Originally published as JCO Early Release 10.1200/JCO.2005.03.209 on March 14 2005

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Phase II Trial of Neoadjuvant Vincristine, Ifosfamide, and Doxorubicin With Granulocyte Colony-Stimulating Factor Support in Children and Adolescents With Advanced-Stage Nonrhabdomyosarcomatous Soft Tissue Sarcomas: A Pediatric Oncology Group Study

Alberto S. Pappo, Meenakshi Devidas, Jessee Jenkins, Bhaskar Rao, Robert Marcus, Patrick Thomas, Mark Gebhardt, Charles Pratt, Holcombe E. Grier

From the Hospital for Sick Children Toronto, Toronto, Ontario, Canada; Pediatric Oncology Group Statistical Office, Gainesville; Tampa Children’s Hospital, Tampa, FL; St Jude Children’s Research Hospital, Memphis, TN; Children’s Healthcare of Atlanta, Emory University, Atlanta, GA; and Dana-Farber Cancer Institute, Boston, MA

Address reprint requests to Alberto S. Pappo, MD, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G1X8, Canada; e-mail: alberto.pappo{at}sickkids.ca

	ABSTRACT

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PURPOSE: To describe the response rate and survival of children and adolescents with unresected or metastatic nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) treated with vincristine, ifosfamide, and doxorubicin.

PATIENTS AND METHODS: Between September 1996 and June 2000, 39 eligible patients received vincristine (1.5 mg/m² weekly for 13 doses), ifosfamide (3 g/m² daily for 3 days every 3 weeks for seven cycles), doxorubicin (30 mg/m² daily for 2 days for six cycles), and mesna (750 mg/m² for four doses after ifosfamide). Granulocyte colony-stimulating factor was administered daily (5 µg/kg) after each cycle of chemotherapy. Radiotherapy was administered from weeks 7 through 12.

RESULTS: The median patient age at diagnosis was 11.7 years; the most common primary tumor site was lower extremity (36%); and synovial sarcoma was the predominant histology. More than three fourths of all tumors were 5 cm or greater at their largest diameters. The overall objective combined partial and complete response rate was 41% (95% CI, 25.7% to 56.7%). The estimated 3-year overall survival and progression-free survival rates (± standard deviation) for eligible patients were 59% ± 8.2% and 43.6% ± 7%, respectively. Patients with clinical group III disease had significantly better 3-year and progression-free survival rates compared with patients who presented with metastatic disease.

CONCLUSION: The vincristine, ifosfamide, and doxorubicin regimen was moderately active against pediatric NRSTS. Patients with synovial sarcoma had higher response rates than other patients, and patients with unresected disease had improved outcomes. Patients with metastatic disease continue to fare poorly, and newer approaches are indicated for these patients.

	INTRODUCTION

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The nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) are a histologically diverse group of neoplasms that account for approximately 4% of all malignant tumors in patients under 20 years old.¹ Most newly diagnosed children with NRSTS have localized resectable disease, and the probability of cure after complete excision, with or without radiotherapy, exceeds 80%.^2,3 In contrast, survival for the remaining 30% of patients with initially unresected or metastatic disease remains poor.^4,5

In a previous Pediatric Oncology Group (POG) study, POG 8654,⁵ 61 patients with unresected or metastatic disease were treated with neoadjuvant vincristine, doxorubicin, and cyclophosphamide with or without dacarbazine; their 2-year survival and event-free survival rates were only 30% and 18%, respectively. During this time, randomized and nonrandomized trials in adults with advanced-stage soft tissue sarcomas suggested that ifosfamide might offer a therapeutic advantage for these patients.^6-8

Given the promising results in adult trials, the POG developed a phase II trial to establish the response rate of NRSTS to an ifosfamide-containing regimen in children and adolescents with unresectable or metastatic disease. In addition, we planned to establish the survival and event-free survival rates after treatment with these agents.

