Chapter 34: Sarcomas

Primary Malignant Bone Tumors: Epidemiology

Classification: WHO Classification of Malignant Bone Tumors

Osteogenic tumors

Osteosarcoma

1. Conventional

   • Chondroblastic

   • Fibroblastic

   • Osteoblastic

2. Telangiectatic

3. Small cell

4. Low-grade central

5. Secondary

6. Parosteal

7. Periosteal

8. High-grade surface

Ewing sarcoma/primitive neuroectodermal tumor

Ewing sarcoma

Cartilage tumors

Chondrosarcoma

1. Central, primary, and secondary

2. Peripheral

3. Dedifferentiated

4. Mesenchymal

5. Clear cell

Fibrogenic tumors

Fibrosarcoma

Fibrohistiocytic tumors

Malignant fibrous histiocytoma

Giant cell tumor

Malignancy in giant cell tumor

Notochordal tumors

Chordoma

Vascular tumors

Angiosarcoma

Smooth muscle tumors

Leiomyosarcoma

Lipogenic tumors

Liposarcoma

Miscellaneous tumors

Adamantinoma

Hematopoietic tumors (see respective sections)

1. Plasma cell myeloma

2. Malignant lymphoma, NOS

Work-up

1. History and physical examination

2. Laboratory tests: CBC with differential; electrolytes; liver function tests; mineral panel, including alkaline phosphatase; lactate dehydrogenase

3. Plain films of affected bone

4. Chest x-ray (PA and lateral)

5. CT scan of chest, abdomen, and pelvis (particularly chest because 80% of metastatic lesions occur here)

6. MRI to ascertain extent of the tumor, involvement of surrounding neurovascular structures, invasion of the adjacent joint, and the presence of skip metastases

7. Bone scan to identify skip lesions within affected bones or distant metastatic disease

8. Bone marrow aspirate for light microscopy examination in the case of Ewing sarcoma

9. No radiologic studies are pathognomonic, so bone biopsy remains essential to diagnosis

10. Echocardiogram or MUGA scan to determine cardiac ejection fraction as clinically indicated

11. Audiogram before cisplatin chemotherapy

Surgical Staging

Clinical Staging: IUCC and TNM Staging

Histologic Grading Systems for Assessing Response to Induction Chemotherapy in Osteosarcoma

5-Year Survival

Regimen: High-Dose Methotrexate, Cisplatin, and Doxorubicin

Meyers PA et al. J Clin Oncol 2005;23:2004–2011

The regimen consists of 10 weeks of induction chemotherapy followed by limb-sparing surgery or amputation, which is followed by adjuvant maintenance chemotherapy beginning in week 12 and continuing until week 31

Note: Adjuvant maintenance chemotherapy should begin at week 12 provided wound healing is adequate

Hydration before and after cisplatin: ≥1000 mL 0.45% sodium chloride injection (0.45% NS); administer intravenously over a minimum of 2–4 hours

Cisplatin 120 mg/m²; administer intravenously in 150–1000 mL 0.9% sodium chloride injection (0.9% NS) over 4 hours, for 4 cycles, during weeks 0 and 5 in the induction phase and weeks 12 and 17 in the maintenance phase (total dosage/cycle = 120 mg/m²)

Note: Encourage patients to increase oral intake of nonalcoholic fluids, and monitor serum electrolytes and replace as needed (potassium, magnesium, sodium)

Doxorubicin 25 mg/m² per day; administer intravenously in 50–1000 mL 0.9% NS or 5% dextrose injection (D5W) over 24 hours for 3 consecutive days, on days 1–3, for 6 cycles, during weeks 0 and 5 in the induction phase, and weeks 12, 17, 22, and 27 in the maintenance phase (total dosage/cycle = 75 mg/m²)

Hydration: 1500–3000 mL/m² per day; administer intravenously. Use a solution containing a total amount of sodium not >0.9% NS (ie, ≤154 mEq sodium/1000 mL) by intravenous infusion during methotrexate administration and for at least 24 hours afterward

• Fluid administration may commence 2–12 hours before starting methotrexate, depending on a patient's fluid status

• Urine output should be at least 100 mL/hour before starting methotrexate infusion

• Maintain hydration at a rate that maintains urine output ≥100 mL/hour until the serum methotrexate concentration is <0.1 μmol/L

• Urine pH should be increased within the range ≥7.0 to ≤8.0 to enhance methotrexate solubility and ensure elimination

  • 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 the parenteral solution to maintain urine pH ≥7.0 to ≤8.0

Methotrexate 12,000 mg/m² (maximum dose = 20,000 mg); administer intravenously in 500–2000 mL 0.9% NS or D5W (or saline and dextrose combinations) over 4 hours for 12 cycles during weeks 3, 4, 8, and 9 in the induction phase, and weeks 15, 16, 20, 21, 25, 26, 30, and 31 in the maintenance phase (total dosage/cycle = 12,000 mg/m²; maximum dose/cycle = 20,000 mg)

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

Leucovorin 10 mg (a fixed dose); administer intravenously in 25–250 mL 0.9% NS or D5W over 15 minutes every 6 hours, starting 24 hours after methotrexate administration began and continuing until the serum methotrexate concentration is <0.1 μmol/L (ie, <1 × 10^-7 mol/L, or <100 nmol/L)

Note: Leucovorin may be administered orally after completing 1 day of parenteral administration if patients are compliant, are not vomiting, and have no other potentially mitigating complications

