Originally published as JCO Early Release 10.1200/JCO.2004.05.184 on March 8 2004

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Efficacy of Topotecan and Cyclophosphamide Given in a Phase II Window Trial in Children With Newly Diagnosed Metastatic Rhabdomyosarcoma: A Children’s Oncology Group Study

From the Children’s Memorial Medical Center, Chicago, IL; Nebraska Medical Center, Omaha, NE; Duke University Medical Center, Durham, NC; Children’s Hospital of Columbus, Columbus, OH; Johns Hopkins Hospital, Baltimore, MD; and the University of Oklahoma Health Sciences Center, Oklahoma City, OK

Address reprint requests to David O. Walterhouse MD, Children’s Memorial Medical Center, Hematology/Oncology, 2300 Children’s Plaza, Box 30, Chicago, IL 60614; e-mail: d-walterhouse{at}northwestern.edu or smason{at}childrensoncologygroup.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION Patients and Methods RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: To determine the antitumor activity and toxicity of topotecan given immediately after cyclophosphamide as window therapy, then in combination with conventional agents in pediatric patients with newly diagnosed metastatic rhabdomyosarcoma (RMS).

PATIENTS AND METHODS: Sixty-one patients younger than 21 years with newly diagnosed metastatic RMS or undifferentiated sarcoma were assigned window therapy (weeks 0 to 6) with topotecan (0.75 mg/m² daily x 5 every 21 days) immediately after cyclophosphamide (250 mg/m² daily x 5 every 21 days; TC). We continued to give these agents in combination with vincristine (VTC) to patients who showed objective improvement, partial response (PR), or complete response (CR) to TC and alternated courses of VTC with vincristine, dactinomycin and cyclophosphamide (VAC) during weeks 6 to 41 (VTC/VAC). Those who showed no response or progressive disease after TC received only VAC. All patients received radiotherapy to sites of unresected disease (weeks 15 to 21).

RESULTS: The overall response rate (CR + PR) to TC was 47% (95% CI, 35% to 60%). Tumor size 5 cm was associated with early response. Myelosuppression was the primary toxicity to TC. Overall 3-year disease-free survival and survival were estimated to be 10% (95% CI, 2% to 19%) and 20% (95% CI, 8% to 32%), respectively. Toxicity profiles for patients who received VTC/VAC or VAC alone were comparable.

CONCLUSION: Topotecan after cyclophosphamide is a combination that is active against newly diagnosed RMS, with an acceptable toxicity profile. Disease-free survival and overall survival, however, remain disappointing for children with metastatic RMS at diagnosis.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Patients and Methods RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Most pediatric patients with metastatic rhabdomyosarcoma (RMS) fare poorly, with little improvement in their outcomes during the past 30 years. Strategies to improve outcomes, in Intergroup Rhabdomyosarcoma Studies IRS-I (1972 to 1978), IRS-II (1978 to 1984), and IRS-III (1984 to 1991), included dose intensification of cyclophosphamide and addition of known active agents, including doxorubicin, cisplatin, dacarbazine, and etoposide to conventional vincristine, dactinomycin, and cyclophosphamide (VAC)^1-3. More recently, as part of the IRS-IV pilot (1988 to 1991), IRS-IV (1991 to 1997) and IRS-V (1994 to present) trials, a series of up-front phase II window studies were conducted to rapidly identify new active single agents or combinations of agents and to define their toxicity profiles when used alone or with conventional VAC chemotherapy in children newly diagnosed with metastatic RMS or undifferentiated sarcoma^4-6. Agents were selected based on mechanism of action, antitumor activity in tumor cell lines and RMS xenografts, and safety profiles in phase I and phase II trials.

