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© 2002 American Society for Clinical Oncology Phase II/III Trial of Etoposide and High-Dose Ifosfamide in Newly Diagnosed Metastatic Osteosarcoma: A Pediatric Oncology Group TrialByFrom the Dana-Farber Cancer Institute, The Children’s Hospital, and Massachusetts General Hospital, Harvard Medical School, Boston, MA; Tomorrow’s Children Institute, Hackensack, and University of Medicine and Dentistry of New Jersey, Hackensack, NJ; Hematology-Oncology, Ste Justine Hospital; University of Montreal, Montreal, Quebec, Canada; Brown Medical School, Division of Pediatric-Hematology-Oncology, Rhode Island Hospital, Providence, RI; Department of Statistics, University of Florida, and Pediatric Oncology Group Statistical Office, Gainesville, FL; Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL; Johns Hopkins Oncology Center, Baltimore, MD; and Division of Hematology, Oncology, and Bone Marrow Transplantation, Stanford University School of Medicine, Stanford, CA. Address reprint requests to Allen M. Goorin, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012; email: allen_goorin{at}dfci.harvard.edu
PURPOSE: The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma. PATIENTS AND METHODS: Eligible patients received infusions of 100 mg/m2 per day of etoposide and 3.5 g/m2 per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor. RESULTS: Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% ± 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% ± 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% ± 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi’s syndrome was observed in five patients. CONCLUSION: The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.
PATIENTS WITH osteosarcoma who present with metastatic disease have a poor prognosis. Their long-term survival ranges from 10% to 40%, as compared with patients without metastatic disease at presentation, who have a long-term disease-free survival of 60% to 80%.1-9 To identify agents that could improve the outcome for patients with metastatic osteosarcoma, as well as to identify active agents that could be used for patients with nonmetastatic osteosarcoma, the Pediatric Oncology Group (POG) used a strategy wherein patients with metastatic osteosarcoma are initially treated with novel agents before treatment with other chemotherapeutic agents (therapeutic windows). The first POG metastatic osteosarcoma trial included two courses of single-agent ifosfamide at a dose of 12 g/m2 over 5 days in a 6-week window period. The rate for both complete and partial response was 30%.10 Etoposide has some single-agent activity against osteosarcoma; one partial response was observed in 11 patients with recurrent disease.11 However, etoposide has also demonstrated synergy with alkylating agents—including ifosfamide—in the treatment of patients with sarcomas and other tumors, probably through the inhibition of DNA topoisomerase II activity.12,13 Patients with recurrent osteosarcoma had a response rate of 33% to the combination of etoposide at 500 mg/m2 and ifosfamide at 9 gm/m2 (divided over 5 days).12 Because of the suspected synergy between etoposide and ifosfamide, and to determine whether there is a dose-response relationship for this combination, a phase I trial of etoposide combined with escalating doses of ifosfamide with granulocyte colony-stimulating factor (G-CSF) was undertaken. A response rate of nearly 50% was noted in patients with recurrent osteosarcoma.14 Therefore, a phase II/III study was begun in patients with newly diagnosed metastatic osteosarcoma at the maximum-tolerated dose of ifosfamide and etoposide. The objective of this trial (POG 9450) was to estimate the response rate to etoposide and high-dose ifosfamide followed by G-CSF, and to determine the outcome of patients who present with metastatic osteosarcoma. This is a report of the response rate and toxicity of this drug combination; we also report the 2-year progression-free survival (PFS) and overall survival rates for these patients presenting with metastatic disease.
