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 Pratt, C. B. Articles by Maurer, H. Search for Related Content PubMed PubMed Citation Articles by Pratt, C. B. Articles by Maurer, H. Social Bookmarking                            What's this?

Role of Adjuvant Chemotherapy in the Treatment of Surgically Resected Pediatric Nonrhabdomyosarcomatous Soft Tissue Sarcomas: A Pediatric Oncology Group Study

Charles B. Pratt, Alberto S. Pappo, Peter Gieser, Jesse J. Jenkins, Arnold Salzberg,, James Neff, Bhaskar Rao, Dan Green, Patrick Thomas, Robert Marcus, David Parham, Harold Maurer

From the St. Jude Children's Research Hospital, Memphis, TN; Roswell Park Memorial Institute, Buffalo, NY; University of Florida Shands Medical Center, Gainesville, FL; University of Nebraska, Omaha, NB; Tampa Children's Hospital, Tampa, FL; and University of Arkansas for Medical Sciences, Little Rock, AK.

Address reprint requests to Charles B. Pratt, MD, Pediatric Oncology Group Operations Office, 645 N Michigan Ave, Suite 910, Chicago, IL 60611; email cpratt{at}stjude.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To prospectively study the value of adjuvant chemotherapy in pediatric patients with surgically resected nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS).

PATIENTS AND METHODS: From June 1986 to May 1992, after complete surgical resection (±radiotherapy) of their NRSTS, 81 eligible patients either received adjuvant chemotherapy comprising vincristine, dactinomycin, cyclophosphamide, and doxorubicin or were observed. Only 30 patients accepted randomization, and 15 were assigned to each regimen. Of the remaining 51 patients, 19 elected adjuvant chemotherapy and 32 elected observation.

RESULTS: Patients were predominantly male, and 69% of all patients were white. The median age at diagnosis was 12.3 years (range, 9.2 to 20.7 years). For the 81 eligible patients, the 5-year overall survival estimate was 84.5% ± 4.4% and event-free survival was 72.2% ± 5.4%. Among randomized patients, the 5-year estimated overall survival rate was 93.3% ± 7%, and the event-free survival rate was 86.7% ± 9.5% for the observation group, compared with 69.2% ± 13% and 40.7% ± 14%, respectively, for those who received chemotherapy. The significantly worse outcome of patients who received adjuvant chemotherapy disappeared when survival was stratified by tumor grade. Among all patients, a grade 3 lesion conferred a significant disadvantage with respect to event-free survival (P = .0001).

CONCLUSION: The administration of adjuvant chemotherapy according to the schedule and dosages used in our trial did not improve the outcome of children with resected NRSTS. In this study, tumor grade was the most important predictor of clinical outcome in patients with resected NRSTS, and this factor should be incorporated into the stratification of patients in future trials.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
NONRHABDOMYOSARCOMATOUS soft tissue sarcomas (NRSTS) comprise a heterogeneous group of tumors that collectively account for 3% of all pediatric malignancies.¹ The clinical behavior and response of these neoplasms is similar to that seen in adults.² Approximately 70% of adult and pediatric patients with surgically resectable disease can be cured with local control measures (surgery and/or radiotherapy) alone. The use of adjuvant chemotherapy in adult patients with surgically resected disease remains controversial³ and has not been prospectively evaluated in pediatric patients. For this reason, the Pediatric Oncology Group (POG) designed a prospective, randomized, controlled clinical trial to evaluate the role of chemotherapy in pediatric patients with completely resected NRSTS.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Eligibility criteria included age 21 years; presence of a previously untreated (except for surgery) biopsy-proven soft tissue sarcoma excluding the following histologies: rhabdomyosarcoma, extraosseous Ewing's sarcoma, fibromatosis, undifferentiated sarcoma, angiofibroma of the nasopharynx, dermatofibrosarcoma protuberans, and malignant mesothelioma; clinical group I or II disease or clinical group III disease expected to be operable after radiotherapy; greater than third percentile for weight; normal serum total protein concentration and albumin/globulin ratio, bilirubin less than 1.5 mg/dL, creatinine level less than 1.5 mg/dL, and registration within 42 days of initial biopsy.

