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© 2000 American Society for Clinical Oncology Randomized Phase III Study Comparing Conventional-Dose Doxorubicin Plus Ifosfamide Versus High-Dose Doxorubicin Plus Ifosfamide Plus Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor in Advanced Soft Tissue Sarcomas: A Trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma GroupFrom the Institut Gustave Roussy, Villejuif; Centre Leon Bérard, Lyon, France; Royal Marsden Hospital, London; Christie Hospital, Manchester, United Kingdom; Antoni van Leuuwenhoek Ziekenhuis, Amsterdam; Academisch Ziekenhuis, Leiden; St Radboud University Hospital, Nijmeven; Rotterdam Cancer Institute, Rotterdam, The Netherlands; Hoechst Marion Roussel, Frankfurt/Main, Germany; European Organization for Research and Treatment of Cancer Data Center, Brussels; Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium. Address reprint requests to Axel Le Cesne, MD, Service de Medecine B, Institut Gustave Roussy, 94805 Villejuif Cedex, France; email lecesne{at}igr.fr
PURPOSE: This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS). PATIENTS AND METHODS: Between 1992 and 1995, 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m2 on day 1) and ifosfamide (5 g/m2 on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m2 on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 µg/m2 on days 3 to 16); all courses were repeated every 3 weeks. RESULTS: The median age of the 294 eligible patients was 50 years. They received a median of five chemotherapy cycles. The median dose and relative doxorubicin dose-intensity achieved were 245 mg and 97% in arm A and 360 mg and 99% in arm B, respectively. Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P = .65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P = .03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P = .98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B. CONCLUSION: The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS.
RESULTS OF first-line chemotherapy in adult advanced soft tissue sarcoma (ASTS) remain disappointing. Only two drugs, doxorubicin and ifosfamide, have demonstrated a consistent single-agent activity, yielding response rates of 15% to 25%.1 In the last 20 years, various cooperative groups have investigated different drug combinations as first-line chemotherapy for ASTS in randomized trials.2-9 Despite the higher response rates achieved in some studies,5,6,8,9 no multidrug regimen has demonstrated any advantage in terms of overall survival when compared with single-agent doxorubicin given at 75 mg/m2 every 3 weeks. One of the major reasons could be that the combination regimens included lower doses of anthracyclines. Despite the fact that there is some evidence of a dose-response relationship for doxorubicin in soft tissue sarcoma, the myelotoxicity of the combination of the two most active drugs, ie, doxorubicin and ifosfamide, precludes any dose escalation of the former within the optimal dose range (> 70 mg/m2).10,11 The use of hematopoietic growth-factors allowed safe administration of doxorubicin 75 mg/m2 with ifosfamide 5 g/m2 in a previous large European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) phase II trial including more than 100 patients.12 Not only was the toxicity profile similar or better than in other reports using lower doses of doxorubicin,10,11 but the response rate in this study was also the highest so far observed by the EORTC STBSG, with 45% of objective responses including 10% of complete responses; the median survival was 15 months. These results compare favorably with those reported in the two successive EORTC first-line chemotherapy studies testing the activity of 50 mg/m2 of doxorubicin in combination with 5 g/m2 of ifosfamide7,10 in which objective responses were observed in 35% and 28% of patients. The promising results of the intensive regimen (dose-intensity of doxorubicin increased by 50%) prompted the EORTC STBSG to design a randomized study to compare the therapeutic activity of the standard regimen with that of the intensified regimen in terms of response rate (primary aim), response duration, time to progression, and survival.