Leucovorin 10 mg (fixed dose); administer orally every 6 hours until the serum methotrexate concentration is <0.1 μmol/L (ie, <1 × 10⁻⁷ mol/L, or <100 nmol/L)

Leucovorin rescue for delayed methotrexate excretion:

• Hydration, urinary alkalinization, and a more intensive leucovorin regimen are required if methotrexate excretion is delayed (eg, worsening renal function, effusions present)

• If 24 hours after the completion of methotrexate administration a patient's serum creatinine is increased by ≥50% above the baseline value, or if serum methotrexate concentration is ≥5 μmol/L (≥5 × 10⁻⁶ mol/L), increase the leucovorin dosage and schedule to 100 mg/m² per dose intravenously (not orally) every 3 hours until serum methotrexate level is <0.1 μmol/L (<1 × 10⁻⁷ mol/L, <100 nmol/L); then resume leucovorin 10 mg/dose orally or intravenously every 6 hours until serum methotrexate concentration is <0.05μmol/L (<5 × 10⁻⁸ mol/L, or <50 nmol/L), or until undetectable (if the lower limit of assay sensitivity is ≥0.05 μmol/L [≥5 × 10⁻⁸ mol/L, or ≥50 nmol/L])

Supportive Care

Antiemetic prophylaxis

Emetogenic potential during cycles with cisplatin + doxorubicin is HIGH. Potential for delayed symptoms

Emetogenic potential with doxorubicin alone is MODERATE

Emetogenic potential with methotrexate is MODERATE

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 per day by subcutaneous injection, or

Sargramostim (GM-CSF) 250 mcg/m² per day by subcutaneous injection

• Begin use from 24–72 hours after doxorubicin is completed

• Discontinue use at least 24 hours before resuming chemotherapy

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

• Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—recommended

• Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Treatment Modifications

Patient Population Studied

A prospective randomized intergroup phase III study of newly diagnosed patients with histologically confirmed high-grade, intramedullary osteosarcoma who were 30 years of age or younger. There were 677 patients enrolled without clinically detectable metastases; 340 received this regimen, including 168 who also received liposomal muramyl tripeptide

Efficacy (N = 172)

Toxicity (N = 172)

Therapy Monitoring

1. During treatment cycles: Daily renal function

2. After high-dose systemic methotrexate administration: Daily methotrexate levels

3. Before each cycle: CBC with differential, serum electrolytes, BUN, and creatinine

Regimen: Etoposide + High-Dose Ifosfamide + Mesna

Goorin AM et al. J Clin Oncol 2002;20:426–433

This regimen was initially developed for newly diagnosed osteosarcoma and included high-dose methotrexate, cisplatin, and doxorubicin as part of the continuation therapy. The protocol summarized here assumes that patients previously received high-dose methotrexate, cisplatin, and doxorubicin as part of their upfront therapy

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE. Potential for delayed symptoms

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 per day by subcutaneous injection, or

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

• Begin use on day 6, at least 24 hours after myelosuppressive chemotherapy is completed

• Continue daily filgrastim use after the neutrophil nadir until ANC ≥5000/mm³ on 2 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 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 or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—consider concomitant use of clotrimazole during periods of neutropenia

• Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Oral care

Prophylaxis and treatment for mucositis/stomatitis

General advice:

• Encourage patients to maintain intake of non-alcoholic fluids

• Evaluate patients for oral pain and provide analgesic medications

• Consider histamine (H₂-subtype) receptor antagonists (eg, ranitidine, famotidine), or a proton pump inhibitor for epigastric pain

• Lactobacillus sp.-containing probiotics may be beneficial in preventing diarrhea

Patients with intact oral mucosa:

• Clean the mouth, tongue, and gums by brushing after every meal and at bedtime with an ultra-soft toothbrush with fluoride toothpaste

• Floss teeth gently every day unless contraindicated. If gums bleed and hurt, avoid bleeding or sore areas, but floss other teeth

• Patients may use saline or commercial bland, non-alcoholic rinses

  • Do not use mouthwashes that contain alcohols

If mucositis or stomatitis is present:

• Keep the mouth moist utilizing water, ice chips, sugarless gum, sugar-free hard candies, or a saliva substitute

• Rinse mouth several times a day to remove debris

  • Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse

  • Do not use mouthwashes that contain alcohols

• Foam-tipped swabs (eg, Toothettes^®) are useful in moisturizing oral mucosa, but ineffective for cleansing teeth and removing plaque

• Advise patients who develop mucositis to:

  • Choose foods that are easy to chew and swallow

  • Take small bites of food, chew slowly, and sip liquids with meals

  • Encourage soft, moist foods such as cooked cereals, mashed potatoes, and scrambled eggs

  • For trouble swallowing, soften food with gravies, sauces, broths, yogurt, or other bland liquids

  • Avoid sharp, crunchy foods; hot, spicy or highly acidic foods (eg, citrus fruits and juices); sugary foods; toothpicks; tobacco products; alcoholic drinks

Treatment Modifications

Repeat chemotherapy 3 weeks after the initiation of treatment if ANC >1,000/μL and the platelet count >120,000/μL

Therapy Monitoring

1. Before each cycle: CBC with differential, serum electrolytes, BUN, and creatinine

2. During treatment cycles: Daily serum electrolytes, BUN, and creatinine; CBC with differential at least twice weekly

Patient Population Studied

A prospective phases II/III trial in 41 evaluable patients ≤30 years of age with measurable, newly diagnosed, biopsy-proven, high-grade, metastatic osteosarcoma with normal renal, hepatic, and bone marrow profile and ECOG performance status ≤2