Staging and Histologic Grading
All patients were staged according to the surgicopathologic staging system developed by the Intergroup Rhabdomyosarcoma Study.⁴ Briefly, group I patients had complete resection (negative surgical margins) of the primary tumor, group II patients had evidence of microscopic residual tumor with or without regional nodal involvement, and group III patients had an incomplete surgical resection of the primary tumor with gross residual tumor. All pathologic material was centrally reviewed by three pathologists. Tumor grade was assigned according to the POG system, which takes into account tumor necrosis, mitotic activity, cellularity, and histology (Table 1).

Treatment
The treatment schema is depicted in Fig 1. Children with clinical group I disease received no postoperative radiation and were randomly assigned to be observed (regimen 2) or to receive adjuvant chemotherapy (regimen 1) with vincristine 1.5 mg/m², doxorubicin 60 mg/m² administered intravenously (IV), and cyclophosphamide 750 mg/m² alternating every 3 weeks with vincristine 1.5mg/m², dactinomycin 1.25 mg/m², and cyclophosphamide 750 mg/m² (VAC) for a total of 31 weeks. From weeks 34 to 50, regimen 1 patients received only VAC chemotherapy. Doses for children younger than 12 months were decreased by 50%; if this dose was tolerated (absolute phagocyte count greater than 500 µL and platelet count greater than 50,000/µL), then doses were escalated in subsequent courses to 75% and 100% of the protocol-specified dose.

View larger version (7K): [in this window] [in a new window]   Fig 1. Treatment schedule for POG protocol 8653. Abbreviations: S, surgery; XRT, radiotherapy; V, vincristine; ADR, doxorubicin; C, cyclophosphamide; A, dactinomycin.

Children with clinical group II disease (microscopic residual tumor) received age-adjusted postoperative megavoltage radiation to the tumor bed at a daily dose of 1.8 Gy per fraction. The clinical tumor volume, defined as the entire area of known clinical involvement including margins of resection plus a 5-cm margin in all directions (except where the margin exceeded anatomic limits of organs), was treated to a dose of 35 Gy in children younger than 6 years and to 45 Gy in older patients. The reduced volume, which included the primary tumor site before surgical resection plus a 2-cm margin in all dimensions, was treated to a total dose of 45 Gy in children younger than 6 years and to 50 Gy in older patients. Only children with clinical group III disease received a boost to the tumor volume before surgery; children younger than 6 years received 55 Gy, whereas older patients received 65 Gy.

One week after completion of radiotherapy, patients with clinical group II disease were randomly assigned to receive chemotherapy as specified in regimen 1 or to observation (regimen 2). Patients with clinical group III disease underwent second-look surgery 6 to 12 weeks after completing radiation therapy as described earlier. If complete tumor regression was documented, these patients were randomly assigned to regimen 1 or regimen 2.

Chemotherapy courses were delayed for 1 week if the absolute phagocyte count was less than 500/µL or the platelet count was less than 50,000/µL. Cyclophosphamide was withheld if hemorrhagic cystitis developed. Vincristine doses were decreased by 50% in the event of peripheral neuropathy or paralytic ileus. The doses of dactinomycin and doxorubicin were reduced by 25% in the event of severe diarrhea or mucositis.

Evaluation of Patients During Study
For all patients, the image modality that yielded tumor-positive results at diagnosis was repeated every 2 to 3 months during the first 18 months of therapy. An echocardiogram was performed when the total dose of doxorubicin reached 240 mg/m². In all patients, chest radiographs were obtained every 2 months during the first year of therapy, then every 3 to 4 months for 4 years. Event-free survival was defined as the time period from the date of randomization to the date of relapse, second malignancy, death, or last follow-up appointment. Disease relapse was defined as the appearance of new lesions or the reappearance of old lesions in patients who had been in complete remission. Patients with clinical group I and II disease whose disease relapsed and patients with group III disease who failed to achieve a complete response after surgery and radiotherapy were registered on POG protocol 8654 and randomized to one of two chemotherapeutic regimens.⁶

Statistical Design
The initial design specified that a sample size of 112 patients would be required to detect a 20% improvement in 2-year event-free survival (70% v 50%) with 80% power. A 5%, one-sided significance level was assumed. Randomization was balanced for clinical group status. Because accrual was lower than expected, an amendment to the protocol allowed patients to register onto the study but refuse randomization; the amendment was initiated 18 months after the study opened. Although patients who declined randomization were observed, the primary analysis was based exclusively on results from patients who accepted randomization. All patients were evaluated according to assigned treatment, regardless of which treatment they actually received. All comparisons were made by using a two-sided log-rank test.⁷ Overall and event-free survival estimates were calculated by using the method of Kaplan-Meier,⁸ with SEs determined according to Peto et al.⁹