Chemotherapeutic agents tested in these up-front window trials included ifosfamide plus doxorubicin (ID) (IRS-IV pilot; 1988 to 1991), vincristine plus melphalan (VM) (IRS-IV; 1991 to 1995), ifosfamide plus etoposide (IE) (IRS-IV; 1991 to 1995), and topotecan (IRS-V; 1994 to 1996).^4-6 All agents showed activity as up-front window therapy against RMS or undifferentiated sarcoma. Patients who had a response at the end of the 6- to 12-week phase II window treatment continued to receive the agent(s) used in window therapy plus conventional VAC chemotherapy and radiotherapy (RT) to sites of unresected disease to complete 41 to 46 weeks of treatment. VM was associated with significant cumulative myelosuppression, necessitating cyclophosphamide dosage reductions when combined with VAC, which may have adversely affected disease-free survival (DFS) on this regimen.⁵

Cell culture and mouse xenograft experiments show enhanced activity of topoisomerase I inhibitors, such as topotecan, when given with alkylating agents.^7-10 It is believed that the combination causes an increased number of unrepaired DNA strand breaks that leads to enhanced cytotoxicity. Phase II multi-institutional trials conducted by the Pediatric Oncology Group in children with recurrent solid tumors showed a greater degree of activity against RMS when topotecan was combined with cyclophosphamide (10 of 15 responses) compared with topotecan alone (no responses).^11,12 Topotecan appeared active without excess toxicity when given as up-front window therapy (complete plus partial response rate of 46%), and combined with VAC, to patients with newly diagnosed metastatic RMS or undifferentiated sarcoma, so a trial (CCG/POG D9501 [IRS-V]) was initiated that tested topotecan given immediately after cyclophosphamide (TC).⁶ The objectives of the study were to evaluate the antitumor activity and toxicity of TC for two courses in children with newly diagnosed metastatic RMS or undifferentiated sarcoma and to evaluate the response rate and toxicity of TC plus vincristine (VTC) given with VAC (VTC/VAC) and RT.

	Patients and Methods

TOP ABSTRACT INTRODUCTION Patients and Methods RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Patients
This study was activated in April 1996 and completed enrollment in August 1999. Eligible patients were younger than 21 years at diagnosis and had stage 4/Group IV pathologically proven RMS or undifferentiated sarcoma that was measurable in at least two dimensions at the start of therapy. After March 1998, children younger than 10 years with embryonal RMS were excluded because they were found to have a more favorable outcome.¹³ Pathologic material from all patients was reviewed centrally by members of the Soft Tissue Sarcoma (STS) Pathology Committee of the Children’s Oncology Group, according to the International Classification of RMS.¹⁴ Normal kidney function, liver function, and bone marrow function (absolute neutrophil count [ANC] > 1,500/µL and platelets > 150,000/µL, unless there was bone marrow infiltration by tumor cells) were required. Patients were not eligible if they had received prior chemotherapy or RT. Patients were not eligible if they had tumors that arose in parameningeal primary sites and evidence of CNS extension. Patients had to be registered and started on protocol treatment within 42 days of the initial surgical procedure or biopsy, be available for periodic follow-up, and they or their guardian had to sign a written informed consent according to institutional guidelines with IRB approval according to the Declaration of Helsinki.

Staging and Surgery
Prestudy evaluation included a history and physical examination, including height and weight, magnetic resonance imaging (MRI) or computed tomography (CT) of the primary tumor, chest CT, chest radiograph, abdominal CT or ultrasound, MRI or CT of the head, bone scan, bone marrow aspirate and biopsy, urinalysis, and blood studies (CBC, differential, serum creatinine, ALT, alkaline phosphatase, lactate dehydrogenase, electrolytes, calcium, phosphorus, total protein, and albumin). Wide and complete resection of the primary tumor was performed only if it could be accomplished without significant functional or cosmetic defects. Primary resection of metastatic disease was not encouraged; however, biopsy of uncertain metastatic sites was required. Stage and Group were assigned according to guidelines established by the Intergroup Rhabdomyosarcoma Study Group (IRSG). Stage, Group, and compliance with protocol treatment guidelines were reviewed by members of the STS Committee of the Children’s Oncology Group (formerly the IRSG).

