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© 2002 American Society for Clinical Oncology High-Dose Chemotherapy in the Treatment of Relapsed Osteosarcoma: An Italian Sarcoma Group StudyByFrom the Department of Pediatrics, University of Turin; Department of Clinical Oncology, Ordine Mauriziano–Institute for Cancer Research and Treatment, Turin; Department of Oncology, Ospedale S. Maria delle Croci, Ravenna; and Department of Chemotherapy, Department of Musculoskeletal Tumors, Istituto Ortopedico Rizzoli, Bologna, Italy. Address reprint requests to Franca Fagioli, MD, Department of Pediatrics, University of Turin, Piazza Polonia 94, 10126 Turin, Italy; email: fagioli{at}pediatria.unito.it
PURPOSE: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse. PATIENTS AND METHODS: Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT. RESULTS: Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%. CONCLUSION: HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.
THE PROGNOSIS OF patients with high-grade osteosarcoma has greatly improved over the past 25 years, with overall survival rates increasing from 15% to 70%. This improvement is attributed to (1) the effect of preoperative chemotherapy,1-4 (2) the introduction of aggressive chemotherapy with various combinations of high-dose methotrexate, doxorubicin, cisplatinum, and ifosfamide,5-8 (3) the identification of the relationship of dose-response between methotrexate, doxorubicin, cisplatinum, and osteosarcoma cells,9,10 and (4) the recognition of the main prognostic factor, such as the histologic response to preoperative chemotherapy, which might change postoperative chemotherapy.11,12 The prognosis of patients with osteosarcoma in metastatic relapse is very poor, with overall survival rates between 0% and 50% after metastasectomy and aggressive second-line chemotherapy.13-17 In an attempt to improve survival for patients in metastatic relapse, the Italian and Scandinavian Sarcoma Group devised a prospective phase II protocol with high-dose chemotherapy (HDCT) and peripheral-blood stem-cell (PBSC) reinfusion.18,19 This approach seems attractive for the pharmacokinetic data available in osteosarcoma patients,20,21 but the nonhematopoietic toxicity of methotrexate, doxorubicin, cisplatinum, and ifosfamide9,22-24 makes these agents unsuitable for dose escalation in HDCT. For HDCT, we chose carboplatin and etoposide because of their suitable toxicity profile. Recent data indicate considerable activity of etoposide against bone and soft tissue sarcomas when it is administered in a long-term infusion, taking advantage of the phase specificity of this agent.25,26 Carboplatin has also been shown to have antitumor activity in osteosarcoma.27-31
Selection of Patients Patients with high-grade osteosarcoma in metastatic relapse were considered eligible for this protocol if they had multiple metastases or solitary metastasis at intervals of less than 30 months from diagnosis, were younger than 40 years of age, and had normal hepatic and renal function, a WBC count greater than 3.0 x 109/L, and platelets greater than 100 x 109/L. Before entering this protocol, patients underwent a physical examination, a chest computed tomography, and a radionuclide bone scan. Careful enumeration and measurement of all metastatic sites was required. All patients or their legal guardians signed a document of informed consent consistent with local institutional review board guidelines.
Treatment High-dose chemotherapy consisted of a 2-hour infusion of carboplatin 375 mg/m2/d for 4 days and continuous-infusion etoposide 450 mg/m2/d for 4 days. PBSCs were infused 48 hours after the end of HDCT. The first cycle of HDCT was planned 1 to 2 weeks after mobilization and the second cycle, 4 to 6 weeks after the first. The protocol outline is shown in Fig 1.
Granulocyte colony-stimulating factor 5 µg/kg/d was administered from day +1 until the neutrophil count was more than 1 x 109/L for 3 consecutive days. Patients were nursed in a single room at positive air pressure and received oral nonabsorbable antibiotics (gentamicin and nystatin). Pneumocystis carinii prophylaxis was performed with nebulized pentamidine 300 mg every 3 weeks from the first day of HDCT. The surgical management of the metastatic sites was left to the discretion of the individual surgeon. However, surgical removal of all metastatic sites was strongly encouraged.