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
The protocol opened for patient entry on June 6, 1986, and closed for patient accrual on May 8, 1992. A total of 99 patients were enrolled onto the study, but 18 were omitted from analysis for the following reasons: seven had inappropriate tumor histologies (two rhabdomyosarcoma, one rhabdoid tumor of the kidney, two fasciitis/fibromatosis, one plexiform fibrohistiocytic tumor, one malignant glioma), six had clinical group III disease at presentation but failed to achieve a complete response after radiation therapy, two were registered onto the study by error, one had no consent form, one had clinical group IV disease (metastatic), and one received radiation therapy before registration. Of the 81 eligible patients, only 30 accepted randomization; 15 were assigned to each treatment regimen. Of the remaining 51 patients, 19 elected adjuvant chemotherapy and 32 elected observation.

The clinical characteristics of all eligible patients (randomized and nonrandomized) are listed in Table 2. The median age at the time of diagnosis was 12.3 years (range, 9.2 to 20.7 years). Patients were predominantly male (n = 53, 65%), and 56 patients (69%) were white. More than two thirds of the patients had clinical group I disease. Primary tumors most frequently occurred in the upper or lower extremity (n = 41, 51%), and the most common histologies were synovial sarcoma (n = 29, 36%), malignant fibrous histiocytoma (n = 10, 12%), malignant peripheral nerve sheath tumor (n = 8, 10%), and fibrosarcoma (n = 8, 10%). Adequate tissue for histologic grading was available in 78 patients (95%), of whom 37 (47%) had grade 3 lesions.

Overall and Event-Free Survival
For the 81 eligible patients, the 5-year overall survival estimate was 84.5% ± 4.4%, and the event-free survival estimate was 72.2% ± 5.4% (Fig 2). There was insufficient evidence to detect a difference in event-free survival between randomized and nonrandomized patients (P = .17). Kaplan-Meier estimates of overall and event-free survival according to treatment assignment and randomization status are depicted in Figs 3 and 4. Among patients who accepted randomization, the 5-year overall survival estimate was 93.3% ± 7% and the estimated event-free survival was 86.7% ± 9.5% for those in the observation group, compared with 69.2% ± 13% and 40.7% ± 14%, respectively, for patients who received adjuvant chemotherapy. Therefore, there is no evidence that the administration of adjuvant chemotherapy improved the clinical outcome of pediatric patients with surgically resected NRSTS.

View larger version (10K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve depicting overall survival and event-free survival for 81 eligible patients with NRSTS.

View larger version (13K): [in this window] [in a new window]   Fig 3. Survival curve incorporating treatment and randomization status.

View larger version (15K): [in this window] [in a new window]   Fig 4. Event-free survival according to treatment and randomization status.

Overall and event-free survival estimates for patients who received adjuvant chemotherapy were significantly worse (P = .016 and P = .01, respectively) than those of patients who were assigned to observation only (Figs 3 and 4). This difference was not due to an excess number of toxic deaths. Furthermore, the difference disappeared (P = .37 and P = .28, respectively) when the analyses of overall and event-free survival were stratified by tumor grade. This finding helps to explain the apparent disadvantage of chemotherapy among randomized patients. There was an imbalance in patients with various tumor grades between the treatment arms, and group 3 lesions predominated among patients who received chemotherapy. Of the 29 randomized patients for whom tumor grade was known, 17 had grade 3 lesions, 11 of whom were assigned to receive adjuvant chemotherapy, whereas the remaining six were observed only. Therefore, 73% of patients who received adjuvant chemotherapy had grade 3 lesions compared with only 40% of those who were observed. Interestingly, a similar (albeit lesser) disparity exists between treatment arms on the nonrandomized cohort, but such selection bias is expected when patients or investigators determine treatment assignment. Figure 5 clearly demonstrates that, among all patients, having a grade 3 lesion confers a significant disadvantage with respect to event-free survival (P = .0,001). Figure 6 shows that event-free survival was significantly worse in patients with grade 3 lesions, regardless of their randomization status.