Eligibility Patients younger than 30 years of age with measurable, newly diagnosed, biopsy-proven, high-grade metastatic osteosarcoma were eligible for inclusion in this study. Patients were required to have normal renal, hepatic, and bone marrow function. Performance status had to be Eastern Cooperative Oncology Group grade 2 or less, which required patients to be ambulatory and capable of age-appropriate self-care. Radiologic evaluation had to be performed within the 2 weeks before chemotherapy began. The evaluation included conventional radiographs; magnetic resonance imaging scan, computerized tomography (CT) scan, or both of the primary site; plain X-ray and CT of the chest; and radionuclide bone scan to quantify the extent of metastatic disease. Biopsy of at least one presumed metastatic site was strongly advised to verify the presence of metastatic disease. To confirm the diagnosis, the reference pathologist reviewed histologic material from the primary tumor site in all cases. Patients with a history of previous cancer, or who had received either previous chemotherapy or radiation therapy, were excluded. The protocol was approved by the independent review boards of the relevant institutions, and written informed consent from the patients or patients’ guardians was obtained before registration.
Induction Chemotherapy
Patients underwent complete radiographic reevaluation after two courses of induction chemotherapy. Surgery for the primary tumor site was encouraged at this time, with representative samples taken during surgery submitted to the reference pathologist. The surgical management of metastatic sites was left to the discretion of the treating doctors; however, surgical removal of all metastatic sites was recommended when feasible.
Continuation Therapy
Assessment of Response Patients were assessed for clinical response to therapy at week 6 (3 weeks after the second course of etoposide and ifosfamide had been provided) by use of CT scan, magnetic resonance imaging scan of the primary tumor, or both; CT scan of the chest; and bone scan. The definitions of clinical response were as follows: complete response, total disappearance of tumors; partial response, 50% or more decrease in the sum of the products of the perpendicular diameter of all measurable lesions; minor response, 25% or more but less than 50% decrease in the sum of the products of the perpendicular diameter of measurable lesions; stable disease, less than 25% decrease in the size of the sum of the products of the perpendicular diameter of all measurable lesions; and progressive disease, 25% or more increase in the sum of the products of the perpendicular diameter of measurable lesions or appearance of disease at a new site. Primary tumor necrosis in patients with nonmetastatic osteosarcoma after chemotherapy is a reproducible predictor of outcome even though the bone primary tumor remains radiographically stable.15,16 Pathologic response of tumor necrosis was also determined in some patients. Complete response was defined as 100% tumor necrosis of the primary tumor after pathologic sectioning (Huvos response grade 4).15 Partial response was defined as 90% or more tumor necrosis, but less than 100% tumor necrosis of the primary tumor specimen (modified Huvos response grade 3). In practice, only rare nests or individual tumor cells were appreciated (> 95% tumor kill) or there was significant residual tumor resulting in more than 10% viable tumor remaining. Thus, patients were divided into three relatively distinct response groups by histologic evaluation of the primary tumor: complete tumor kill, near-complete tumor kill, or extensive residual disease. For the analyses in this report, only responses after the second course of chemotherapy were considered.
Toxicity
Statistical Analysis Time to an adverse event was defined as days from the date of registration until recurrence of tumor at any site, progressive disease, second malignancy, or death from any cause. Patients not experiencing an event were censored as of the date of last contact. Survival and PFS estimates were computed via the Kaplan-Meier method, and SEs of the estimates were determined according to Peto and Peto.17,18
Patient Characteristics The study accrued a total of 43 patients. Two were ineligible; one patient began treatment before being registered, and the second had an unresectable primary tumor without metastatic disease. Twenty-eight of the 41 eligible patients had metastatic disease in their lungs; 12 patients had metastatic disease within other bones (six of whom also had lung metastases); and one other patient had metastatic disease to liver and lung. The patient characteristics of the 41 eligible patients are listed in Table 1.
Response Two patients were not assessable for response but were assessable for outcome. One patient was removed from the study after the development of Fanconi’s syndrome during the first course of chemotherapy, and the second refused further therapy after the first course. Thirty-nine patients were assessable for response (Table 2). Twelve of the responses were evaluated solely by tumor necrosis. The total response rate (± SE), including both complete and partial response, for the 39 patients was 59% ± 8%. Table 2 also gives responses by site of metastatic disease.
