Phase II Trial of Neoadjuvant Vincristine, Ifosfamide, and Doxorubicin With Granulocyte Colony-Stimulating Factor Support in Children and Ad
http://www.100md.com
《临床肿瘤学》
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
Dana-Farber Cancer Institute, Boston, MA
ABSTRACT
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
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
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.
All pathologic material was reviewed centrally and typed according to WHO classification of soft tissue sarcomas as modified by Enzinger and Weiss. Pathologic grade was assigned to each patient according to the POG grading system depicted in Table 1.
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.
The local control phase of the trial spanned weeks 7 through 13. When feasible, removal of the primary tumor and metastatic sites was advised at week 7. All patients were to receive radiation therapy. If surgery was performed in week 7, radiotherapy was begun as soon as possible after the operation. If the tumor was not resectable, surgery was reassessed at week 16. During the local control phase, patients received chemotherapy as outlined for the induction phase on weeks 7, 8, and 9. Doxorubicin was omitted at week 10. The dose of local radiotherapy to the primary site was age dependent (54 Gy for patients under 6 years old and 64.8 Gy for patients who were older). For metastatic disease, whole-lung irradiation was prescribed at doses of 12 Gy for patients under 6 years old and 18 Gy for older patients.
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
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%).
Response to Therapy and Clinical Outcome
After two cycles of induction chemotherapy, 15 patients achieved PR, and one achieved CR, for an overall response rate (CR+PR) of 41% (95% CI, 26.4% to 57.6%). As shown in Table 3, most responses (56%) were in patients with synovial sarcoma (nine of 16 patients). No responses were documented in patients with epithelioid sarcoma, fibrosarcoma, mesenchymal chondrosarcoma, or alveolar soft part sarcoma.
The median follow-up time for survivors was 4.4 years. Estimated 3-year OS and PFS rates (± SE) for all eligible patients were 59% ± 8% and 43.6% ± 8%, respectively (Fig 2). Patients with clinical group III disease had significantly better 3-year OS and PFS rates compared with patients who presented with metastatic disease (80% ± 8% v 21.4% ± 11%, P = .0001; and 60% ± 10% v 14.3% ± 9%, P = .001, respectively; Figs 3 and 4). Three-year PFS and OS rates were statistically significantly better for patients with synovial sarcoma histology compared with patients with other histologic subtypes (56.3% ± 12% v 34.8% ± 10% and 81.3% ± 10% v 43.5% ± 11%, respectively). However, this comparison did not reach statistical significance when histology was analyzed within clinical group III patients.
Local Control Measures, Response to Therapy, and Outcome of Group III Patients
Local control measures in patients with group III disease included amputation (n = 3), surgery plus radiotherapy (n = 7), surgery alone (n = 7), and radiation therapy alone (n = 6). The degree of tumor necrosis among patients who had primary tumor resection was available for five patients; only one patient had significant necrosis (60% to 90%). Disease recurrence or progression was documented in 11 patients, and the sites included lung (n = 5), locoregional (n = 5), and combined locoregional and lung (n = 1). Eighteen of 25 group III patients were still alive at this reporting, but only one of the six patients who developed pulmonary metastases survived long term. Nine patients whose initial chemotherapy failed but who were then given local tumor control measures survived long term and were disease free as of the writing of this article.
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
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
The authors indicated no potential conflicts of interest.
Appendix
Acknowledgment
We thank Vivien Bramwell, MD, for critical review of the manuscript.
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
Ries LAG, Smith MA, Gurney JG, et al: Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, MD, National Cancer Institute, SEER program publication 99-4649, 1999
Spunt SL, Poquette CA, Hurt YS, et al: 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 17:3697-3705, 1999
Pratt CB, Pappo AS, Gieser P, et al: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group study. J Clin Oncol 17:1219-1226, 1999
Pappo AS, Rao BN, Jenkins JJ, et al: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: The St. Jude Children’s Research Hospital experience. Med Pediatr Oncol 33:76-82, 1999
Pratt CB, Maurer HM, 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
Blackledge G, Steward WP, Verweij J, et al: Experience with ifosfamide in the EORTC Soft Tissue and Bone Sarcoma Group. Semin Oncol 19:14-18, 1992
Antman KH, Ryan L, Elias A, et al: Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 7:126-131, 1989
Bramwell VH, Mouridsen HT, Santoro A, et al: Cyclophosphamide versus ifosfamide: Final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 23:311-321, 1987
Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study: I. A final report. Cancer 61:209-220, 1988
Chang MN, O’Brien PC: Confidence intervals following group sequential tests. Control Clin Trials 7:18-26, 1986
Wodowski K, Hill DA, Pappo AS, et al: A chemosensitive pediatric extraosseous osteosarcoma: Case report and review of the literature. J Pediatr Hematol Oncol 25:73-77, 2003