Efficacy (N = 23–41)

Toxicity (N = 41)

Notes

1. Although few patients were treated, the response to ifosfamide and etoposide seemed to be dose dependent

2. This combination may be more active against bony metastases than other regimens

Regimen: Recurrent or Refractory Bone [or Soft-Tissue Sarcoma] (Children and Young Adults): Gemcitabine + Docetaxel

Navid F et al. Cancer 2008;113:419–425

Gemcitabine 675 mg/m² per dose; administer intravenously, diluted in 0.9% sodium chloride injection (0.9% NS) to a concentration as low as 0.1 mg/mL, over 90 minutes for 2 doses, on days 1 and 8, every 21 days (total dosage/cycle = 1350 mg/m²)

Premedication for docetaxel:

Dexamethasone 8 mg/dose; administer orally twice daily for 3 days, starting 1 day before docetaxel administration (total dose/cycle = 48 mg)

Optional premedication for docetaxel:

• Diphenhydramine HCl 25 mg; administer orally 30–60 minutes or intravenously 5–30 minutes prior to docetaxel administration

• Ranitidine 150 mg; administer orally 30–60 minutes prior to docetaxel administration, or

• Ranitidine 50 mg; administer intravenously 5–30 minutes prior to docetaxel administration

Docetaxel 75–100 mg/m²; administer intravenously, in a volume of 0.9% NS or D5W sufficient to produce a docetaxel concentration within the range 0.3–0.74 mg/mL, over 60 minutes, on day 8 after completing gemcitabine administration, every 21 days (total dosage/cycle = 75–100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential 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 per day by subcutaneous injection, or

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

• Begin use on cycle day 9; that is, 24 hours after myelosuppressive chemotherapy is completed

• Continue daily filgrastim use until ANC ≥10,000/mm³ on 2 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 administering myelosuppressive treatment

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 retrospective analysis of 22 patients with recurrent or progressive bone or soft-tissue sarcoma

Therapy Monitoring

1. At start of therapy: Clinical examination and laboratory testing

2. Day 1 of each treatment cycle: Physical examination, ECOG PS, complete blood count with leukocyte differential count, and serum chemistries

3. Weekly CBC with leukocyte differential count: At least the first 6 cycles of therapy

4. After every 2 cycles of therapy: Tumor measurements

Treatment Modifications

Efficacy (N = 14)

Toxicity (N = 22)

Primary Malignant Bone Tumors: Ewing Sarcoma: Epidemiology

Stage at Diagnosis

5-Year Survival

Pathology

Ewing sarcoma family of tumors (includes primitive neuroectodermal tumors):

1. Rare tumors arising in the bone marrow from primitive neural crest elements

2. Constitute approximately 10% of bone sarcomas

3. Subtypes include:

   • Classic Ewing sarcoma (most commonly associated with bone)

   • Primitive neuroectodermal tumor (generally not associated with bones)

4. Distinguished immunohistochemically from other pediatric tumors by expression of the MIC2 gene

5. Most commonly detected translocation is t(11;22)(q24;q12), one of a series of related translocations that occur in >95% of the Ewing sarcoma family of tumors (including primitive neuroectodermal tumors)

6. The t(11;22) translocation joins the Ewing sarcoma gene EWS on chromosome 22 to friend leukemia insertion (FLI 1) on chromosome 11 (ie, t[11;22])

   Note: FLI1 is a member of the ETS (E-twenty six) family

7. The EWS-FLI1 fusion transcript encodes a 68-kDa protein with 2 primary domains

   • EWS domain = a potent transcriptional activator

   • FLI1 domain = a highly conserved ETS DNA-binding domain

     The EWS-FLI1 fusion protein thus acts as an aberrant transcription factor

8. In an individual patient, t(11;22) fuses one of many observed combinations of exons from EWS and FLI1 to form the fused message. Most common combination = EWS exon 7 fused to FLI1 exon 6 ("7/6") in ≈50–64% of tumors of the Ewing sarcoma family

Regimen: Newly Diagnosed—Ewing Sarcoma, Primitive Neuroectodermal Tumor of Bone, Primitive Sarcoma of Bone: Vincristine, Cyclophosphamide, and Doxorubicin or Dactinomycin alternating with Ifosfamide and Etoposide

Grier HE et al. N Engl J Med 2003;348:694–701

Patients receive 2 complete courses of alternating induction chemotherapy (1 course includes 1 cycle with vincristine, doxorubicin, and cyclophosphamide followed by 1 cycle with ifosfamide and etoposide). Local therapy (surgery or radiation) occurs at week 12 and, after recovery, adjuvant chemotherapy with the same chemotherapy regimens ensues for a further 7 cycles of vincristine, doxorubicin, and cyclophosphamide, in alternation with 6 cycles of ifosfamide and etoposide (total: 17 cycles of chemotherapy)

Cycles of vincristine, doxorubicin (or dactinomycin), and cyclophosphamide + mesna:

Vincristine 2 mg/m² (maximum single dose "capped" at 2 mg); administer by intravenous injection over 1–3 minutes on day 1, every 42 days (total dosage/cycle = 2 mg/m²; maximum dose/cycle = 2 mg)

Doxorubicin 75 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 42 days (total dosage/cycle = 75 mg/m²; total cumulative dosage permitted = 375 mg/m²)