Five patients noted in Table 2, indicated by the letters A, B, C, D, and E, displayed discordance between the radiologic response of their metastases and the pathologic tumor necrosis of the primary tumor. Four (A to D) had a more significant radiologic than histologic response. One patient (A) experienced complete response on the basis of the clearing of the pulmonary metastases on CT scan but only had 30% tumor necrosis of the primary tumor. A second patient (B) demonstrated a more than 50% decrease in the size of pulmonary nodules on CT scan but had a poor primary tumor necrosis of 20%. A third patient (C) had the soft tissue component of the primary tumor decrease by more than 50% but only had an overall tumor necrosis of 35% of the remaining tumor. Bone scan of the fourth patient (D) showed a complete disappearance of metastases (the patient presented with multiple bony lesions), but the necrosis within the primary tumor approached only 75%. The fifth patient (E), whom we classified as exhibiting a minor response, showed a 32% decrease in area of the tumor on chest CT scan as well as 90% tumor necrosis in the primary tumor.
Pathologic Response
Radiologic Response Only By use of the World Health Organization radiologic response (see Patients and Methods) as the only criteria of response, there were 27 assessable patients. Table 4 gives the radiologic response by metastatic site. The overall radiologic response (14 of 27) rate was 52% ± 9%.
PFS The 2-year PFS for the 41 patients was 43% ± 8% (Fig 3). Adverse events occurred a median of 11 months after initial diagnosis (range, 1 to 32 months). As of this writing, 16 patients are progression free, 11 of whom show no evidence of disease and five of whom have stable disease. PFS by metastatic site at presentation is shown in Fig 4A. Twenty-eight patients had metastases only in the lung; 10 are without failure. The 2-year PFS rate for these patients was 34% ± 10%. Twelve patients had metastases to other bones (including six with metastatic disease in the lungs as well). Six of these 12 have not had disease progression. The 2-year PFS rate for these patients was 58% ± 14%. The single patient with liver metastases experienced a relapse.
Survival Figure 3 shows the overall survival for the 41 patients. The 2-year survival probability was 55% ± 8%. Median follow-up for all patients was 26 months. Eighteen patients are still alive. Survival rates by metastatic site at presentation are shown in Fig 4B. Eleven of the 28 patients with metastases to the lung are alive. The 2-year survival rate was 52% ± 10%. Of the 12 patients with bone metastases with or without lung metastases, seven are still alive. The 2-year survival rate was 58% ± 14%. The single patient who had liver metastases at the time of presentation is dead.
Toxicity
Grade 3 and 4 toxicities for the continuation therapy are listed in Tables 6 and 7. This was an extremely toxic regimen. Two deaths were recorded among the 41 patients, both of which occurred while the patients were in remission during continuation therapy. The most common toxicity was again hematologic (Table 6). Grade 3 and 4 nonhematopoietic toxicities are listed in Table 7. Six patients (13%) developed bacteremia, including one patient who died of Gram-negative sepsis. Five patients had abscesses, and an additional three patients had other significant infections.
Grade 3 Fanconi’s syndrome, although recognized by the treating doctors and easy to control with electrolyte replacement, occurred in two patients. Electrolyte abnormalities were observed in an additional seven patients, with two of them being grade 4, and included abnormal potassium, calcium, and magnesium. The electrolyte abnormalities were observed as a result of combination chemotherapy that included ifosfamide and cisplatin. Acute congestive heart failure occurred in three patients, one of whom died. Two patients experienced severe bilateral sensorineural hearing loss of the type associated with cisplatin toxicity. Despite serious toxicity associated with this regimen, patients were generally able to receive chemotherapy in the dosages and the schedule prescribed in the protocol.