Steward WP, Verweij J, Somers R, et al: Doxorubicin plus ifosfamide with rhGM-CSF in the treatment of advanced adult soft-tissue sarcomas: Preliminary results of a phase II study from the EORTC Soft-Tissue and Bone Sarcoma Group. J Cancer Res Clin Oncol 117:S193-S197, 1991 (suppl 4)
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
Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-1545, 1995
Antman K, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276-1285, 1993
Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11:1269-1275, 1993
Schutte J, Mouridsen HT, Steward W, et al: Ifosfamide plus doxorubicin in previously untreated patients with advanced soft-tissue sarcoma. Cancer Chemother Pharmacol 31:S204-S209, 1993 (suppl 2)
Patel SR, Vadhan-Raj S, Papadopolous N, et al: High-dose ifosfamide in bone and soft tissue sarcomas: Results of phase II and pilot studies—Dose-response and schedule dependence. J Clin Oncol 15:2378-2384, 1997
Steward WP, Verweij J, Somers R, et al: The use of recombinant human granulocyte-macrophage colony-stimulating factor with combination chemotherapy in the treatment of advanced adult soft-tissue sarcomas: Early results from the EORTC Soft-Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 31:S241-S244, 1993 (suppl 2)
Bramwell VH, Anderson D, Charette ML, et al: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: A meta-analysis and clinical practice guideline. Sarcoma 4:103-112, 2000
Spunt SL, Hill DA, Motosue AM, et al: Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 20:3225-3235, 2002
Gortzak E, Azzarelli A, Buesa J, et al: A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer 37:1096-1103, 2001
DeLaney TF, Spiro IJ, Suit HD, et al: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 56:1117-1127, 2003
Eilber FC, Rosen G, Eckardt J, et al: Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol 19:3203-3209, 2001
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
Sawyers CL: Imatinib GIST keeps finding new indications: Successful treatment of dermatofibrosarcoma protuberans by targeted inhibition of the platelet-derived growth factor receptor. J Clin Oncol 20:3568-3569, 2002
Dematteo RP, Heinrich MC, El-Rifai WM, et al: Clinical management of gastrointestinal stromal tumors: Before and after STI-571. Hum Pathol 33:466-477, 2002
Thall PF, Wathen JK, Bekele BN, et al: Hierarchical Bayesian approaches to phase II trials in diseases with multiple subtypes. Stat Med 22:763-780, 2003
Rosen G, Forscher C, Lowenbraun S, et al: Synovial sarcoma: Uniform response of metastases to high dose ifosfamide. Cancer 73:2506-2511, 1994
Singer S, Baldini EH, Demetri GD, et al: Synovial sarcoma: Prognostic significance of tumor size, margin of resection, and mitotic activity for survival. J Clin Oncol 14:1201-1208, 1996
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(Alberto S. Pappo, Meenaks)
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
Dana-Farber Cancer Institute, Boston, MA
ABSTRACT
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
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
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.
All pathologic material was reviewed centrally and typed according to WHO classification of soft tissue sarcomas as modified by Enzinger and Weiss. Pathologic grade was assigned to each patient according to the POG grading system depicted in Table 1.
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.
The local control phase of the trial spanned weeks 7 through 13. When feasible, removal of the primary tumor and metastatic sites was advised at week 7. All patients were to receive radiation therapy. If surgery was performed in week 7, radiotherapy was begun as soon as possible after the operation. If the tumor was not resectable, surgery was reassessed at week 16. During the local control phase, patients received chemotherapy as outlined for the induction phase on weeks 7, 8, and 9. Doxorubicin was omitted at week 10. The dose of local radiotherapy to the primary site was age dependent (54 Gy for patients under 6 years old and 64.8 Gy for patients who were older). For metastatic disease, whole-lung irradiation was prescribed at doses of 12 Gy for patients under 6 years old and 18 Gy for older patients.
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
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%).
Response to Therapy and Clinical Outcome
After two cycles of induction chemotherapy, 15 patients achieved PR, and one achieved CR, for an overall response rate (CR+PR) of 41% (95% CI, 26.4% to 57.6%). As shown in Table 3, most responses (56%) were in patients with synovial sarcoma (nine of 16 patients). No responses were documented in patients with epithelioid sarcoma, fibrosarcoma, mesenchymal chondrosarcoma, or alveolar soft part sarcoma.
The median follow-up time for survivors was 4.4 years. Estimated 3-year OS and PFS rates (± SE) for all eligible patients were 59% ± 8% and 43.6% ± 8%, respectively (Fig 2). Patients with clinical group III disease had significantly better 3-year OS and PFS rates compared with patients who presented with metastatic disease (80% ± 8% v 21.4% ± 11%, P = .0001; and 60% ± 10% v 14.3% ± 9%, P = .001, respectively; Figs 3 and 4). Three-year PFS and OS rates were statistically significantly better for patients with synovial sarcoma histology compared with patients with other histologic subtypes (56.3% ± 12% v 34.8% ± 10% and 81.3% ± 10% v 43.5% ± 11%, respectively). However, this comparison did not reach statistical significance when histology was analyzed within clinical group III patients.