Chemotherapy
Patients received two courses of cyclophosphamide (250 mg/m² intravenously [IV] daily x 5 over 30 minutes) followed by topotecan (0.75 mg/m² IV daily x 5 over 30 minutes) 21 days apart (weeks 0 and 3; TC; Fig 1). A single dose of mesna (250 mg/m² IV daily x 5) could be given before each dose of cyclophosphamide. We gave granulocyte colony-stimulating factor 5 µg/kg/d 24 hours after the end of each TC course and continued until the ANC recovered to greater than 5,000/µL. The second course of TC was started 3 weeks later if the ANC was more than 1,000/µL and platelets were more than 100,000/µL (unless there was evidence of bone marrow infiltration with tumor cells), and if there was no evidence of progressive disease on physical examination. Patients with objective improvement, partial response, or complete response (see Response Definitions section) at week 6, based on physical examination, bone marrow examination, and diagnostic imaging, were considered responders to TC and received vincristine (1.5 mg/m² [maximum dose 2 mg] on day 1) plus TC (VTC) weeks 9, 26, 32, and 38, and vincristine (1.5 mg/m² [maximum dose 2 mg]), dactinomycin (1.5 mg/m² [maximum dose 2.5 mg]) and cyclophosphamide (2.2 g/m²; VAC) weeks 6, 12, 29, 35, and 41. Dactinomycin was held from VAC courses given during RT (weeks 16 and 19). Vincristine (1.5 mg/m² [maximum dose 2 mg]) was given alone weeks 7, 8, 10, 11, 13, 17, 18, 24, 25, 27, 33, and 34. Patients with progressive disease at week 3 received VAC at week 3 followed by vincristine on weeks 4 and 5. Patients with progressive disease at week 3 or no response or progressive disease at week 6 were considered nonresponders and received VAC weeks 6, 9, 12, 23, 26, 29, 32, 35, 38, and 41. Dactinomycin was held from VAC courses given during RT (weeks 16 and 19). Vincristine was given alone weeks 7, 8, 10, 11, 13, 17, 18, 24, 25, 27, 33, and 34. Courses of VTC or VAC were given when the ANC was more than 1,000/µL and platelets were more than 100,000/µL. A single dose of mesna (250 mg/m² IV daily x 5) could be given before each dose of cyclophosphamide during VTC courses. Mesna (450 mg/m²) was given immediately before cyclophosphamide, then every 3 hours for three additional doses (450 mg/m²) during VAC courses. We administered granulocyte-colony stimulating factor 5 µg/kg/d 24 hours after the end of each course and continued until the ANC had recovered to more than 5,000/µL. All patients received Pneumocystis carinii prophylaxis with trimethoprim/sulfamethoxazole. Infants younger than 12 months received 50% of these doses.

View larger version (11K): [in this window] [in a new window]   Fig 1. Therapeutic schema for D9501 (IRS-V). (A), phase 1: topotecan (T)/cyclophosphamide (C) window; (B) Phase 2: induction therapy; (C), Phase 3: induction therapy, local control phase; (D) Phase 4: continuation therapy. T*, patients who responded to TC; T** patients who did not progress following week 0 of TC treatment; EVAL, evaluation of response; V, vincristine; A, dactinomycin; RT, radiotherapy.

Response Definitions
Response was assessed at week 3 by physical examination and at weeks 6, 15, 25, and 44 by physical examination, bone marrow examination, and diagnostic imaging. Complete response (CR) was defined as disappearance of all tumor. Partial response (PR) was defined as a decrease in the size of all measurable lesions by 50% or more. Objective improvement was defined as a 25% to 49% decrease in the size of all measurable lesions. No response (NR) was defined as decrease in the size of all measurable lesions by less than 25%. Progressive disease (PD) was defined as an increase in the size of measurable lesions by 25% or more at any site or the appearance of new lesions. Relapse/recurrence was defined as the appearance of new lesions or reappearance of old lesions.

Toxicity
Chemotherapy and RT toxicity were reported at weeks 6, 15, 25, and 44 and were graded according to criteria established by the National Cancer Institute. The IRSG study coordinator was notified of any grade 2 to 4 unexpected toxicities and grade 4 known toxicities to topotecan and other unacceptable toxicities or death on study secondary to toxicity.