• When a total doxorubicin dosage of 375 mg/m² has been administered, no additional doxorubicin is given. Instead, doxorubicin is replaced by:

Dactinomycin 1.25 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 42 days (total dosage/cycle = 1.25 mg/m²)

• Dactinomycin is used only after doxorubicin is discontinued from the regimen

An admixture containing cyclophosphamide 1200 mg/m² + mesna 240 mg/m²; administer intravenously in 100–250 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 15–30 minutes on day 1 every 42 days (total cyclophosphamide dosage/cycle = 1200 mg/m²)

Then, either:

Mesna 240 mg/m² per dose; administer intravenously diluted with 0.9% NS or D5W to a concentration of 1–20 mg/mL, over 15 minutes for 2 doses at 4 hours and 8 hours after cyclophosphamide administration is completed, on day 1, every 42 days (total mesna dosage/cycle = 720 mg/m²; includes 240 mg dose given with cyclophosphamide), or

Mesna 480 mg/m² per dose; administer orally for 2 doses at 2 hours and 6 hours after cyclophosphamide administration is completed on day 1, every 42 days (total mesna dosage/cycle = 1200 mg/m²; includes 240 mg dose given with cyclophosphamide)

Cycles of ifosfamide + mesna and etoposide:

An admixture containing ifosfamide 1800 mg/m² + mesna 360 mg/m² per day; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce ifosfamide concentrations between 0.6 and 20 mg/mL, over 60 minutes for 5 consecutive days, on days 22–26, every 42 days (total ifosfamide dosage/cycle = 9000 mg/m²)

Then, either:

Mesna 360 mg/m² per dose; administer intravenously diluted with 0.9% NS or D5W to a concentration of 1–20 mg/mL, over 15 minutes for 2 doses per day at 4 hours and 8 hours after ifosfamide administration is completed, for 5 consecutive days, on days 22–26, every 42 days (total mesna dosage/cycle = 5400 mg/m²; includes 360 mg doses given daily with cyclophosphamide), or

Mesna 720 mg/m² per dose; administer orally for 2 doses per day at 2 hours and 6 hours after ifosfamide administration is completed, for 5 consecutive days, on days 22–26, every 42 days (total mesna dosage/cycle = 9000 mg/m²; includes 360 mg doses given daily with cyclophosphamide)

Etoposide 100 mg/m² per day; administer intravenously diluted with 0.9% NS to a concentration of 0.2–0.4 mg/mL over 60 minutes for 5 consecutive days, on days 22–26, every 42 days (total dosage/cycle = 500 mg/m²)

After the first 4 cycles of chemotherapy (2 complete courses, 12 weeks), local control is planned to consist of radiation therapy, surgery, or both

Radiation alone:

• Treat the extent of the initial soft tissue and osseous involvement with a 3-cm margin to a dose 4500 cGy

• Then treat with an additional 1080 cGy to the postchemotherapy, preradiation therapy tumor volume

Surgery without residual disease:

• No radiation therapy is administered

Gross residual tumor after surgery

• Treat as if treating with radiation alone

Microscopic residual disease after surgery

• Treat the extent of the initial soft tissue and osseous involvement with a 1-cm margin to a dose 4500 cGy

Supportive Care

Antiemetic prophylaxis

Emetogenic potential during cycles with vincristine, doxorubicin or dactinomycin, and cyclophosphamide is HIGH. Potential for delayed symptoms

Emetogenic potential during cycles with ifosfamide and etoposide is MODERATE

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 per day by subcutaneous injection, or

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

• Begin use at least 24 hours after myelosuppressive chemotherapy is completed (days 6 and 27)

• Continue daily filgrastim use after the neutrophil nadir until ANC ≥5000/mm³ on 2 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 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 or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—consider concomitant use of clotrimazole during periods of neutropenia

• Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Treatment Modifications

None specified

Patient Population Studied

This was a prospective randomized intergroup phase III study in newly diagnosed patients with primary bone tumors who were 30 years of age or younger. Patients had adequate renal, liver, and cardiac function; 300 patients were enrolled and 198 received this regimen

Efficacy (N = 198)

Therapy Monitoring

1. Weekly: CBC with differential

2. Before each cycle: CBC with differential, serum creatinine, liver function tests, and urinalysis

3. Response evaluation: At conclusion of first 4 cycles of chemotherapy

Regimen: Cyclophosphamide + Topotecan

Saylors RL, III et al. J Clin Oncol 2001;19:3463–3469

Pretreatment hydration: 500 mL/m² 0.9% sodium chloride injection (0.9% NS), or 0.45% sodium chloride injection, or 5% dextrose injection/0.45% sodium chloride injection; administer intravenously over 2–4 hours before starting chemotherapy

Cyclophosphamide 250 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS or 5% dextrose injection (D5W) over 30 minutes for 5 consecutive days, on days 1–5, every 21 days (total dosage/cycle = 1250 mg/m²)

Topotecan HCl 0.75 mg/m² per day; administer intravenously in 50–250 mL 0.9% NS or D5W over 30 minutes for 5 consecutive days, after cyclophosphamide on days 1–5, every 21 days (total dosage/cycle = 3.75 mg/m²)

Posttreatment hydration: Hydration continues orally or intravenously at a rate of 3000 mL/m² per 24 hours until 24 hours after the last dose of chemotherapy is completed

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

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 per day by subcutaneous injection, or

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

• Begin use at least 24 hours after myelosuppressive chemotherapy is completed (day 6)