View larger version (10K): [in this window] [in a new window]   Fig 5. Event-free survival according to histologic grade.

View larger version (13K): [in this window] [in a new window]   Fig 6. Event-free survival incorporating histologic grade and randomization status.

Evaluation of potential prognostic factors by using univariate analysis disclosed that tumor grade was the only variable consistently associated with clinical outcome. Whereas 5-year event-free survival was estimated at 52.2% ± 8.8% for patients with grade 3 tumors, patients with grade 1 or 2 tumors fared significantly better (5-year event-free survival, 92.9% ± 7.8% for patients with grade 1 tumors and 92.6% ± 5.4% for patients with grade 2 lesions, P = .0001). Among the 38 eligible patients with grade 3 NRSTS, clinical outcome for those who were observed did not differ significantly (P = .09) from that of patients who received adjuvant chemotherapy. Outcome did not differ between patients with histologic grade 1 versus 2 tumors or between patients with clinical group I versus group II disease.

Treatment Failures
Among randomized patients, nine of the 15 who received chemotherapy developed disease recurrence. The histologic grade of the tumor was known for eight of these nine patients, and seven of these eight patients had grade 3 lesions. The sites of relapse were the lung (n = 6), local (n = 2), and the mediastinum (n = 1). Of interest, the two patients that developed local recurrence had group I lesions and did not receive adjuvant radiotherapy; one of these children had a very large (20 x 19 cm) mass at diagnosis. Six of the nine patients whose tumors recurred have died of disease progression. Among the 15 patients who were randomized to observation, one developed progressive disease and one developed dissemination to the CNS. Both of these patients had grade 3 lesions; one patient was lost to follow-up and one died of tumor progression.

For nonrandomized patients, six of 19 patients who received chemotherapy developed disease recurrence; all of these patients had histologic grade 3 lesions. In two patients, the site of recurrence was the lung. The remaining four patients developed local disease recurrence; three of these patients had clinical group I disease and did not receive postoperative radiation. Of the 26 nonrandomized patients who were observed only, five experienced a recurrence in the lung (n = 3) or locally (n = 2). Three of these patients had grade 3 tumors, and three had clinical group I disease.

Toxicity
Overall, therapy was well tolerated, and side effects were reversible and manageable. The most common grade 3 or 4 toxicity was reversible myelosuppression, which was seen in 11 patients. Six patients had severe nausea and vomiting, and two developed sepsis or bacteremia. Weight loss, thrombocytopenia, bleeding, and abnormalities in shortening fraction were infrequently encountered. Two patients, both of whom were not randomized, died of viral encephalitis (n = 1) or cardiomyopathy (n = 1).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This report details the results of the first randomized, pediatric trial of adjuvant combination chemotherapy for children with surgically resected NRSTS. Our study shows that outcome for these children is excellent: more than 80% are alive at least 5 years after diagnosis. The long follow-up period (median, 6.5 years) for this cohort of patients provides solid and accurate information about the biology and natural history of this group of rare pediatric neoplasms. The results of this trial are similar to those from other single-institution and multi-institutional nonrandomized pediatric and adult series of patients with NRSTS.^2,10-18

Despite the relatively good prognosis of patients with localized NRSTS, 20% to 50% of patients (depending on initial tumor characteristics) will develop disease recurrence, typically confined to the lung.^18,19 Therefore, hematogenous spread seems to be the primary route for disease dissemination, making the use of adjuvant single-agent or combination chemotherapy appealing to prevent or eradicate micrometastatic disease. For this reason, our patients were randomized after resection to receive either adjuvant chemotherapy with vincristine, dactinomycin, cyclophosphamide, and doxorubicin, or observation only. The drug combination used in this trial has been studied in the adjuvant and neoadjuvant setting in adults with soft tissue sarcomas.^20,21

Because of the controversy surrounding the use of adjuvant chemotherapy for NRSTS, accrual and randomization were problematic in our trial. The failure to document a therapeutic benefit from the administration of adjuvant chemotherapy in this trial might be due in part to heterogeneous patient assignments and low accrual. Our experience highlights the difficulties of conducting prospective randomized studies in pediatric patients with relatively rare tumors for which therapy has not been clearly defined. A similar experience was encountered in the multi-institutional osteosarcoma trial conducted by Link et al²² in which two thirds of all eligible patients declined randomization. The few single-institution pediatric reports published to date have also failed to show a survival advantage when adjuvant chemotherapy is administered to patients with surgically resected NRSTS.^2,11,23 However, these reports have been largely retrospective, spanning several decades during which therapies and surgical approaches differed greatly.