Statistics
The study was originally designed as a two-stage phase II study.¹⁵ A total of 18 patients were entered in the first stage. If less than eight favorable responses (CR or PR) had been observed in the window phase, accrual would have been stopped, and TC would not have been considered for further study. If eight or more favorable responses were observed in stage I, an additional 28 patients were to be accrued in the second stage (46 total). If the observed response rate was 23 of 46 patients or more, then TC would be considered for further testing. This design was associated with a probability of considering further testing of 10% when the true CR + PR rate is 40%, but with a probability of further testing of 90% when the true CR + PR rate is 60%. Comparisons of response rates by patient characteristics were made using Fisher’s exact test. All patients were followed for survival (time from start of treatment to death) and DFS (time from start of treatment to the first occurrence of progression, relapse after response, or death from any cause). Estimates of the time-to-event distributions were calculated using the Kaplan-Meier method, and CIs for specific estimates of time-to-event distributions were calculated using Greenwood’s formula for the variance of the estimates.¹⁶ Comparisons of outcome by prognostic factors and among responders and nonresponders were made using the log-rank test. A P value of less than .05 was considered statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION Patients and Methods RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
A sufficient number of responders were observed in the first stage (n = 18) to continue accrual into the second stage. Accrual was extended beyond the planned 46 patients to allow for a greater experience with TC window therapy in patients with metastatic embryonal histology tumors. Sixty-seven patients were entered between April 1996 and August 1999; two had no measurable disease, three had diagnoses that were not RMS, based on central review; and one had CNS extension. Thus, 61 patients were eligible for analysis. The median length of follow-up for the 16 patients alive at the time of this analysis was 2.6 years.

Patient Characteristics
Characteristics of the 61 eligible patients are shown in Table 1. The median age was 11 years (range, 0 to 19 years). Thirty-nine patients(64%) were 10 years old or older. Bone marrow was the most common metastatic site (n = 22), followed by distant lymph nodes (n = 8), soft tissues (n = 8), lung (n = 6), ascites (n = 5), liver (n = 4), bone (n = 3), and pleural effusion (n = 1). Twenty-eight patients (60%) had two or more metastatic sites. Forty patients (66%) had histologic variants of RMS considered unfavorable, including 35 patients (57%) with alveolar histology and five patients (8%) with undifferentiated sarcoma. There were only four patients (7%) who were younger than 10 years with embryonal histology.

Grade 3 or 4 toxicities in more than 5% of patients during TC window therapy included leukopenia (n = 31; 52%), neutropenia (n = 30; 50%), anemia (n = 22; 37%), thrombocytopenia (n = 13; 22%), infection (n = 10; 17%), alopecia (n = 4; 7%) and nausea (n = 4; 7%). There were no unexpected toxicities reported.

Outcome
Twenty-one patients (34%) ultimately achieved a CR. Three-year DFS was estimated at 10% (95% CI, 2% to 19%) and 3-year overall survival 20% (95% CI, 8% to 32%; Fig 2). Responders to TC (n = 42) who went on to receive VTC/VAC had significantly improved DFS and survival compared with nonresponders to TC (n = 19) who went on to receive VAC alone (DFS, 14% [95% CI, 3% to 24%] v 0%; P < .001; survival, 33% [95% CI, 17% to 48%] v 0%; P = .001; Fig 3). Four TC nonresponders had a PR to VAC at week 15, and six demonstrated objective improvement. Other prognostic factors that might affect DFS and survival were examined, including age, sex, histology, tumor size, tumor invasion, nodal status, number of metastatic sites present at diagnosis, and bone marrow involvement. None of these factors were statistically significant influences on outcome individually, although number of metastatic sites was marginally associated with DFS (P = .11) and sex with survival (P = .072); males had better outcome than females.

View larger version (11K): [in this window] [in a new window]   Fig 2. Disease-free (DFS) and overall (OS) survival.

View larger version (12K): [in this window] [in a new window]   Fig 3. Survival for responders to topotecan with cyclophosphamide, compared with nonresponders.