• Continue daily filgrastim use after the neutrophil nadir until ANC ≥5000/mm³ on 2 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 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 or no prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—consider concomitant use of clotrimazole during periods of neutropenia

• Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Toxicity (N = 307 Cycles)

Therapy Monitoring

1. Daily during therapy: Urinalysis

2. Twice weekly: CBC with differential until recovery from hematopoietic toxicity

3. Weekly: Physical examination

4. Before each cycle: Serum creatinine, LFTs with bilirubin, serum electrolytes, including calcium, magnesium, and phosphorus

5. Response evaluation: After the first and second cycles, then after every 2 cycles

Treatment Modifications

None specified

Patient Population Studied

A study of 91 pediatric patients with recurrent or refractory solid tumors, including Ewing sarcoma (n = 17), rhabdomyosarcoma (n = 15), and neuroblastoma (n = 13)

Efficacy

Notes

Responses were observed in patients who had received >1 year of intensive alkylating agent therapy and/or ablative therapy with autologous stem cell rescue

Regimen: Relapsed/Refractory Ewing Sarcoma or Peripheral Neuroectodermal Tumor (PNET): Temozolomide + Irinotecan

Casey DA et al. Pediatr Blood Cancer 2009;53:1029–1034

Wagner LM et al. Pediatr Blood Cancer 2007;48:132–139

Temozolomide 100 mg/m² per day; administer orally for 5 consecutive days, on days 1–5, 1 hour before irinotecan, every 21–28 days (total dosage/cycle = 500 mg/m²)

Note: Temozolomide doses are rounded to the nearest 5 mg by using commercially available products

Irinotecan 10–20 mg/m² per dose; administer intravenously, diluted with 5% dextrose injection to a concentration within the range of 0.12–2.8 mg/mL, over 90 minutes for 10 doses, on days 1–5 and days 8–12, every 21–28 days (total dosage/cycle = 100–200 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

Acute cholinergic syndrome

Atropine sulfate 0.25–1 mg 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 minutes 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

• The potential for developing diarrhea and abdominal pain should be discussed with all patients and their caretakers, and instructions given to start loperamide immediately if these symptoms occur and to ensure adequate hydration is maintained. See "Dose Modifications" (below) for instructions

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 2 tablets 4 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 2 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 primary prophylaxis and treatment during latent or delayed onset diarrhea:

Consider the following to prevent or lessen irinotecan-associated diarrhea:

• Prophylactic oral cefixime 8 mg/kg (maximum dose of 400 mg) orally once daily, beginning 1–2 days prior to the start of irinotecan therapy and continuing continue until completion of the cycle, alternatively:

• Cefpodoxime proxetil 5 mg/kg/day per day orally twice daily (maximum dose of 200 mg twice daily)

  • Previous studies suggest prophylaxis with cephalosporin antibiotics can ameliorate irinotecan-associated diarrhea by reducing the enteric bacteria responsible for producing β-glucuronidase, which regenerates in the gut irinotecan's toxic metabolite, SN-38, by cleaving the glucuronide moiety from SN-38 (Wagner LM et al. Pediatr Blood Cancer 2008;50:201–207)

• Alternatively, activated charcoal at a dose equal to 5 times the irinotecan dose up to a maximum dose of 260 mg orally 3 times daily during irinotecan therapy (Michael M et al. J Clin Oncol 2004;22:4410–4417)

  Antibiotic treatment 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 a patient is hospitalized with prolonged diarrhea, and should be continued until diarrhea resolves

Dose Modifications

Efficacy (N = 14)

Efficacy (N = 20)

Table Graphic Jump Location

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Efficacy (N = 20)^✫

Casey DA et al. Pediatr Blood Cancer 2009;53:1029–1034

Best response achieved (n = 19)
Complete response†	5 patients‡
Partial response	7 patients
Progressive disease	7 patients
Stable disease	0
Overall objective response	63%
Overall survival (n = 20)§	55%§
Median TTP
All evaluable patients (n = 20)	8.3 months
Patients with recurrent ES (n = 14)	16.2 months
>2-year remission after primary diagnosis (n = 6)	22.8 months
<2-year remission after primary diagnosis (n = 14)	3.7 months
Localized disease at initial diagnosis (n = 9)	16.4 months
Metastatic disease at initial diagnosis (n = 11)	2.4 months
Single-site disease recurrence	24.3 months
Multiple-site recurrence	2.4 months
✫WHO criteria †Each of the 5 completed 12 planned cycles of irinotecan/temozolomide; all were in remission with a median follow-up time of 28.3 months ‡Two patients disease free > additional radiation or chemotherapy. Five patients experienced PD > a median of 6 months and 9 cycles of therapy §Eleven patients (55%) alive with median follow up 25.7 months at conclusion of cohort analysis Four of 6 achieved a CR and were in remission >12 cycles of therapy with a median follow-up time of 26.4 months

Toxicity

Patient Population Studied

All patients had either progressive disease (PD) during initial therapy (n = 5) or relapse within 2 years of diagnosis (n = 1). Twelve patients had metastatic disease at diagnosis, including 5 with bone and/or marrow metastases

Therapy Monitoring

1. Prior to enrollment: Complete medical history, clinical examination, performance status, hematologic and serum chemistries cardiac evaluation in case of prior treatment with anthracyclines or mediastinal irradiation, and tumor target assessment