Patient Population Patients eligible for entry in the study were required to have histologically proven bidimensionally measurable metastatic or unresectable locoregional recurrent soft tissue sarcoma. Patients who had received prior chemotherapy or cytokines, whether adjuvant or for advanced disease, were not eligible for the trial. All eligible patients were to have progressive disease with defined index lesions at physical examination and on x-rays, ultrasound, or computed tomographic scan. No concurrent therapy was allowed. Other eligibility criteria were as follows: age 18 to 76 years; Karnofsky performance status  70%; no functionally important cardiovascular disease; no prior cancer (except adequately treated carcinoma-in-situ of the cervix or basal cell carcinoma); presence of measurable lesions not previously irradiated; no CNS metastases; no major surgery 3 weeks before entry; adequate bone-marrow reserve (absolute WBC count > 3,000/µL and platelet count 100,000/µL); and adequate renal and hepatic function (serum creatinine < 150 mmol/L and bilirubin < 25 mmol/L). Patients with mesothelioma, chondrosarcoma, neuroblastoma, osteosarcoma, Ewing’s sarcoma, embryonal rhabdomyosarcoma, and dermatofibrosarcoma were excluded. In addition, all patients were required to give written informed consent.
Treatment Doxorubicin was dissolved in distilled water at a concentration of 5 mg/mL and given as an intravenous bolus infusion over a period of 5 to 20 minutes through the tubing of saline infusion. Ifosfamide was dissolved in sterile water for injection (12.5 mL of water per gram of ifosfamide). The total dose was further diluted in 3 L of dextrose saline and infused over 24 hours immediately after the bolus doxorubicin. A diuresis was established using 1 L of dextrose saline given over 2 hours before treatment, and 200 mL of 20% mannitol was infused over 30 minutes using a Y connection starting 1 hour before chemotherapy. Mesna (2-mercaptoethane sodium sulfonate) 600 mg/m2 intravenous bolus preceded the continuous infusion of mesna/ifosfamide. Mesna was added at a dose of 2.5 g/m2 to the dextrose saline solution for the 24-hour infusion. At the end of the ifosfamide infusion, a further 2 L of dextrose saline containing 1.25 g/m2 of mesna was infused over 12 hours. Doxorubicin, ifosfamide, and mesna were available from local suppliers in each country. Yeast-derived rhGM-CSF (sargramostim) was supplied by Behringwerke A.G. (Marburg, Germany). Vials (500 µg per vial) were reconstituted in sterile water for injection immediately before subcutaneous administration using 1 mL/vial. The maximal daily dose of rhGM-CSF was 500 µg even if body-surface area was greater than 2 m2. GM-CSF was given subcutaneously once daily.
Follow-Up Investigations and Dose Modifications
Evaluation of Response Patients were considered assessable for response if they had received a minimum of two cycles of chemotherapy. In case of rapidly progressive disease after one course of chemotherapy, the patient was removed from study and classified as treatment failure. If response had not been assessed, they were included in the following categories: early death from toxicity if death occurred within 6 weeks with signs of toxicity; early death from malignant disease if death occurred within 6 weeks after commencing chemotherapy as a result of soft tissue sarcoma and without signs of toxicity; and early death from other cause if death occurred within 6 weeks from a cause not related to malignant disease. Patients who had stable disease or exhibited complete or partial responses remained on treatment until disease progression or to a total doxorubicin dose of 550 mg/m2. Initially, the number of chemotherapeutic courses was limited to six courses in the rhGM-CSF arm (arm B) and to 10 courses in the standard-dose arm (arm A). A seventh and eighth cycle of chemotherapy could be given in arm A and an eleventh cycle could be administered in arm B if the radionucleotide cardiac ejection fraction remained more than 50% at rest or more than 60% during maximal exercise. After completion of treatment, a follow-up was performed every 3 months for the first year and every 6 months for the following years. The duration of response was measured from the date of randomization to the date of documented progression for all responding patients (complete response or partial response), according to the first end point of WHO guidelines. The progression-free survival (PFS) was measured from the date of randomization to the date of documented progression. Patients who had not progressed at the date of last follow-up and patients who died from other causes than their sarcoma were censored at the date of last follow-up or death. Survival was measured from the date of randomization to the date of death; patients alive at the time of the analysis were censored at the date of last follow-up.