Among randomized patients, the 5-year overall and event-free survival estimates for the observation group were significantly better than those of patients treated with adjuvant chemotherapy. The poor results in the chemotherapy group can be at least partially explained by the increased number of patients with grade 3 lesions, the only factor that had a significant adverse affect on outcome in our trial. After overall and event-free survival were stratified by tumor grade, no difference between the two patient groups could be demonstrated.

Another noteworthy finding of our study is that tumor grade is the most important predictor of treatment outcome in children with localized surgically resected NRSTS. Using a histologic grading system adapted from Costa et al,²⁴ 92% of children with grade 1 or 2 lesions were disease-free at 5 years, compared with 52% of patients with grade 3 lesions. Among randomized patients, 90% of all relapses were seen in patients with grade 3 lesions. Of the 11 relapses, six (55%) occurred in the lung, among which four (80%) were seen in patients with grade 3 lesions. Our trial expands preliminary observations (published more than 3 years ago) on this classification system and confirms that this grading model is an accurate predictor of clinical outcome in children with surgically resected NRSTS.⁵

The administration of adjuvant chemotherapy in a randomized setting for the treatment of surgically resected NRSTS has been studied in more than 1,500 adult patients.²⁵ Only two of the trials that were reported in full articles documented an improvement in disease-free survival for patients who received adjuvant single-agent or combination chemotherapy.^26,27 These trials enrolled a relatively small number of patients, and the benefit was confined to patients with extremity lesions. In addition, the largest randomized trial of adjuvant chemotherapy in adults with soft tissue sarcomas showed improved relapse-free survival and decreased local recurrence among patients who received adjuvant chemotherapy (cyclophosphamide, vincristine, doxorubicin, and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide). The reduced incidence of local recurrence was restricted to patients with primary tumors of the head, neck, or trunk, and neither overall survival nor the incidence of distant metastases were favorably affected by this therapy.²⁸

Meta-analysis of adjuvant studies in adult patients suggests that adjuvant chemotherapy increases the time to distant and local recurrences as well as the duration of recurrence-free survival.²⁵ Interpretation of these results is difficult and may be invalid, because the trials that were analyzed vary markedly in their design, patients enrolled, heterogeneity of pathologic diagnoses and presenting risk features, and evaluation for outcome in terms of survival, distant failure, and local failure. In addition, the risks associated with administering chemotherapy (eg, sepsis and cardiotoxicity) must be weighed against the potential—but as yet unproven—benefit for survival.

Our data and those from adult studies that incorporated several histologic grading systems strongly support stratification of patients according to tumor grade.^29,30 Other tumor characteristics that are known to affect clinical outcome in adult and pediatric NRSTS, such as tumor size, histologic subtype, invasiveness, ploidy, proliferative index, and MDR-1 expression, were not prospectively examined in our trial but should be included in the stratification and design of future trials of adjuvant chemotherapy.^17,18,31 At present, we cannot recommend the routine use of adjuvant chemotherapy in pediatric patients with completely resected NRSTS unless it is provided in the context of a well-controlled multi-institutional clinical trial. Because patients with grade 1 and 2 lesions have an excellent prognosis, they should not be considered as candidates for receiving potentially toxic chemotherapy. Future studies should aim to identify active single agents or combinations in patients with unresectable or metastatic disease. These treatments can then be offered in the adjuvant setting in intergroup randomized trials for patients who are at high risk for treatment failure.

	ACKNOWLEDGMENTS

 
Supported in part by grants no. CA31566, CA29139, CA28383, and CA30969 from the National Cancer Institute.