The single-agent chemotherapy response rate in measurable osteosarcoma is 15% or less for many agents, including cyclophosphamide,19-21 melphalan,22 mitomycin,23 dacarbazine,24-26 and dactinomycin.27 The most active single agents in osteosarcoma have a response rate between 20% and 40% and include doxorubicin,28-33 high-dose methotrexate with leucovorin rescue,34-40 cisplatin,41-44 and ifosfamide.1,10 Although the response rate of ifosfamide alone in relapsed osteosarcoma was only 10%,11 the combination of etoposide and lower-dose ifosfamide seems to be more active in recurrent osteosarcoma than ifosfamide alone, with 14 (33%) of 42 patients experiencing a response to this combination.12 Because of the presumed synergy between etoposide and ifosfamide and the expectation that the addition of G-CSF would permit dose intensification of ifosfamide, a phase I trial in patients with recurrent osteosarcoma was completed, with six of 13 patients exhibiting partial responses.14 The order of etoposide and ifosfamide was chosen empirically and was consistent with previous POG trials. To our knowledge, the overall response rate of 59% for the combination of etoposide and high-dose ifosfamide used in this study is unprecedented in osteosarcoma. This response to ifosfamide and etoposide seems to be dose dependent when compared with other studies, although the number of patients treated on each study are few.12,14,45,46 Additionally, previous studies have demonstrated that patients who present with bone metastases (synchronous osteosarcoma) have a poor prognosis. The tumors are often unresponsive to chemotherapy provided shortly after diagnosis, leading to progression and death.1,5,9 However, in this trial, patients with synchronous bony metastatic osteosarcoma had at least as good a response rate as those with metastases limited to the lungs, with eight of 10 patients with bone (with or without lung) metastasis exhibiting responses, compared with 15 of 28 patients whose metastases were only in the lung. This was true whether radiologic, pathologic, or all responses were considered. Although the minimum follow-up was only 2 years, the PFS and survival of more than 40% for this group of patients are encouraging. In addition, the 2-year PFS and survival rates of more than 50% for patients who presented with metastatic disease to other bones with or without lung metastases are unique.1,4-6,9 We expect some of these patients to ultimately relapse. Particularly at risk are the patients who presented with multiple bone metastases that were not resectable. Nevertheless, this 2-year outcome is encouraging and should give medical, surgical, and radiation oncologists data to support aggressive management of these patients. Toxicities associated with the first two courses of etoposide and high-dose ifosfamide with G-CSF were primarily hematopoietic, with 83% of patients experiencing severe neutropenia that led to sepsis in 10% and other bacterial infections in an additional 7% of the patients. No grade 4 renal toxicity was observed. However, grade 3 Fanconi’s syndrome occurred in 7% of the patients. The combined toxicity of both induction and maintenance chemotherapy was severe. Two patients died in remission, one as a result of Gram-negative sepsis and another as a result of congestive heart failure. The major toxicity was bone marrow suppression, occurring in more than 90% of patients, leading to bacteremia, which occurred in 24% of patients enrolled onto this trial. Renal salt wasting also was common, occurring in 22% of patients. Congestive heart failure occurred in 7% of patients. We conclude that although morbidity was high, the response rates of 59% overall and 80% for the patients with synchronous bony metastatic osteosarcoma are encouraging. If this translates into long-term survival advantage for these patients, then the additional toxicity may be acceptable, especially for patients with bone metastases; previous experience indicates that all of whom would be expected to die within 2 years of diagnosis. The overall clinical utility of this active combination remains to be studied in further trials.
APPENDIX
Supported by grant no. CA-41573 to Dana-Farber Cancer Institute, CA-29139 to the National Institutes of Health, National Cancer Institute, CA-30969 to the POG Operations Office, CA-33603 to Stanford University/Packard Children’s Hospital, CA-15989 to University of Mississippi Medical Center, CA-28476 to Johns Hopkins Hospital, CA-29293 to Rhode Island Hospital, CA-25408 to University of Alabama–Birmingham, and CA-35906 to Tomorrow’s Children’s Fund.
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Eur J Cancer 33: 232–237, 1997 Submitted April 13, 2001; accepted September 4, 2001. This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