2. Day 1 of each treatment cycle: Physical examination, ECOG PS, complete blood count with leukocyte differential count, and serum chemistries

3. Weekly CBC with leukocyte differential count: At least the first 6 cycles of therapy

4. After every 2 cycles of therapy: Tumor measurements

Epidemiology

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

Cellular Classification of Adult Soft-Tissue Sarcoma

Soft-tissue sarcomas are classified histologically according to the soft-tissue cell of origin. The histologic grade reflects the metastatic potential of these tumors more accurately than the classic cellular classification listed below. Pathologists assign grade based on the number of mitoses per high-powered field, presence of necrosis, cellular and nuclear morphology, and the degree of cellularity. Discordance among expert pathologists can reach 40%

Alphabetical Listing (Percent of All Soft-Tissue Sarcomas)

(Note, however, that the frequency of histologic type is site dependent)

• Alveolar soft-part sarcoma (≤3%)

• Angiosarcoma (≤3%)

• Dermatofibrosarcoma protuberans (≤3%)

• Epithelioid sarcoma (≤3%)

• Extraskeletal chondrosarcoma (≤3%)

• Extraskeletal osteosarcoma (≤3%)

• Fibrosarcoma (≤3%)

• Gastrointestinal stromal tumor (GIST) (≤3%) (see separate section on GIST)

• Leiomyosarcoma (≈12%)

• Liposarcoma (≈15–25%)

• Malignant fibrous histiocytoma (≈28–40%)

• Malignant hemangiopericytoma (≤3%)

• Malignant mesenchymoma (≤3%)

• Malignant schwannoma (≤3%)

• Malignant peripheral nerve sheath tumor (≈6%)

• Peripheral neuroectodermal tumors (≤3%)

• Rhabdomyosarcoma (≈5%) (see separate section on rhabdomyosarcoma)

• Synovial sarcoma (≈10%)

• Sarcoma, NOS (not otherwise specified) (≤3%)

Abraham JA et al. Ann Surg Oncol 2007;14:1953–1967

Alvegård TA, Berg NO. J Clin Oncol 1989;7:1845–1851

Fayette J et al. Ann Oncol 2007;18:2030–2036

Fury MG et al. Cancer J 2005;11:241–247

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Marcus SG et al. Arch Surg 1993;128:1336–1343

Mendenhall WM et al. Cancer 2004;101:2503–2508

van Ruth S et al. Eur J Cancer 2002;38:1324–1328

Work-up

1. History and physical examination

2. Laboratory tests: CBC with differential, electrolytes, liver function tests, and mineral panel, including alkaline phosphatase and lactate dehydrogenase

3. Radiologic imaging modality is variable and dictated by the site of disease. This involves a combination of plain x-rays, CT, MRI, and PET imaging. Although CT remains the imaging modality of choice in the staging of retroperitoneal soft-tissue sarcoma, MRI is used more frequently to stage soft-tissue sarcoma of the extremity

4. Bone marrow aspirate for light microscopy examination in Ewing sarcoma

5. No radiologic studies are pathognomonic, so biopsy remains essential to diagnosis. Carefully plan biopsy to establish grade and histologic subtype and if needed molecular and cytogenetic studies

6. Echocardiogram or MUGA scan to determine cardiac ejection fraction as clinically indicated

Disease Distribution

Soft-Tissue Sarcomas: Adult Soft-Tissue Sarcomas, Other Than GIST: Classification of Malignant Adult Soft-Tissue Sarcomas

1. Fibrous tumors

   1. Fibrosarcoma:

      • (1)  Adult fibrosarcoma

      • (2)  Inflammatory fibrosarcoma

2. Fibrohistiocytic tumors

   1. Malignant fibrous histiocytoma

      • (1)  Storiform-pleomorphic

      • (2)  Myxoid (myxofibrosarcoma)

      • (3)   Giant cell (malignant giant cell tumor of the soft parts)

      • (4)  Inflammatory

3. Lipomatous

   1. Liposarcoma

      • (1)  Well-differentiated liposarcoma

        • (a)  Lipoma-like liposarcomas

        • (b)  Sclerosing liposarcoma

        • (c)  Inflammatory liposarcoma

      • (2)  Dedifferentiated liposarcoma

      • (3)  Myxoid or round cell liposarcoma

      • (4)  Pleomorphic liposarcoma

4. Smooth muscle tumors

   1. Leiomyosarcoma

   2. Epithelioid leiomyosarcoma

5. Skeletal muscle tumors

   1. Rhabdomyosarcoma

      • (1)  Embryonal rhabdomyosarcoma

      • (2)  Botryoid rhabdomyosarcoma

      • (3)  Spindle cell rhabdomyosarcoma

      • (4)  Alveolar rhabdomyosarcoma

      • (5)  Pleomorphic rhabdomyosarcoma

   2. Rhabdomyosarcoma with ganglionic differentiation (ectomesenchymoma)

6. Tumors of the blood and lymph nodes

   1. Epithelioid hemangioendothelioma

   2. Angiosarcoma and lymphangiosarcoma

   3. Kaposi sarcoma

7. Perivascular tumors

   1.  Malignant glomus tumor (glomangiosarcoma)

   2.  Malignant hemangiopericytoma

8. Synovial tumors

   1. Malignant giant cell tumor of tendon sheath

9. Neural tumors

   1. Malignant peripheral nerve sheath tumor (MPNST)

      • (1)   Malignant triton tumor (MPSNT with rhabdomyosarcoma)

