Combination Chemotherapy in Treating Patients With Previously Untreated Rhabdomyosarcoma

• Early response rate (ERR) (i.e., complete response/partial response [CR/PR]) at end of therapy & at 3, 5, and 10 yrs after completion of therapy [ Designated as safety issue: No ]
• Failure-free survival (FFS) at end of therapy & at 3, 5, and 10 yrs after completion of therapy [ Designated as safety issue: No ]
• Survival at end of therapy & at 3, 5, and 10 yrs after completion of therapy [ Designated as safety issue: No ]
• Acute and late effects (e.g., sterility, second malignancy, radiation effects, and growth effects) of these regimens continuously for up to 10 years [ Designated as safety issue: No ]

• Rate of second-look surgery in patients with bulk residual tumor at diagnosis and those who become "tumor free" or have microscopic tumor only and are treated with reduced dose radiation at the end of therapy [ Designated as safety issue: No ]
• Rate of local failure in selected patients with bulk residual tumors at diagnosis who undergo second-look resection and response-adjusted radiotherapy dose reduction ongoing for up to 10 years [ Designated as safety issue: No ]
• Preoperative radiotherapy followed by second-look surgery indicated for patients who respond poorly to induction chemotherapy [ Designated as safety issue: No ]
• Define and compare clinical features (demographics such as age, disease site and stage, node involvement, or outcome) of patient subgroups with alveolar rhabdomyosarcoma whose tumors carry t(2;13), t(1;13) or neither transloc. at end of the study [ Designated as safety issue: No ]
• Estimation of ERR, FFS, and survival of patients with alveolar rhabdomyosarcoma with t(2;13), t(1;13), or neither transloc. by pos. or neg. RTPCR on peripheral blood and marrow spec. at diagnosis and at end of tx [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy, such as dactinomycin, cyclophosphamide, vincristine, and topotecan, use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which combination chemotherapy regimen is more effective in treating rhabdomyosarcoma.

PURPOSE: This randomized phase III trial is comparing two different combination chemotherapy regimens to see how well each works in treating patients with previously untreated rhabdomyosarcoma or sarcoma.

OBJECTIVES:

• Compare the early response rates, failure-free survival, and survival of patients with intermediate-risk rhabdomyosarcoma treated with surgery, radiotherapy, and vincristine, dactinomycin, and cyclophosphamide (VAC) vs VAC alternating with vincristine, topotecan, and cyclophosphamide.
• Compare the acute and late effects of these two treatment regimens in these patients.
• Determine the rate of second-look surgery in selected patients with bulk residual tumor at diagnosis (i.e., Clinical Group III) and the proportion of these that render the patient tumor free or with microscopic tumor only.
• Determine the rate of local failure in selected patients with bulk residual tumors at diagnosis (i.e., Clinical Group III) who, after second-look resection, have response-adjusted radiotherapy dose reduction.
• Determine if preoperative radiotherapy followed by second-look surgery is feasible for selected patients with bulk residual disease (i.e., Clinical Group III) who respond poorly to induction chemotherapy.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to disease (embryonal histology, stage II or III, Clinical Group III vs embryonal histology, Clinical Group IV, less than 10 years of age vs alveolar or undifferentiated sarcoma histology, stage I, Clinical Group I vs alveolar or undifferentiated sarcoma histology, stage II or III, Clinical Group II or III). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive vincristine IV over 5-10 minutes once a week on weeks 0-12, 15, 18-24, 27, 30-36, and 39. Dactinomycin IV is administered over 15-20 minutes once a week on weeks 0, 3, 6, 9, 12, 21, 24, 27, 30, 33, 36, and 39. Cyclophosphamide IV is administered over 30-60 minutes once a week on weeks 0, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, and 39. After the initial 12 weeks of chemotherapy, depending on tumor shrinkage, patients may undergo surgery. After recovery from surgery, patients receive radiotherapy once a day, 5 days a week, during weeks 12-18. For patients receiving radiotherapy during weeks 0-6, dactinomycin is omitted during weeks 3 and 6 and administered during weeks 15 and 18. For patients receiving radiotherapy during weeks 12-18, dactinomycin is omitted during weeks 15 and 18. Patients showing an adequate response at week 24 continue chemotherapy during weeks 24-39.

Patients with Clinical Group III tumors of a parameningeal site with documented evidence of intracranial extension receive radiotherapy within the first 2 weeks of the initiation of the first course of chemotherapy (day 0).

Patients with Clinical Group II parameningeal tumors and Clinical Group III parameningeal tumors with base of skull erosion and/or cranial nerve palsy without evidence of intracranial extension receive radiotherapy on week 12 (day 84) or immediately thereafter.

Patients with Clinical Group IV parameningeal tumors with distant metastases receive radiotherapy to the primary site on week 12 (day 84). Patients with distant metastases confined to one site may receive radiotherapy to the metastatic site concurrently with therapy to the primary site if it began within 2 weeks of the initiation of chemotherapy (day 0).

• Arm II: Patients receive treatment as in arm I, except dactinomycin is replaced with topotecan IV over 15-30 minutes daily for 5 days during weeks 3, 9, 21, 27, 33, and 39.