	PATIENTS AND METHODS

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Eligibility criteria included age 21 years, histologic diagnosis of initially unresected (clinical group III) or metastatic (clinical group IV)⁹ NRSTS with radiographically measurable disease, registration on study within 42 days of definitive biopsy, no prior chemotherapy or radiotherapy, no HIV infection, normal renal and cardiac function, no hydronephrosis, approval of protocol by local institutional review board, and signed informed consent form. Exclusion criteria included pregnancy, lactation, and diagnoses of rhabdomyosarcoma, the Ewing sarcoma family of tumors, undifferentiated sarcoma, Kaposi sarcoma, mesothelioma, desmoplastic small round-cell tumor, angiofibroma of nasopharynx, and all grade 1 NRSTSs depicted in Table 1. Studies required before entry included CBC count, serum chemistry analysis, echocardiogram and ECG, renal ultrasound for suspected hydronephrosis, bone scan, chest computed tomography, and computed tomography or magnetic resonance imaging of primary tumor.

Treatment (Fig 1)
Induction therapy (weeks 1 to 6) consisted of vincristine (1.5 mg/m²) for 1 day weekly for weeks 1 to 4; ifosfamide (3 g/m²) daily for 3 consecutive days with mesna 750 mg/m² in 150 mL/m² administered over 1 hour followed by mesna 750 mg/m² at hours 4, 7, and 10 after ifosfamide on weeks 1 and 4; and doxorubicin 30 mg/m² in 0.9% NaCl daily for 2 consecutive days administered by continuous infusion in weeks 1 and 4. Granulocyte colony-stimulating factor was administered at 5 µg/kg 24 hours after the last dose of chemotherapy every 3 weeks and was continued for at least 7 days until the absolute neutrophil count was greater than 10,000/µL. Patients under 1 year old received chemotherapy as follows: vincristine 0.05 mg/kg, ifosfamide 100 mg/kg, doxorubicin 1 mg/kg, and mesna 25 mg/kg.

View larger version (27K): [in this window] [in a new window]   Fig 1. Treatment schema for Pediatric Oncology Group trial 9553. (#) Progressive disease (PD) off study; complete response (CR) or partial response (PR) continue on study; no response (NR) discuss with principle investigator. (##) PD or NR off study; CR or PR continue on study. Granulocyte colony-stimulating factor (G-CSF) was administered at 5 µg/kg 24 hours after the last dose of chemotherapy every 3 weeks and was continued for at least 7 days until the absolute neutrophil count was greater than 10,000/µL. V, vincristine 1.5 mg/m2 intravenous (IV) for 1 day (maximum, 2.0 mg); I, ifosfamide 3 g/m2 IV for 3 days followed by mesna 750 mg/m2 at hours 4, 7, and 10 after ifosfamide; D, doxorubicin 30 mg/m2 IV for 2 days; XRT, radiotherapy.

The continuation phase of the trial spanned weeks 14 to 23. Chemotherapy was administered as outlined for the induction phase on weeks 14, 15, 16, 17, and 20.

Definition of Response
Complete response (CR) was defined as disappearance of all clinical evidence of tumor. A partial response (PR) was defined as a more than 50% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions. No response or stable disease was defined as a less than 50% decrease in the sum of the products of the maximum perpendicular diameters of measurable lesions, and progressive disease was defined as a more than 25% increase in the sum of the products of the maximum perpendicular diameters of measurable lesions at any involved site and/or appearance of new lesions. Patients were evaluated for therapy response at weeks 6, 16, and 23 and for resection at weeks 7 and 16.

Off-study criteria included recurrent disease at any site during any evaluation, progressive disease at the weeks 6 and 16 evaluations, lack of response at week 6, and unacceptable toxicity. Investigators had the option of removing patients from study if there was no response at the weeks 6 and 16 evaluations.

Statistical Methods
Patients were stratified according to clinical group III or IV. A sequential design, which monitored for early acceptance of the null hypothesis, was devised. The two-stage design had a two-sided of 4.4% for testing the null hypothesis that the response rate is 25% and 81% power to reject the null hypothesis when the true response is 45%. The 95% CIs for response rates were developed using the methods of Chang and O’Brien.¹⁰ Overall survival (OS) and progression-free survival (PFS) curves were obtained using the Kaplan-Meier method.