	NOTES

 
Deceased.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Miller RW, Young JL, Novakovic B: Childhood cancer. Cancer 75:395-405, 1995[Medline]

2. Rao BN: Nonrhabdomyosarcoma in children: Prognostic factors influencing survival. Semin Surg Oncol 9:524-531, 1993[Medline]

3. Zalupski MM, Baker LH: Systemic adjuvant chemotherapy for soft tissue sarcomas. Hematol Oncol Clin North Am 9:787-800, 1995[Medline]

4. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study I. Cancer 61:209-220, 1988[Medline]

5. Parham DM, Webber BL, Jenkins JJ, et al: Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: Formulation of a simplified system for grading. Mod Pathol 8:705-710, 1995[Medline]

6. Pratt C, Maurer H, Gieser P, et al: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: A Pediatric Oncology Group study. Med Pediatr Oncol 30:201-209, 1998[Medline]

7. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc 135:185-198, 1972

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

9. Peto R, Pike M, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient, I: Analysis and examples. Br J Cancer 35:1-39, 1977[Medline]

10. DeCou JM, Rao BN, Parham DM, et al: Malignant peripheral nerve sheath tumors: The St. Jude Children's Research Hospital experience. Ann Surg Onc 2:524-529, 1995[Medline]

11. Pappo AS, Fontanesi J, Luo X, et al: Synovial sarcoma in children and adolescents: The St Jude Children's Research Hospital experience. J Clin Oncol 12:2360-2366, 1994[Abstract/Free Full Text]

12. Pappo AS, Parham DM, Cain A, et al: Alveolar soft part sarcoma in children and adolescents: Clinical features and outcome of 11 patients. Med Pediatr Oncol 26:81-84, 1996[Medline]

13. Kazanowska B, Boguslawska-Jaworska J, Kijowski J, et al: Results of treatment of the non-rhabdomyosarcoma soft tissue tumors in children: A report of the Polish Paediatric Solid Tumor Group. Third International Congress on Soft Tissue Sarcoma in Children and Adolescents, Stuttgart, Germany, April 30, 1997 (abstr)

14. Greffe B, Odom L, Stork L, et al: Non-rhabdomyosarcoma soft tissue sarcomas: Clinical characteristics and outcome in 42 children over 18 years at Denver Children's Hospital. Med Pediatr Oncol 27:339,1996 (abstr)

15. Skene AI BL, Robinson M, Fisher C, et al: Adult type (nonembryonal) soft tissue sarcomas in childhood. Med Pediatr Oncol 21:645-648, 1993[Medline]

16. Koscielniak E, Jurgens H, Winkler K, et al: Treatment of soft tissue sarcoma in childhood and adolescence. Cancer 70:2557-2567, 1992[Medline]

17. Sommelet-Olive D, Oberlin O, Flamant F, et al: Non rhabdo malignant mesenchymal tumors in children: Results of SIOP MMT 84 and 89 protocols. Proc Am Soc Clin Oncol 14:446, 1995 (abstr 1427)

18. Gaynor JJ, Tan CC, Casper ES, et al: Refinement in the clinicopathologic staging for localized soft tissue sarcoma of the extremity: A study of 423 adults. J Clin Oncol 10:1317-1329, 1992[Abstract/Free Full Text]

19. Pisters P, Leung D, Woodruff J, et al: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14:1679-1689, 1996[Abstract/Free Full Text]

20. Ravaud A, Bui NB, Coindre JM, et al: Adjuvant chemotherapy with CYVADIC high risk soft tissue sarcoma: A randomized prospective trial in Salmon SE (ed):Adjuvant Therapy of Cancer VI: Proceedings of the Sixth International Conference on the Adjuvant Therapy of Cancer, Tucson, Arizona, March 7-10, 1990556-566Philadelphia, PA, WB Saunders, 1990

21. Yap B, Baker LH, Sinkovics JG, et al: Cyclophosphamide, vincristine, adriamycin, and DTIC (CYVADIC) combination chemotherapy for the treatment of advanced sarcomas. Cancer Treat Rep 64:93-98, 1980[Medline]

22. Link M, Goorin A, Miser A, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600-1606, 1986[Abstract]

23. Horowitz ME, Pratt CB, Webber BL, et al: Therapy for childhood soft-tissue sarcomas other than rhabdomyosarcoma: A review of 62 cases treated at a single institution. J Clin Oncol 4:559-564, 1986[Abstract/Free Full Text]

24. Costa J, Wesley R, Glatstein E, et al: The grading of soft tissue sarcomas: Results of a clinicopathologic correlation in a series of 163 cases. Cancer 53:530-541, 1984[Medline]

25. Tierney JF: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data—A Sarcoma Meta-Analysis Collaboration. Lancet 350:1647-1654, 1997[Medline]