All patients receive filgrastim (G-CSF) or sargramostim (GM-CSF) subcutaneously beginning 24 hours after completion of each course of chemotherapy and continuing 1 year, until hematopoietic recovery.

Patients are followed every 1-2 months for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 518 patients will be accrued for this study within 5 years.

• Biological: dactinomycin
• Biological: filgrastim
• Biological: sargramostim
• Drug: cyclophosphamide
• Drug: topotecan hydrochloride
• Drug: vincristine sulfate
• Procedure: surgical procedure
• Radiation: radiation therapy

• Lin C, Donaldson SS, Meza JL, Anderson JR, Lyden ER, Brown CK, Morano K, Laurie F, Arndt CA, Enke CA, Breneman JC. Effect of Radiotherapy Techniques (IMRT vs. 3D-CRT) on Outcome in Patients With Intermediate-Risk Rhabdomyosarcoma Enrolled in COG D9803-A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys. 2011 Apr 4; [Epub ahead of print]
• Rodeberg DA, Stoner JA, Garcia-Henriquez N, Randall RL, Spunt SL, Arndt CA, Kao S, Paidas CN, Million L, Hawkins DS. Tumor volume and patient weight as predictors of outcome in children with intermediate risk rhabdomyosarcoma: a report from the children's oncology group. Cancer. 2010 Dec 14; [Epub ahead of print]
• Rodeberg DA, Wharam MD, Lyden E, et al.: Second-look operation with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma (RMS): A report from the Children's Oncology Group (COG). [Abstract] J Clin Oncol 28 (Suppl 15): A-9504, 2010.
• Arndt CA, Stoner JA, Hawkins DS, Rodeberg DA, Hayes-Jordan AA, Paidas CN, Parham DM, Teot LA, Wharam MD, Breneman JC, Donaldson SS, Anderson JR, Meyer WH. Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803. J Clin Oncol. 2009 Sep 21; [Epub ahead of print]
• Arndt CA, Hawkins DS, Stoner JA, et al.: Randomized phase III trial comparing vincristine, actinomycin, cyclophosphamide (VAC) with VAC/V topotecan/cyclophosphamide (TC) for intermediate risk rhabdomyosarcoma (IRRMS). D9803, COG study. [Abstract] J Clin Oncol 25 (Suppl 18): A-9509, 528s, 2007.
• Arndt C, Hawkins D, Anderson JR, Breitfeld P, Womer R, Meyer W. Age is a risk factor for chemotherapy-induced hepatopathy with vincristine, dactinomycin, and cyclophosphamide. J Clin Oncol. 2004 May 15;22(10):1894-901. Erratum in: J Clin Oncol. 2004 Aug 15;22(16):3434. Correction of dosage error in text.
• Malempati S, Rodeberg DA, Donaldson SS, Lyden ER, Anderson JR, Hawkins DS, Arndt CA. Rhabdomyosarcoma in infants younger than 1 year: A report from the Children's Oncology Group. Cancer. 2011 Jan 24; [Epub ahead of print]
• Minn AY, Lyden ER, Anderson JR, Million L, Arndt CA, Brown K, Hawkins DS, Donaldson SS. Early Treatment Failure in Intermediate-Risk Rhabdomyosarcoma: Results From IRS-IV and D9803--A Report From the Children's Oncology Group. J Clin Oncol. 2010 Aug 16; [Epub ahead of print]
• Petricoin EF 3rd, Espina V, Araujo RP, Midura B, Yeung C, Wan X, Eichler GS, Johann DJ Jr, Qualman S, Tsokos M, Krishnan K, Helman LJ, Liotta LA. Phosphoprotein pathway mapping: akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res. 2007 Apr 1;67(7):3431-40.

DISEASE CHARACTERISTICS:

• Histologically proven disease of any of the following types:

  • Nonmetastatic alveolar rhabdomyosarcoma

    • Stage I, II, or III; Clinical Group I, II, or III

  • Stage II or III, Clinical Group III embryonal rhabdomyosarcoma

    • Botryoid
    • Spindle cell

  • Under 10 years, stage IV, Clinical Group IV embryonal rhabdomyosarcoma

    • Botryoid
    • Spindle cell

  • Undifferentiated sarcoma

    • Stage I, II, or III; Clinical Group I, II, or III

  • Ectomesenchymoma

    • Stage I, II, or III; Clinical Group I, II, or III, with alveolar features
    • Under 10 years, Stage IV, Clinical Group IV, with embryonal features
• No more than 6 weeks since initial surgical procedure (e.g., biopsy) giving the definitive diagnosis
• No parameningeal rhabdomyosarcoma with positive CSF cytology or multiple intracranial metastases

PATIENT CHARACTERISTICS:

Age:

• Under 50

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 1.5 mg/dL

Renal:

• Creatinine normal* for age NOTE: *Patients with tumor obstruction causing creatinine elevation may be enrolled

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Prior steroids allowed

Radiotherapy:

• No prior radiotherapy

Surgery:

• See Disease Characteristics