	RESULTS

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Patient and Tumor Characteristics
We enrolled 43 patients from September 1996 through June 2000. Four patients (9%) were ineligible because of wrong diagnosis (n = 2), protocol violation at registration (n = 1), and lack of measurable disease at entry (n = 1). Therefore, 39 patients from 26 POG institutions were eligible for analysis. Their clinical characteristics are listed in Table 2. Median age at diagnosis was 11.7 years (range, 0.1 to 20.5 years). The most common primary tumor sites were the lower extremity (36%), head and neck (26%), and trunk (15%). Synovial sarcoma was the most common histology (41%), followed by malignant peripheral-nerve sheath tumor (13%) and alveolar soft part sarcoma (10%). Twenty-seven (71%) of 38 patients for whom pathologic material was available for assignment of histologic grade had grade 3 lesions. Over three fourths of all tumors were 5 cm or greater in their largest diameter. Fourteen patients presented with metastatic disease that involved lung (n = 12, 86%), bone (n = 5, 35%), lymph nodes (n = 2, 14%), brain (n = 2, 14%), bone marrow (n = 2, 14%), ovary (n = 1, 7%), and subcutaneous tissue (n = 1, 7%).

View larger version (9K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve of overall survival ( · · · ) and progression-free survival (PFS; ——) for 39 patients with unresected or metastatic nonrhabdomyosarcomatous soft tissue sarcoma.

View larger version (10K): [in this window] [in a new window]   Fig 3. Survival according to clinical group in 39 patients enrolled onto the Pediatric Oncology Group 9553 trial.

View larger version (10K): [in this window] [in a new window]   Fig 4. Progression-free survival according to clinical group in 39 patients enrolled onto the Pediatric Oncology Group 9553 trial.

Among group IV patients, five underwent primary tumor resection, and three received radiotherapy to control local or lung disease. Ten patients died from recurrence or progression, and one patient died of postoperative complications. The most common sites of progression or recurrence were lung (n = 8), brain (n = 2), bone (n = 1), bone marrow (n = 1), nodes (n = 1), and subcutaneous tissue (n = 1). Three patients were still alive as of the writing of this article, but only one was disease free. The latter patient had an extraskeletal osteosarcoma, which responded to chemotherapy and was treated with surgery and radiotherapy.¹¹

Toxicity During Induction
The most common type of toxicity after the first two cycles of chemotherapy was hematologic toxicity. Grade 3 to 4 toxicities included neutropenia in 77% of patients, anemia in 43%, and thrombocytopenia in 33%. Infections, including fever without identifiable source, were seen in 18 patients (46%), and six patients developed bacteremia. Severe stomatitis was seen in 5% of patients, whereas severe nausea, vomiting, and peripheral neuropathy were encountered in approximately 2% of patients. Other severe toxicities during treatment included Staphylococcus aureus bacteremia (n = 2), Pseudomonas bacteremia (n = 2), hemorrhagic cystitis (n = 2), hepatic veno-occlusive disease (n = 1), radiation recall (n = 1), exfoliative dermatitis (n = 1), vision disturbances after ifosfamide (n = 1), and varicella zoster infection (n = 1).

	DISCUSSION

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Our results show that 41% of patients with unresected or metastatic pediatric NRSTS will respond to an ifosfamide-doxorubicin–based regimen. This rate is similar to a previous POG trial of a cyclophosphamide-doxorubicin–based regimen.⁵ In that trial, 28 (46%) of 61 eligible patients had CR or PR. The response rate in the current report is similar to the rates in various adult studies (28% to 45%) that evaluated the doxorubicin-ifosfamide combination.^12-17 The limited number of patients in the current and previous POG studies and their nonrandomized designs precludes us from definitively establishing whether ifosfamide offers a significant therapeutic advantage over cyclophosphamide in these patients. However, the remarkably similar response rates in the two POG trials and the results of a randomized European Organisation for Research and Treatment of Cancer adult trial¹⁴ suggest that, for most patients with NRSTS, the combination of ifosfamide and doxorubicin has an activity profile that is similar to cyclophosphamide and doxorubicin. As suggested by some investigators, it is uncertain whether higher doses of doxorubicin or ifosfamide could have translated into improved response rates in our population.^18,19 Even if that was so, modest improvements in response with combination chemotherapy have not improved survival in adults with soft tissue sarcomas.²⁰