26. Chang A, Kinsella T, Glatstein E, et al: Adjuvant chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity. J Clin Oncol 9:1491-1500, 1988

27. Gherlinzoni F, Bacci G, Picci P, et al: A randomized trial for the treatment of high-grade soft tissue sarcomas of the extremities: Preliminary observations. J Clin Oncol 4:552-558, 1986[Abstract/Free Full Text]

28. Bramwell V, Rouesse J, Steward W, et al: Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma: Reduced local recurrence but no improvement in survival—A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 12:1137-1149, 1994[Abstract/Free Full Text]

29. van Unnik J, Coindre J, Contesso C, et al: Grading of soft tissue sarcomas: Experience of the EORTC soft tissue and bone sarcoma group. Eur J Cancer 29A:2089-2093, 1993

30. Guillou L, Coindre J, Bonichon F, et al: Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15:350-362, 1997[Abstract/Free Full Text]

31. Levine E, Holzmayer T, Bacus S, et al: Evaluation of newer prognostic markers for adult soft tissue sarcomas. J Clin Oncol 15:3249-3257, 1997[Abstract]

Submitted September 16, 1998; accepted December 7, 1998.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. L. Spunt, S. X. Skapek, and C. M. Coffin Pediatric Nonrhabdomyosarcoma Soft Tissue Sarcomas Oncologist, June 1, 2008; 13(6): 668 - 678. [Abstract] [Full Text] [PDF]

				S. L. Spunt and A. S. Pappo Childhood Nonrhabdomyosarcoma Soft Tissue Sarcomas Are Not Adult-Type Tumors J. Clin. Oncol., April 20, 2006; 24(12): 1958 - 1959. [Full Text] [PDF]

				A. S. Pappo, M. Devidas, J. Jenkins, B. Rao, R. Marcus, P. Thomas, M. Gebhardt, C. Pratt, and H. E. Grier 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 J. Clin. Oncol., June 20, 2005; 23(18): 4031 - 4038. [Abstract] [Full Text] [PDF]

				A. Ferrari, M. Casanova, P. Collini, C. Meazza, R. Luksch, M. Massimino, G. Cefalo, M. Terenziani, F. Spreafico, S. Catania, et al. Adult-Type Soft Tissue Sarcomas in Pediatric-Age Patients: Experience at the Istituto Nazionale Tumori in Milan J. Clin. Oncol., June 20, 2005; 23(18): 4021 - 4030. [Abstract] [Full Text] [PDF]

				L. H. Baker Medical and Pediatric Oncology, Not Adult and Pediatric Oncology J. Clin. Oncol., June 20, 2005; 23(18): 4003 - 4005. [Full Text] [PDF]

				W.-M. Chan, D. T.L. Liu, C. K.C. Lai, M. W.Y. Tse, J. S.K. Ng, and D. S.C. Lam Soft Tissue Sarcomas: CASE 2. Orbital Alveolar Soft Part Sarcoma in a Child J. Clin. Oncol., May 15, 2004; 22(10): 2027 - 2029. [Full Text] [PDF]

				S. L. Spunt, D. A. Hill, A. M. Motosue, C. A. Billups, A. M. Cain, B. N. Rao, C. B. Pratt, T. E. Merchant, and A. S. Pappo Clinical Features and Outcome of Initially Unresected Nonmetastatic Pediatric Nonrhabdomyosarcoma Soft Tissue Sarcoma J. Clin. Oncol., August 1, 2002; 20(15): 3225 - 3235. [Abstract] [Full Text] [PDF]

				S. L. Spunt, C. A. Poquette, Y. S. Hurt, A. M. Cain, B. N. Rao, T. E. Merchant, J. J. Jenkins, V. M. Santana, C. B. Pratt, and A. S. Pappo Prognostic Factors for Children and Adolescents With Surgically Resected Nonrhabdomyosarcoma Soft Tissue Sarcoma: An Analysis of 121 Patients Treated at St Jude Children's Research Hospital J. Clin. Oncol., December 1, 1999; 17(12): 3697 - 3705. [Abstract] [Full Text] [PDF]

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 Pratt, C. B. Articles by Maurer, H. Search for Related Content PubMed PubMed Citation Articles by Pratt, C. B. Articles by Maurer, H. Social Bookmarking                            What's this?