combination 150/1) or 2 mg (combination 150/2) or 150 mg of dabrafenib monotherapy twice daily. There were no significant differences among groups except that patients in the combination 150/2 group were older than those in the monotherapy group (P = 0.04).

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Dabrafenib and Trametinib Dose Modifications

Dabrafenib Dose Levels

Dose Reductions

Dose and Schedule

First dose reduction

100 mg dabrafenib orally twice daily

Second dose reduction

75 mg dabrafenib orally twice daily

Third dose reduction

50 mg dabrafenib orally twice daily

If unable to tolerate 50 mg twice daily

Discontinue dabrafenib

Dabrafenib Dose Modification

Target Organ

Adverse Reactions^✫

Dose Modification

Febrile drug reaction

Fever of 101.3°F to 104°F

Withhold dabrafenib until AE resolves then resume dabrafenib at same dose or at a reduced dose

• Fever higher than 104°F

• Fever complicated by rigors, hypotension, dehydration or renal failure

• Permanently discontinue dabrafenib or

• Withhold dabrafenib until AE resolves then resume dabrafenib at same dose or at a reduced dose

Other

• Intolerable G2 AE

• Any G3 AE

Withhold dabrafenib until AE resolves to ≤G1 then resume dabrafenib at a reduced dose

First occurrence of any G4 AE

Either:

• Permanently discontinue dabrafenib or

• Withhold dabrafenib until AE resolves to ≤G1 then resume dabrafenib at a reduced dose

Recurrent G4 AE

Intolerable G2 or any G3/4 AE on dabrafenib 50 mg twice daily

Permanently discontinue dabrafenib

Trametinib Dose Modification

Cutaneous

G2 rash

Reduce dose of trametinib by 0.5 mg or discontinue trametinib in patients taking trametinib 1 mg daily

Intolerable G2 rash that does not improve within 3 weeks following dose reduction G3/4 rash

Withhold trametinib for up to 3 weeks. If improved resume trametinib at a lower dose (reduced by 0.5 mg)

Intolerable G2 or G3/4 rash that does not improve within 3 weeks despite interruption of trametinib dosing

Permanently discontinue trametinib

Cardiac

Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline and is below institutional lower limits of normal (LLN) from pretreatment value

Withhold trametinib for up to 4 weeks

Asymptomatic, absolute decrease in LVEF of ≥10% from baseline and is<LLN that improves to normal LVEF value within 4 weeks following interruption of trametinib

If improved within 4 weeks, resume trametinib at a lower dose (reduced by 0.5 mg) or discontinue trametinib in patients taking trametinib 1 mg daily

• Symptomatic congestive heart failure

• ≤Absolute decrease in LVEF of ≥20% from baseline that is <LLN

• Absolute decrease in LVEF of ≥10% from baseline and is <LLN that does not improve to normal LVEF value within 4 weeks following interruption of trametinib

Permanently discontinue trametinib

Ocular

G2/3 retinal pigment epithelial detachments (RPED)

Withhold trametinib for up to 3 weeks

G2/3 RPED that improves to Grade 0–1 within 3 weeks

If improved within 3 weeks, resume trametinib at a lower dose (reduced by 0.5 mg)

• Retinal vein occlusion

• G2/3 RPED that does not improve to at least G1 within 3 weeks

Permanently discontinue trametinib

Pulmonary

Interstitial lung disease/pneumonitis

Permanently discontinue trametinib

Other

G3 AE

Withhold trametinib for up to 3 weeks

If G3 AE improves to G0/1 following interruption of trametinib within 3 weeks

Reduce dose of trametinib by 0.5 mg or discontinue trametinib in patients taking trametinib 1 mg daily

• G4 AE

• G3 AE that does not improve to G0/1 within 3 weeks

Permanently discontinue trametinib

AE, adverse event; RPED, retinal pigment epithelial detachments

^✫National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

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Efficacy End Points as Assessed by the Site Investigators (Intention-to-Treat Population)^✫

End Point

Dabrafenib Monotherapy (N = 54)

Dabrafenib 150 mg + Trametinib 1 mg (N = 54)

Dabrafenib 150 mg + Trametinib 2 mg (N = 54)

Progression-free survival — mo

Median (95% CI)

5.8 (4.6–7.4)

9.2 (6.4–11.0)

9.4 (8.6–16.7)

HR for death or progression (95% CI)

Reference

0.56 (0.37–0.87)

0.39 (0.25–0.62)

P value

Reference

0.006

<0.001

PFS at 12 mo (95% CI) — %

9 (3–20)

26 (15–39)

41 (27–54)

Best response — no. (%)

Complete response

2 (4)

3 (6)

5 (9)

Partial response

27 (50)

24 (44)

36 (67)

Stable disease

22 (41)

24 (44)

13 (24)

Progressive disease

3 (6)

2 (4)

Could not be evaluated

1 (2)