In our trial, patients with unresected disease fared much better than patients with metastatic disease, which was also the case for patients in the previous POG trial and patients at St Jude Hospital.^4,5,21 This supports the notion that unresected or initially unresected NRSTSs are a distinct clinicopathologic entity with an intermediate prognosis.²¹ The reasons for the relatively good outcomes in our series for this subgroup are unknown but might be related to the high rate of responses seen in patients with synovial sarcoma and the number of patients in whom local control was successful. In our series, nine patients who experienced treatment failure with neoadjuvant chemotherapy and underwent local tumor control with surgery with or without radiotherapy were alive and disease free as of the writing of this article. One patient experienced disease progression after two cycles of chemotherapy but was subsequently treated successfully with salvage radiotherapy and surgery. Another patient had delayed response to chemotherapy (until week 14) and was alive and disease free as of the writing of this article. These findings suggest that the definition of unresectable tumors might be arbitrary and more indicative of individual institutional or physician preferences. Like other trials,²² we found that initial response to chemotherapy does not predict survival accurately and that neoadjuvant chemotherapy alone does not improve survival of patients with initially unresected lesions. The encouraging reports in adults of preoperative radiotherapy or chemoradiotherapy to maximize local control and improve survival in patients with large-extremity sarcomas²³ warrant further investigation in pediatrics. The Children’s Oncology Group will conduct a prospective trial of concomitant chemoradiotherapy for pediatric patients with large unresected lesions.

Although degree of tumor necrosis has been correlated with clinical outcome in adults,²⁴ we had too few patients to assess adequately the relationship between percentage of tumor necrosis and outcome. A further confounding factor was continued chemotherapy after local control with stable disease after neoadjuvant chemotherapy. Thus, we encourage an aggressive surgical approach to remove all identifiable tumor, even with no response to neoadjuvant chemotherapy.

Our patients with metastatic disease fared poorly and had similar outcomes to those reported by others.^15,25 Only one patient in our trial survived disease free long term as of the writing of this article. The lack of progress for patients with metastatic NRSTS over the past decades, the lack of new active agents, and the relatively crude way of identifying factors that accurately predict outcome in these patients (young age, good performance, histologic grade, and no liver metastases) strongly argues in favor of developing an aggressive and concentrated effort to identify novel therapeutic targets and accurate predictors of response. Recent advances in molecular techniques will allow us to recognize sarcoma-specific signatures, and it is expected that these findings will facilitate the development of histology-specific translational trials that mimic those recently conducted in patients with gastrointestinal stromal tumors and dermatofibrosarcoma protuberans.^26,27 In addition, the use of novel statistical methods, such as the hierarchical Bayesian model, for evaluation of potentially active agents in diseases with multiple histologic subtypes, such as pediatric NRSTS, should be strongly encouraged.²⁸ In the interim, for younger patients, the combination of cyclophosphamide or ifosfamide with doxorubicin seems to maximize response, although it offers a low possibility of cure. For patients with synovial sarcoma, however, an ifosfamide-based regimen might be a better alternative given the high response rates observed with this agent in our trial and other adult studies.^29-31 Enrollment onto phase II trials of newly diagnosed patients with poorly chemoresponsive tumors, such as alveolar soft part sarcoma, also seems appropriate.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

	NOTES

 
Deceased.

Grant numbers and participating institutions are listed in the Appendix. A complete listing of grant support for research conducted before the initiation of the COG grant is available at http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Presented in part in abstract form at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

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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13. Steward WP, Verweij J, Somers R, et al: Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose-intensity of chemotherapy in metastatic adult soft tissue sarcomas: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 11:15-21, 1993[Abstract]

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25. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al: Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: An analysis of 2,185 patients treated with anthracycline-containing first-line regimens—A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 17:150-157, 1999[Abstract/Free Full Text]

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31. Nielsen OS, Judson I, van Hoesel Q, et al: Effect of high-dose ifosfamide in advanced soft tissue sarcomas: A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 36:61-67, 2000

Submitted March 29, 2004; accepted August 20, 2004.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pappo, A. S. Articles by Grier, H. E. Search for Related Content PubMed PubMed Citation Articles by Pappo, A. S. Articles by Grier, H. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB DOXORUBICIN IFOSFAMIDE VINCRISTINE Medline Plus Health Information Soft Tissue Sarcoma Related Articles Related Editorial Social Bookmarking                            What's this?