      • (2)  Glandular MPNST

      • (3)  Epithelioid MPNST

   2. Malignant granular cell tumor

   3. Primitive neuroectodermal tumor

      • (1)  Neuroblastoma

      • (2)  Ganglioneuroblastoma

      • (3)   Neuroepithelioma (peripheral neuroectodermal tumor)

10. Paraganglionic tumors

    1. Malignant paraganglioma

11. Extraskeletal cartilaginous and osseous tumors

    1. Extraskeletal chondrosarcoma

       • (1)  Myxoid chondrosarcoma

       • (2)  Mesenchymal chondrosarcoma

    2. Extraskeletal osteosarcoma

12. Pluripotential mesenchymal tumors

    1. Malignant mesenchyma

13. Miscellaneous tumors

    1. Alveolar soft-part sarcoma

    2. Epithelioid sarcoma

    3. Malignant extrarenal rhabdoid tumor

    4. Desmoplastic small cell tumor

    5. Ewing sarcoma—extraskeletal

    6. Clear cell sarcoma

    7. Gastrointestinal stromal tumors

    8. Synovial sarcoma

    9. Dermatofibrosarcoma protuberans

Brennan MF et al. Sarcomas of the soft tissues and bone. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1581–1637

Staging

Follow-up

• There are no published data to indicate the optimal routine follow-up policy of surgically treated patients with localized disease

• Malignancy grade affects the likelihood and speed at which relapses may take place. Risk assessment is based on:

  • Tumor grade

  • Tumor size

  • Tumor site

• High-risk patients generally relapse within 2–3 years

• Low-risk patients may relapse later, although it is less likely

• Relapses most often occur to the lungs

• Early detection of local or metastatic recurrence to the lungs may have prognostic implications. Lung metastases typically are asymptomatic at a stage in which they are suitable for surgery

5-Year Survival

Epidemiology

Incidence: 350 estimated new cases in the United States per year; rhabdomyosarcoma represents 50% of all diagnosed soft-tissue sarcomas

Staging

Pathology

Disease Sites at Diagnosis

5-Year Survival

Regimen: Vincristine + Dactinomycin + Cyclophosphamide (VAC)

Crist WM et al. J Clin Oncol 2001;19:3091–3102

Vincristine 1.5 mg/m² per dose (maximum single dose = 2 mg); administer by intravenous injection over 1–2 minutes on day 1 (total dosage during the weeks in which vincristine is administered = 1.5 mg/m²; maximum dose/treatment = 2 mg)

Dactinomycin 0.015 mg/kg per day (maximum single dose = 0.5 mg); administer by intravenous injection over 1–2 minutes for 5 consecutive days, on days 1–5 (total dosage during the weeks in which dactinomycin is administered = 0.075 mg/kg; maximum dose/cycle = 2.5 mg)

An admixture containing cyclophosphamide 2200 mg/m² + mesna 120 mg/m²; administer intravenously in 100–1000 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 10–30 minutes, on day 1 (total dosage during the weeks in which cyclophosphamide is administered = 2200 mg/m²), followed by

Mesna 1200 mg/m²; administer intravenously in 250–1000 mL of 0.9% NS or D5W over 24 hours (rate of 50 mg/m² per hour), starting immediately after each dose of cyclophosphamide (total dosage during the weeks in which cyclophosphamide is administered = 1320 mg/m²; includes 120 mg administered with cyclophosphamide)

• The administration schedules for vincristine, dactinomycin, and cyclophosphamide appears in the table (above)

Supportive Care: Antiemetic prophylaxis

Emetogenic potential during weeks with vincristine, dactinomycin, and cyclophosphamide is HIGH. Potential for delayed symptoms

Emetogenic potential on days with vincristine and cyclophosphamide is HIGH

Emetogenic potential on days with vincristine alone is MINIMAL

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 from 24 hours after myelosuppressive chemotherapy is completed; that is, day 6 during VAC cycles and day 2 during vincristine and cyclophosphamide (VC) cycles

• Filgrastim may be given on days when vincristine is administered alone

• Continue daily filgrastim use until ANC ≥15,000/mm³

• Discontinue daily filgrastim use at least 24 hours before administering resuming myelosuppressive treatment (containing dactinomycin or cyclophosphamide)

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

• Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—recommended

• Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Treatment Modifications

Toxicity (N = 884)

Patient Population Studied

A study of 884 patients with previously untreated nonmetastatic rhabdomyosarcoma who had undergone surgery. Randomization to 1 of 4 study arms: VA (vincristine + dactinomycin, n = 134), VAC (n = 291), VAI (vincristine + dactinomycin + ifosfamide, n = 223), and VIE (vincristine, ifosfamide, and etoposide, n = 236). Patients with preexisting renal abnormalities predisposing to nephrotoxicity were assigned to VAC

Therapy Monitoring

1. Daily during therapy: Urinalysis

2. Twice per week: CBC with differential until recovery from hematopoietic toxicity

3. Weekly: Physical examination

4. Before each cycle: Serum creatinine, LFTs with bilirubin, serum electrolytes, including calcium, magnesium, and phosphorus

5. Response evaluation: After the third, sixth, and eighth cycles

Efficacy (N = 134)

Regimen: Irinotecan

Cosetti M et al. J Pediatr Hematol Oncol 2002;24:101–105

Irinotecan 20 mg/m² per dose; administer intravenously in a volume of 5% dextrose injection (preferred) or 0.9% sodium chloride injection sufficient to produce a concentration within a range of 0.12–2.8 mg/mL over 60 minutes for 10 doses, on days 1–5 and days 8–12, every 21–28 days (total dosage/cycle = 200 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be 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 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 minutes 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 2 tablets 4 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 2 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