Local Control Measures, Response to Therapy, and Outcome of Group III Patients
Local control measures in patients with group III disease included amputation (n = 3), surgery plus radiotherapy (n = 7), surgery alone (n = 7), and radiation therapy alone (n = 6). The degree of tumor necrosis among patients who had primary tumor resection was available for five patients; only one patient had significant necrosis (60% to 90%). Disease recurrence or progression was documented in 11 patients, and the sites included lung (n = 5), locoregional (n = 5), and combined locoregional and lung (n = 1). Eighteen of 25 group III patients were still alive at this reporting, but only one of the six patients who developed pulmonary metastases survived long term. Nine patients whose initial chemotherapy failed but who were then given local tumor control measures survived long term and were disease free as of the writing of this article.
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
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
The authors indicated no potential conflicts of interest.
Appendix
Acknowledgment
We thank Vivien Bramwell, MD, for critical review of the manuscript.
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
Ries LAG, Smith MA, Gurney JG, et al: Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, MD, National Cancer Institute, SEER program publication 99-4649, 1999
Spunt SL, Poquette CA, Hurt YS, et al: 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 17:3697-3705, 1999
Pratt CB, Pappo AS, Gieser P, et al: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group study. J Clin Oncol 17:1219-1226, 1999
Pappo AS, Rao BN, Jenkins JJ, et al: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: The St. Jude Children’s Research Hospital experience. Med Pediatr Oncol 33:76-82, 1999
Pratt CB, Maurer HM, 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
Blackledge G, Steward WP, Verweij J, et al: Experience with ifosfamide in the EORTC Soft Tissue and Bone Sarcoma Group. Semin Oncol 19:14-18, 1992
Antman KH, Ryan L, Elias A, et al: Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 7:126-131, 1989
Bramwell VH, Mouridsen HT, Santoro A, et al: Cyclophosphamide versus ifosfamide: Final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 23:311-321, 1987
Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study: I. A final report. Cancer 61:209-220, 1988
Chang MN, O’Brien PC: Confidence intervals following group sequential tests. Control Clin Trials 7:18-26, 1986
Wodowski K, Hill DA, Pappo AS, et al: A chemosensitive pediatric extraosseous osteosarcoma: Case report and review of the literature. J Pediatr Hematol Oncol 25:73-77, 2003
Steward WP, Verweij J, Somers R, et al: Doxorubicin plus ifosfamide with rhGM-CSF in the treatment of advanced adult soft-tissue sarcomas: Preliminary results of a phase II study from the EORTC Soft-Tissue and Bone Sarcoma Group. J Cancer Res Clin Oncol 117:S193-S197, 1991 (suppl 4)
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
Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-1545, 1995
Antman K, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276-1285, 1993
Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11:1269-1275, 1993
Schutte J, Mouridsen HT, Steward W, et al: Ifosfamide plus doxorubicin in previously untreated patients with advanced soft-tissue sarcoma. Cancer Chemother Pharmacol 31:S204-S209, 1993 (suppl 2)
Patel SR, Vadhan-Raj S, Papadopolous N, et al: High-dose ifosfamide in bone and soft tissue sarcomas: Results of phase II and pilot studies—Dose-response and schedule dependence. J Clin Oncol 15:2378-2384, 1997
Steward WP, Verweij J, Somers R, et al: The use of recombinant human granulocyte-macrophage colony-stimulating factor with combination chemotherapy in the treatment of advanced adult soft-tissue sarcomas: Early results from the EORTC Soft-Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 31:S241-S244, 1993 (suppl 2)
Bramwell VH, Anderson D, Charette ML, et al: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: A meta-analysis and clinical practice guideline. Sarcoma 4:103-112, 2000
Spunt SL, Hill DA, Motosue AM, et al: Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 20:3225-3235, 2002
Gortzak E, Azzarelli A, Buesa J, et al: A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer 37:1096-1103, 2001
DeLaney TF, Spiro IJ, Suit HD, et al: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 56:1117-1127, 2003
Eilber FC, Rosen G, Eckardt J, et al: Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol 19:3203-3209, 2001
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
Sawyers CL: Imatinib GIST keeps finding new indications: Successful treatment of dermatofibrosarcoma protuberans by targeted inhibition of the platelet-derived growth factor receptor. J Clin Oncol 20:3568-3569, 2002
Dematteo RP, Heinrich MC, El-Rifai WM, et al: Clinical management of gastrointestinal stromal tumors: Before and after STI-571. Hum Pathol 33:466-477, 2002
Thall PF, Wathen JK, Bekele BN, et al: Hierarchical Bayesian approaches to phase II trials in diseases with multiple subtypes. Stat Med 22:763-780, 2003
Rosen G, Forscher C, Lowenbraun S, et al: Synovial sarcoma: Uniform response of metastases to high dose ifosfamide. Cancer 73:2506-2511, 1994
Singer S, Baldini EH, Demetri GD, et al: Synovial sarcoma: Prognostic significance of tumor size, margin of resection, and mitotic activity for survival. J Clin Oncol 14:1201-1208, 1996
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(Alberto S. Pappo, Meenaks)