Complete or partial response

Number of patients

Percent of patients (95% CI)

54 (40–67)

50 (36–64)

76 (62–86)

P value

Reference

0.77

0.03

Duration of response — mo

Median (95% CI)

5.6 (4.5–7.4)

9.5 (7.4–NA)

10.5 (7.4–14.9)

HR, hazard ratio; PFS, progression-free survival; NA, not achieved

^✫Hazard ratios and P values are for the comparison between each combination-therapy group and the monotherapy group

Adverse Events

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Adverse Events^✫

Adverse Event

Dabrafenib Monotherapy (N = 53)^†

Dabrafenib 150 mg + Trametinib 1 mg (N = 54)

Dabrafenib 150 mg + Trametinib 2 mg (N = 55)^†

G3/4

All Grades

G3/4

All Grades

G3/4

All Grades

Number of Patients (percent)

Any event

23 (43)

53 (100)

26 (48)

53 (98)

32 (58)

55 (100)

Pyrexia

14 (26)

5 (9)

37 (69)

3 (5)

39 (71)

Chills

9 (17)

1 (2)

27 (50)

1 (2)

32 (58)

Fatigue

3 (6)

21 (40)

1 (2)

31 (57)

2 (4)

29 (53)

Nausea

11 (21)

3 (6)

25 (46)

1 (2)

24 (44)

Vomiting

8 (15)

2 (4)

23 (43)

1 (2)

22 (40)

Diarrhea

15 (28)

14 (26)

1 (2)

20 (36)

Headache

15 (28)

1 (2)

20 (37)

16 (29)

Peripheral edema

9 (17)

13 (24

16 (29)

Cough

11 (21)

6 (11)

16 (29)

Arthralgia

18 (34)

24 (44)

15 (27)

Rash

19 (36)

11 (20)

15 (27)

Night sweats

3 (6)

8 (15)

13 (24)

↓ Appetite

10 (19)

16 (30)

12 (22)

Myalgia

1 (2)

12 (23)

13 (24)

1 (2)

12 (22)

Constipation

6 (11)

1 (2)

9 (17)

12 (22)

↑ alkaline phosphatase

1 (2)

3 (6)

12 (22)

5 (9)

Hyperkeratosis

16 (30)

3 (6)

5 (9)

Alopecia

18 (34)

5 (9)

3 (5)

G3^‡

All Grades

G3^‡

All Grades

G3^‡

All Grades

Cutaneous squamous-cell carcinoma^§

9 (17)

10 (19)

1 (2)

3 (5)

4 (7)

Skin papilloma

8 (15)

4 (7)

2 (4)

Hyperkeratosis

16 (30)

3 (6)

5 (9)

↑ ejection fraction

1 (2)

2 (4)

5 (9)

Cardiac failure

1 (2)

Hypertension

2 (4)

1 (2)

5 (9)

Chorioretinopathy

1 (2)

^✫Adverse events reported in ≥20% of patients in any group, regardless of whether a causal relationship was likely. In addition to these events, there was one death from sepsis in 150/1 combination group and three deaths in the 150/2 combination group (two from brain hemorrhage and one from pulmonary embolism). None were considered related to study drug. Neutropenia (G3/4) occurred in 11% of patients in the 150/2 combination group, with one case of febrile neutropenia. Acneiform dermatitis occurred in 11% of patients in the 150/1 combination group, 16% in the combination group, and 4% in the 150/2 monotherapy group, with no G3/4 events reported

^†One patient who was assigned to the monotherapy group received combination 150/2 and so was included in the combination 150/2 safety analyses

^‡For these categories, no G4 events were reported

§Keratoacanthoma was classified as cutaneous squamous-cell carcinoma

Treatment Monitoring

At baseline: Contrast CT or MRI of the brain, chest, abdomen, pelvis, and other anatomical regions as clinically indicated; physical and dermatologic examination; electrocardiography; CBC with differential; LFTs; basic metabolic panel; and LDH
Every 3 weeks: Physical examination, CBC with differential, LFTs, basic metabolic panel, and LDH
Tumor assessments are performed at baseline, at weeks 6 and 12, and every 9 weeks thereafter

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Chapter 25: Melanoma

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INTRODUCTION

Expert Opinion

REGIMEN: INTERFERON ALFA-2B

REGIMEN: PEGYLATED INTERFERON ALFA-2B

REGIMEN: DACARBAZINE (DTIC)

REGIMEN: TEMOZOLOMIDE

ADVANCED DISEASE REGIMEN: CARBOPLATIN + PACLITAXEL

ADVANCED/UNRESECTABLE MELANOMA REGIMEN: IPILIMUMAB

ADVANCED/UNRESECTABLE MELANOMA REGIMEN: VEMURAFENIB

ADVANCED/UNRESECTABLE MELANOMA REGIMEN: DABRAFENIB + TRAMETINIB

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