Patient Population Studied

A study of 22 heavily pretreated children with multiply relapsed tumors. Four patients with rhabdomyosarcoma; the rest had other diagnoses, but clinically very similar

Efficacy (N = 4)

Toxicity (N = 22)

Treatment Modifications

Therapy Monitoring

1. Weekly: CBC with differential

2. Before each cycle: CBC with differential, LFTs with bilirubin

3. Response evaluation: After every 2 cycles

Intermediate Risk Rhabdomyosarcoma: Vincristine, Doxorubicin, Cyclophosphamide, and Etoposide/Ifosfamide (VDC/IE)

Arndt CAS et al. Eur J Cancer 1998;34:1224–1229

Arndt CAS et al. Pediatr Blood Cancer 2008;50:33–36

VINCRISTINE + DOXORUBICIN + CYCLOPHOSPHAMIDE (VDC)

Vincristine 1.5 mg/m² (maximum dose 2 mg); administer by intravenous injection over 1–2 minutes on day 1, during weeks 0, 1, 2, 6, 7, 8, 12, 18, 24, 30, and 36 (week 36, if VDC is given) (total dosage/week = 1.5 mg/m²; maximum dose/week = 2 mg)

Doxorubicin 37.5 mg/m² per day; administer by intravenous infusion in 25–1000 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 18 hours for 2 consecutive days, on days 1 and 2, during weeks 0, 6, 12, 18, 24, 30, and 36 (if VDC is given) (total dosage/week = 75 mg/m²)

An admixture of cyclophosphamide 600 mg/m² plus mesna 360 mg/m² per dose; administer by intravenous infusion, in a volume of 0.9% NS or D5W sufficient to produce a mesna concentration within the range of 1–20 mg/mL, over 15–60 minutes for 2 consecutive days, on days 1 and 2, during weeks 0, 6, 12, 18, 24, 30, and 36 (week 36, if VDC is given) (total cyclophosphamide dosage/week = 1200 mg/m²), followed each day by:

Mesna 360 mg/m² per dose; administer by intravenous infusion, in a volume of 0.9% NS or D5W sufficient to produce a mesna concentration within the range of 1–20 mg/mL, over 15–60 minutes every 3 hours for 4 doses per day, starting 3 hours after commencing administration of cyclophosphamide + mesna (a total of 5 mesna doses/day), for 2 consecutive days, days 1 and 2, during weeks 0, 6, 12, 18, 24, 30, and 36 (if VDC is given) (total dosage/week = 3600 mg/m²; includes 360 mg doses given with cyclophosphamide)

IFOSFAMIDE + ETOPOSIDE (IE)

An admixture of ifosfamide 1800 mg/m² plus mesna 360 mg/m² per dose; administer by intravenous infusion, in a volume of 0.9% NS or D5W sufficient to produce an ifosfamide concentration within the range of 0.6–20 mg/mL, and a mesna concentration within the range of 1–20 mg/mL over 15–60 minutes for 5 consecutive days, on days 1–5, during weeks 3, 9, 15, 21, 27, 33, 36 (week 36, if EI is given instead of VDC), and 39 (total ifosfamide dosage/week = 9000 mg/m²), followed each day by:

Mesna 360 mg/m² per dose; administer by intravenous infusion, in a volume of 0.9% NS or D5W sufficient to produce a mesna concentration within the range of 1–20 mg/mL, over 15–60 minutes, every 3 hours, for 4 doses per day, starting 3 hours after commencing administration of ifosfamide + mesna (a total of 5 mesna doses/day), for 5 consecutive days, on days 1–5, during weeks 3, 9, 15, 21, 27, 33, 36 (week 36, if EI is given instead of VDC), and 39 (total dosage/week = 9000 mg/m²; includes 360 mg doses given with cyclophosphamide)

Etoposide 100 mg/m² per day; administer intravenously, diluted in 0.9% NS to a concentration within the range of 0.2–0.4 mg/mL, over 60 minutes for 5 consecutive days, on days 1–5, during weeks 3, 9, 15, 21, 27, 33, 36 (week 36, if EI is given instead of VDC), and 39 (total dosage/week = 500 mg/m²)

Notes:

• Patients with positive cerebrospinal fluid cytology: Administer triple intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone

CNS treatment (confirmed CNS disease)—possible regimen^✫:

Methotrexate 6 mg per dose +

Cytarabine 30 mg per dose +

Hydrocortisone 15 mg per dose

Induction: All 3 drugs are given together, twice weekly for at least 4 consecutive weeks, or for 2 weeks after CSF specimens are without evidence of lymphoma, whichever is greater

Administer intrathecally in a volume of preservative-free 0.9% NS equivalent to the amount of CSF removed via lumbar puncture, intraventricular catheter or reservoir. Total doses/week:

• Methotrexate = 12 mg

• Cytarabine = 60 mg

• Hydrocortisone = 30 mg

Consolidation: All 3 drugs are given together, once weekly for 6 weeks. Administer intrathecally in a volume of preservative-free 0.9% NS equivalent to the amount of CSF removed via intraventricular catheter or reservoir. Total doses/week:

• Methotrexate = 6 mg

• Cytarabine = 30 mg

• Hydrocortisone = 15 mg