	DISCUSSION

TOP ABSTRACT INTRODUCTION Patients and Methods RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
This trial shows that TC is an active chemotherapy combination in children with newly diagnosed RMS. Those with primary tumors up to 5 cm in diameter had a better response rate to TC window therapy than those with large tumors. Myelosuppression was the primary toxicity and was tolerable. The identification of significant clinical activity for this combination of agents in a relatively large number of children with metastatic RMS expands our therapeutic options.

Existing prognostic factors for patients with metastatic RMS include age and histology^13,17 (patients < 10 years old who have embryonal histology fare favorably), number of metastatic sites^17,18 (patients with fewer metastatic sites fare favorably), and gene fusion variants in patients with the alveolar subtype¹⁹ (patients whose tumors have a t[1;13] fare favorably compared with those with a t[2;13]). During the TC window study, we altered the eligibility criteria to exclude children younger than 10 years with metastatic embryonal histology tumors, and few of these patients were enrolled. Consequently, patients on the current trial must be considered extremely high risk, because most were older than 10 years and had two or more metastatic sites with histologic variants of RMS considered unfavorable. Comparisons between our successive window trials must be made with caution based on differing characteristics of patients on these trials.

This study and the topotecan window trial showed trends, which did not reach statistical significance in either case, suggesting a higher response rate to window therapy for alveolar than embryonal RMS.⁶ Neither study was specifically designed to examine response rates by histology; however, it would not be surprising if fundamental biologic differences between the histiotypes result in differing responses to specific classes of therapeutic agents. It should be noted, however, that TC showed activity in both major histologic subtypes (alveolar [19 of 35] and embryonal [4 of 14]) to warrant inclusion in the current phase III intermediate-risk RMS trial being conducted by the Children’s Oncology Group (D9803).

The response rate to window therapy on this study was similar to that on the topotecan window trial.⁶ The overall response to TC (CR + PR) in patients with newly diagnosed RMS or undifferentiated sarcoma was 47% (95% CI, 35% to 60%) compared with 46% (95% CI, 31% to 61%) to topotecan alone. The dose of topotecan in this study was approximately one third of that on the topotecan window trial. However, phase II studies that used topotecan (2.0 mg/m² daily x 5) or topotecan (0.75 mg/m² daily x 5) plus cyclophosphamide (250 mg/m² daily x 5) in patients who had recurrent RMS suggested that increased cytotoxicity from addition of cyclophosphamide enhances therapeutic efficacy, overcoming any deleterious effects of topotecan dosage reduction.^11,12 We were somewhat disappointed in the current study because we could only show comparable therapeutic efficacy in patients who had newly diagnosed RMS or undifferentiated sarcoma. In fact, the response rate observed in this study also was comparable with the response rate reported for cyclophosphamide when used as a single agent for RMS.²⁰ Based on differences in patient populations and drug administration between this trial and the earlier studies, it is not possible to determine the extent to which synergistic or additive effects between the agents contributed to the response rate seen in this trial.

The rate of PD during window treatment was of concern on this trial and the topotecan trial; 20% on TC and 29% on topotecan. This compares unfavorably with PD rates (unadjusted for any differences in populations) on the vincristine/melphalan (13%), ifosfamide/etoposide (12%), and ifosfamide/doxorubicin (13%) window trials. Higher risk characteristics of patients on the more recent trials may account for some of these differences in response to window therapy. There were no early deaths reported secondary to PD during window therapy on this trial; however, it is possible that the higher rate of PD during window therapy contributed to the overall poor outcome for nonresponders to TC.

The only factor predictive of outcome on this study was response to window therapy. Responders on this trial fared better than nonresponders, unlike the topotecan window trial, in which there was no difference in outcome between responders and nonresponders.⁶ This difference between the studies surprised us somewhat because the only difference in therapy was two courses of upfront TC window therapy on this trial and topotecan (2.0 to 2.4 mg/m²/d x 5 IV) on the previous trial. After window therapy, patients on each trial received identical VTC/VAC for responders or VAC for nonresponders to week 41. Four of 19 TC nonresponders on this trial had a PR to VAC and 6 had objective improvement, suggesting some degree of noncross resistance between TC and VAC. The effect of VTC added to conventional VAC chemotherapy is being tested prospectively in patients who have newly diagnosed intermediate-risk RMS (D9803).