Toxicity
Clinical Response
Definitions of response were as follows: complete remission (CR), radiologic disappearance of all evidence of metastasis; partial response (PR),
Statistical Analysis
Thirty-two Italian patients (19 male and 13 female) were enrolled onto this study. At the time of study, median patient age was 15 years (range, 8 to 38 years). The site of relapse was mainly the lung. Twenty-one patients were in first relapse at a median of 20 months (range, 10 to 52 months) from diagnosis. All except one had two or more mono- or bilateral metastases. Eight patients were in second relapse at a median of 28.5 months (range, 15 to 77 months), and three patients were in third relapse at 29, 32, and 39 months from diagnosis (Tables 1 and 2).
Surgery was performed in 14 patients before chemotherapy (primary surgery). Surgery was complete in 11 of these patients. After the mobilizing cycle, 29 patients achieved the required CD34+ cell number (median, 12.1 x 106/kg; range, 5.52 to 25.5) with a median of two aphereses (range, one to six). Three patients failed (CD34+ 0, 1.29, and 2.41 x 106/kg) and received only one course of HDCT (in the first two patients bone marrow was added). Another patient received only one course because she had veno-occlusive disease after the first course and died of multiple organ failure. As of April 1, 2001, 28 patients had undergone two courses of high-dose carboplatin and etoposide, whereas four patients had one course, for a total of 60 courses. A median of 10 days (range, 7 to 14 days) was required to reach a granulocyte count greater than 0.5 x 109/L, a median of 11 days (range, 8 to 16 days) was required to reach a granulocyte count greater than 1 x 109/L, a median of 12 days (range, 4 to 30 days) was required to reach a platelet count greater than 25 x 109/L, and a median of 15 days (range, 7 to 30 days) was required to reach a platelet count greater than 50 x 109/L. The median time for hematologic recovery was similar (no significant difference) after the first and the second course of high-dose carboplatin and etoposide. Severe nonhematologic toxicity, according to the Bearman score, was present in only five courses: grade 3 stomatitis was present in four courses and grade 3 hepatic toxicity was present in one course. There was no significant difference in nonhematologic toxicity between the first and the second course of chemotherapy. As shown in Table 3, 11 of 32 patients were in CR before HDCT, whereas 21 patients underwent HDCT with evident disease. After the mobilizing cycle, 11 patients were in CR, eight were in PR, and 13 had SD. After HDCT, 15 patients were in CR, three were in PR, eight had SD, five had PD, and one patient died of toxicity. Four additional CRs were obtained with HDCT among the eight patients in PR after induction chemotherapy. None of the 13 patients in SD entered a remission after HDCT. Surgery was performed in 11 patients after HDCT (secondary surgery) and was definitive in 10 patients. Surgery was not performed in five patients because of PD and in four patients because of CR. At the end of treatment, 25 patients were in CR and six had PD.
As of April 1, 2001, 14 patients (43.7%) are alive, with a median survival time of 20 months from study entry (range, 7 to 36 months): four are in first CR at a median of 21 months (range, 7 to 36 months) from study entry, three are in second CR at 8, 20, and 24 months, and one is in fourth CR at 30 months. Six patients are alive with disease at 18 months (range, 11 to 26 months). Eighteen patients (56%) died: 17 of disease at 16 months from study entry (range, 8 to 39 months) and one of toxicity at 3 months (multiple organ failure). Transplantation-related mortality was 3.1%. The relapse or PD rate was 84.4%: 21 patients (65.6%) relapsed with a median time of 8 months (range, 2 to 15 months) and six patients (18.8%) did not respond to treatment. The 3-year overall survival rate is 20% (Fig 2) and the 3-year disease-free survival is 12% (Fig 3). The median follow-up time is 18.5 months (range, 3 to 39 months).