Dose-Intensity
Statistical Design
Overall survival, time to progression, and duration of response were estimated by the Kaplan-Meier method; comparisons were made using the log-rank test. Response rates were compared using the
Patient Characteristics From March 1992 to January 1995, 314 adult patients from seven countries and 19 European centers were enrolled onto the study. Twenty patients (6%) were considered not eligible for the following reasons: histology review not showing sarcoma in 12 cases; no target lesions in three cases; inappropriate performance status in three cases; CNS metastases in one case; and second primary malignant tumor in one case. Therefore, all analyses (except feasibility and toxicity) are reported on 294 eligible off-study patients. A total of 242 (82%) out of 294 eligible patients were centrally reviewed. In 207 cases (86%), the reviewed diagnosis corresponded with the local diagnosis. The analysis is based on the review diagnosis when available and on the local diagnosis for other cases. Patient characteristics are listed in Table 1. The median age of the 170 females and 124 males was 50 years (range, 19 to 76 years). Seventy percent of patients had a Karnofsky performance status of 90% to 100%. Ninety-five patients (32%) had received prior radiotherapy. The incidence of histologic tumor types is listed in Table 1. Of note, 112 patients (38%) had leiomyosarcomas. All but 37 patients had metastatic disease (lung metastases, 58% of patients; and liver metastases, 23%). The primary site (untreated or recurrence) was involved in 145 (49%) out of 294 patients. Patient characteristics were well-balanced between the two therapeutic arms.
Treatment and Tolerance The median number of cycles given was five in each therapeutic arm (range, one to 11 cycles). The maximum number of cycles was 11 and eight in the standard-dose and high-dose arms, respectively. Fifty-one patients (17%) discontinued therapy for toxicity reasons, 15 in the conventional arm and 36 in the intensive arm. There were three early deaths caused by toxicity, two in the rhGM-CSF arm (one patient died of renal failure and one of septic shock during neutropenia) and one in the standard-dose arm (septic shock during neutropenia). One early death from other causes was observed in the standard-dose arm. Eleven patients (six in arm A and five in arm B) stopped treatment because of both progression and toxicity. In addition, 13 patients (seven in arm A and six in arm B) refused to continue the treatment. Hematologic grade 3/4 toxicities are listed in Table 2. This table is based on the lowest value of hematologic counts and the worst toxicity observed during the whole treatment. Hematologic toxicity was the most frequent side effect, with grade 3 or 4 neutropenia documented in 92% and 90% of patients in arm A and arm B, respectively. The median neutrophil nadir was similar in both arms. However, incidence of febrile neutropenia was higher in arm B than arm A (16.6% v 4.6%, respectively; P = .0004). Similarly, platelet toxicity was significantly more frequent in the rhGM-CSF arm, with 50% of grade 3/4 thrombocytopenia and a median platelet nadir of 45 x 109/L (v 8% and 141 x 109/L, respectively, in arm A). In addition, this latter toxicity was cumulative, with a median platelet nadir of 142 x 109/L on cycle 1 versus 32 x 109/L on cycle 6 in the rhGM-CSF arm and a median nadir of 213 x 109/L on cycle 1 versus 146 x 109/L on cycle 6 in the standard arm.
The other toxicities, listed in Table 3, were mainly mild and manageable in both arms, in particular cardiac toxicity (grade 2/3 cardiac toxicity occurred in only two patients [1.3%] in the rhGM-CSF arm v three patients [1.9%] in the standard-dose arm. Arm B demonstrated a significantly higher rate of asthenia and stomatitis. Very few side effects seemed directly attributable to rhGM-CSF (Table 3).
Dose-Intensity A total of 738 cycles of therapy were administered in arm A, and 664 cycles were administered in arm B. Treatment was delayed in 49 cycles (6.6% of cycles, 18.2% of patients) in the standard-dose arm and in 25 cycles (3.8% of cycles; 15.2% of patients) in the high-dose arm because of hematologic toxicity. In addition, the dose of doxorubicin was reduced in six cycles (0.4%) and ifosfamide in 37 cycles (2.5%) because of hematologic toxicity. The median duration of treatment was 106 days (range, 21 to 272 days) in the standard-dose arm and 107 days (range, 21 to 176 days) in the high-dose arm. The median doses of doxorubicin and ifosfamide were 245 mg/m2 and 23 g/m2 in arm A and 360 mg/m2 and 21 g/m2 in arm B, respectively. The median relative dose-intensities of the chemotherapy regimen were 97% in the standard-dose arm and 98% in the high-dose arm.