Although several active combinations of agents with acceptable toxicity profiles have been identified against RMS through the phase II window trials, the overall outcome remains poor when we combine the agents with standard VAC therapy for patients who have metastatic RMS or undifferentiated sarcoma. This underscores the need for rapid identification of new agents with novel mechanisms of action in patients with metastatic disease. We are pursuing this goal in the current vincristine plus irinotecan window study (D9802). Active agents identified through window trials can also be utilized in novel drug schedules or combinations or combined with biologic agents instead of with VAC in future trials. Successful therapy for patients with metastatic RMS or undifferentiated sarcoma will likely depend on a better understanding of tumor biology and the development of therapies based specifically on molecular genetic defects in the tumors.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION Patients and Methods RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION Patients and Methods RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
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4. Sandler E, Lyden E, Ruymann F, et al: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37:442-448, 2001[CrossRef][Medline]

5. Breitfeld PP, Lyden E, Raney RB, et al: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: A report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23:225-233, 2001[CrossRef][Medline]

6. Pappo AS, Lyden E, Breneman J, et al: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An Intergroup Rhabdomyosarcoma Study. J Clin Oncol 19:213-219, 2001[Abstract/Free Full Text]

7. Kaufmann SH, Peereboom D, Buckwalter CA, et al: Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines. J Natl Cancer Inst 88:734-741, 1996[Abstract/Free Full Text]

8. Janss AJ, Cnaan A, Zhao H, et al: Synergistic cytotoxicity of topoisomerase I inhibitors with alkylating agents and etoposide in human brain tumor cell lines. Anti Cancer Drugs 9:641-652, 1998[Medline]

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10. Coggins CA, Elion GB, Houghton PJ, et al: Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol 41:485-490, 1998[CrossRef][Medline]

11. Saylors RL, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: A Pediatric Oncology Group phase II study. J Clin Oncol 19:3463-3469, 2001[Abstract/Free Full Text]

12. Nitschke R, Parkhurst J, Sullivan J, et al: Topotecan in pediatric patients with recurrent and progressive solid tumors: A Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 20:315-318, 1998[CrossRef][Medline]

13. Anderson JR, Ruby E, Link M, et al: Identification of a favorable subset of patients (pts) with metastatic (MET) rhabdomyosarcoma (RMS): A report from the Intergroup Rhabdomyosarcoma Study Group (IRSG). Proc Amer Soc Clin Oncol 16:510a, 1997 (abstr 1836)

14. Qualman SJ, Coffin CM, Newton WA, et al: Intergroup Rhabdomyosarcoma Study: Update for pathologists. Pediatr Dev Pathol 1:550-561, 1998[CrossRef][Medline]

15. Simon R, White RE: Methodologic guidelines for reports of clinical trials. Cancer Treat Rep 69:1-3, 1985[Medline]

16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

17. Breneman JC, Lyden E, Pappo AS, et al: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21:78-84, 2003[Abstract/Free Full Text]

18. Raney RB, Tefft M, Maurer HM, et al: Disease patterns and survival rate in children with metastatic soft-tissue sarcoma: A report from the Intergroup Rhabdomyosarcoma Study (IRS)-I. Cancer 62:1257-1266, 1988[CrossRef][Medline]

19. Sorenson PH, Lynch JC, Qualman SJ, et al: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: A report from the Children’s Oncology Group. J Clin Oncol 20:2672-2679, 2002[Abstract/Free Full Text]

20. Haddy TB, Nora AH, Sutow WW, et al: Cyclophosphamide treatment for metastatic soft tissue sarcoma: Intermittent large doses in the treatment of children. Am J Dis Child 114:301-308, 1967[Abstract/Free Full Text]

Submitted May 28, 2003; accepted December 8, 2003.

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