The outlook for patients with high-grade osteosarcoma in metastatic relapse remains poor. When the lung is the only site of the disease recurrence, a surgical approach in which all metastases are removed has been advocated as potentially curative, with a reported 5-year survival rate from the first thoracotomy of 23% to 50%.13,34-41 The prognosis of these patients is correlated with the relapse-free interval from initial diagnosis, the number and the sites of the metastases, and the complete metastasectomy.13 Incomplete surgery or development of bone metastases carries a worse prognosis, with a 0% 4-year overall survival rate.39 Chemotherapy in the management of metastatic osteosarcoma has no proven benefit, especially in heavily pretreated patients.35,40-44 However, a number of regimens have been reported to have been used in these situations, and the published data are difficult to analyze.25,45-47 There are but isolated reports of the use of HDCT in patients with metastatic osteosarcoma.18,19,27,48,49 In an attempt to improve the survival of patients affected by high-grade osteosarcoma in metastatic relapse, the Italian and Scandinavian Sarcoma Group devised a phase II protocol that consists of high doses of carboplatin and etoposide and PBSC reinfusion. Each of these agents has considerable activity against osteosarcoma and a suitable toxicity profile. Dose-limiting toxicity consists of stomatitis and diarrhea for high-dose etoposide and neuropathy, nephrotoxicity, and hepatic toxicity for high-dose carboplatin. Toxicity data on double high-dose treatment using carboplatin and etoposide are derived from phase I/II studies on adult germ cell tumors and from one pediatric study on mixed tumors. In one study, high-dose therapy was a part of the primary therapy.50 In the other three, high-dose therapy was a part of salvage therapy, usually after extensive use of chemotherapy containing platinum.27,51,52 The patients enrolled onto this study do not have a good prognosis. Twenty-one patients were in first relapse at a median of 20 months from diagnosis. All of these patients except one had two or more mono- or bilateral metastases. Eight patients were in second relapse with bilateral metastases of the lung (five patients), lung and bone (one patient), lung and lymph nodes (one patient), and bone (one patient). Three patients were in third relapse. The first-line therapy is shown in Table 1. The patients in second or in third relapse received surgery. Therefore, all patients were heavily pretreated, even though a single course of cyclophosphamide and etoposide allowed an adequate collection for two re-infusions. Only three patients failed to achieve the required number of CD34+ cells, and they received just one course of high-dose carboplatin and etoposide. During the mobilizing cycle, no patients had PD and five patients were in PR. After carboplatin and etoposide administration, trilineage engraftment was promptly observed in all patients, and there was no significant difference between the first and the second course of chemotherapy. Furthermore, our results showed that a two-drug conditioning regimen containing carboplatin and etoposide is well tolerated. We observed severe extra-hematopoietic toxicity in only five courses: severe stomatitis requiring morphine in four courses and severe hepatic toxicity in one course (this patient died of multiorgan failure only 3 months after study entry). After two cycles of HDCT, five patients were in PD, five were in PR, and four were in CR. At the end of treatment, with primary or secondary surgery, there were 25 patients in CR and six in PD. It is important to note that most of these patients had received cisplatin in first-line therapy and such patients may develop resistance to platinum agents. Such acquired cross-resistance after exposure to cisplatin has been reported in an osteosarcoma cell line.53 Twenty one patients (65.6%) relapsed, with a median time of 8 months. In conclusion, combining surgery with HDCT can render a large proportion of patients disease-free. The evidence that patients in PR after induction therapy can reach CR after HDCT indicates that this procedure may be useful for these patients. Additional maintenance treatment or completely novel strategies, such as nonmyeloablative allogeneic transplantation, need to be explored to eliminate minimal residual disease. For patients in SD after primary treatment, HDCT seems scarcely efficacious. For these chemoresistant patients, completely new strategies are warranted.
Supported in part by the Italian Association for Cancer Research, Milan, Italy (E.M. and M.A). We thank Andrew M. Garvey, BA(Hons), Licentiate of Trinity College London(Teaching English as a Second or Foreign Language) for editorial assistance.
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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
50% reduction in the tumor diameters at all sites; stable disease (SD), less than 50% decrease or less than 25% increase in the size of one or more lesions; and progressive disease (PD), more than 25% increase in the size of one or more of the metastases. 
, Dead.