Response to Therapy
The analysis of response according to certain prognostic categories (age, performance status, primary site, metastatic site, histology, and disease-free interval) is listed in Table 5. Responses were obtained over the full range of metastatic sites: 27% in lung metastases (47 out of 171 patients with lung involvement) and 10% in liver metastases (seven out of 68 patients with liver lesions). Objective tumor regressions occurred in 29% of patients with malignant fibrous histiocytoma, in 28% with synovial-sarcomas, and in 14% with leiomyosarcomas. Despite the small number of patients, the analysis of response by primary site of the leiomyosarcoma shows no difference between the four groups of patients with leiomyosarcoma (gastrointestinal, 11%; retroperitoneal, 12%; uterine, 16%; and other, 18%). Liver involvement is more frequent in patients with leiomyosarcoma (36%) than in patients with other histologic types (14%), but response rates are similar in both groups of patients (four out of 41 and three out of 27, respectively).
Responses were observed in 24% of patients registered in the trial less than 6 months since the first diagnosis of sarcoma, whereas 15% of patients included more than 2 years after initial diagnosis achieved a complete or partial response. There were no differences between the two therapeutic arms. The median duration of response was 47 weeks in arm A and 37 weeks in arm B (P = .12). The PFS and overall survival curves are presented in Fig 1A and 1B. The median time to progression was 19 weeks in arm A and 29 weeks in arm B. In arms A and B, the 1-year PFS estimates were 20% and 28%, respectively (SE, 4%), and the 2-year estimates were 11% and 16%, respectively (SE, 4%). PFS was statistically better in arm B (P = .03), even after adjustment for institution and performance status. The median duration of overall survival was 56 weeks in arm A and 55 weeks in arm B. In arms A and B, the 1-year overall survival estimates were 53% and 57%, respectively (SE, 4%), and the 2-year estimates were 24% and 26%, respectively (SE, 4%). There was no difference in overall survival (P = .98) between the two therapeutic arms, even after adjustment for institution and performance status.
Since the beginning of the 1980s, more than 1,700 patients with ASTS have been included in randomized phase III trials comparing the activity of single-agent doxorubicin with various doxorubicin-containing combination chemotherapy regimens. All these studies failed to demonstrate any advantage of the multidrug regimens in terms of overall survival despite differences in response rates in favor of the combination regimens in some studies.5,6,8,9 Several factors, such as the low complete response rate with combination regimens, the use of drugs with minor, if any, activity in soft tissue sarcomas,2,4,15 and the use of too inadequate doses of doxorubicin (< 60 mg/m2) given in combination,2,7 may at least partly explain these results. A dose-response relationship for doxorubicin has never formally been assessed in a randomized study, but based on data from an extensively cited nonrandomized study, it was considered critical to use a dose of at least 75 mg/m2 every 3 weeks.16 Further support for this came from an EORTC study investigating the interval between doxorubicin cycles.17 However, the myelotoxicity of doxorubicin at 75 mg/m2 precludes its being safely combined with ifosfamide, the most active alkylating agent in ASTS.18 The maximum-tolerated dose of doxorubicin given with a standard dose of ifosfamide (5 g/m2) without hematologic support is 60 mg/m2.11,19 The use of rhGM-CSF between cycles of optimal dose (75 mg/m2) doxorubicin with ifosfamide in a large EORTC phase II study results in manageable hematologic toxicities and a promising 45% response rate with a relatively long median survival.12 As observed with doxorubicin alone, these results and others corroborate the hypothesis of a dose-response relationship of doxorubicin when given in combination with an identical standard dose of ifosfamide (5 g/m2); 7%, 27%, 36%, and 45% of objective responses were achieved with 40 mg/m2,19 50 mg/m2,7 60 mg/m2,11 and 75 mg/m212 of doxorubicin, respectively. However, these are comparisons between nonrandomized studies, and results have to be interpreted with caution. The expected dose-response relationship was not confirmed by the results of this randomized trial, which clearly opens controversies on the role of dose-intensified combinations in soft tissue sarcoma20 and highlights the well-known discrepancies between results of noncontrolled studies on one hand and randomized studies on the other. Despite a 50% increase of doxorubicin dose-intensity in arm B, the differences in terms of objective response, complete remission, and overall survival were not statistically significant between the two therapeutic arms. However, a stringent and careful analysis of these conflicting results is necessary before drawing valid and definitive conclusions on the impact and theoretical benefit of high-dose regimens in these tumors. The rhGM-CSF used in arm B of the present study was a yeast-derived glycosylated cytokine (sargramostim); whereas the Escherichia coli–derived nonglycosylated rhGM-CSF (molgramostim) had been given in the previous phase II study.12 Molgramostim was not available for this phase III trial. It is unlikely that this minor substitution would influence the major difference in the tumor response between the two studies (23% v 45% of objective response rate). Nevertheless, these products display different biologic activities,21 and molgramostim, as a single therapeutic agent or in combination with chemotherapy, was reported to be associated with some tumor regressions in sarcoma patients.22,23 Although of interest, it would be impractical in sarcoma to design a novel randomized study comparing these two rhGM-CSFs using the same chemotherapy regimen. The high incidence of leiomyosarcoma in our present study (38%) may in part explain the low objective response rate in both arms. This histologic subtype seems more resistant to doxorubicin and/or ifosfamide regimens.9,17,24-26 In a large three-armed phase III study, Edmonson et al9 reported a 14% objective response rate in 116 patients with leiomyosarcoma receiving combination treatments similar to ours and an 88% rate of tumor regressions observed in patients with synovial sarcoma. A recent EORTC-STBSG retrospective analysis of 2,185 patients treated with anthracycline-containing first-line regimens shows that advanced age and liver metastases, two times more frequent in leiomyosarcoma than in other histologies (38% v 15%, respectively), are two independent unfavorable prognostic factors for chemotherapy response.26 The increased proportion of patients with leiomyosarcoma (39%) and liver involvement (23%) included in the three more recent EORTC STBSG trials testing the activity of high-dose anthracycline regimens27 may, therefore, contribute to the dismal results of the present study. If we exclude all leiomyosarcomas from the analysis, response rates were 26% and 24% in the standard arm and high-dose arm, respectively. Of note, only 29% of patients included in the previous phase II trial had leiomyosarcomas.12 Future studies should perhaps exclude leiomyosarcomas originating from the gastrointestinal tract (stromal sarcomas) or in the retroperitoneal area (67% with liver metastases in our study) or integrate a stratification by age and liver involvement, for a more realistic assessment of the response rate achieved with doxorubicin and/or ifosfamide schedules. New therapeutic strategies and/or new active drugs are eagerly awaited for this particularly chemoresistant histologic tumor type, beyond the already suggested role of dacarbazine.8 The lengthening of the PFS in the intensive arm is not related to an increase of complete remission rate, which was similar and very low in both arms, or to a difference in partial response rate. Moreover, the duration of objective responses was higher in the standard-dose arm compared with the high-dose arm (47 weeks v 37 weeks, respectively). The number of patients experiencing stabilization of their disease in the rhGM-CSF arm (46.2% v 41.6% in the standard-dose arm) could maybe partly explain the difference in time to progression. Interestingly, 46 patients are classified as no change after receiving no more than six cycles of treatment, 18 patients (40%) in the standard-dose arm and 28 (60%) in the rhGM-CSF arm (data not shown). If we analyze the favorable tumor response status of patients after six cycles of therapy in both arms, ie, complete response, partial response, and no change, 45 patients (60%) received the rhGM-CSF arm (three complete responses, 14 partial responses, and 28 no changes), whereas 31 (40%) received the standard-dose arm (two complete responses, 11 partial responses, and 18 no changes). In the future, the WHO criteria of response could integrate the tumor status at the end of the planned chemotherapy schedule and the median duration of the disease stabilization in metastatic soft tissue sarcoma because a high proportion (30% to 60%) of patients with metastatic soft tissue sarcomas experience this type of response with tumor changes insufficient to enable classification into distinct response categories (complete response, partial response, and progressive disease). However, the improvement of the PFS in the intensive arm could be equally explained by an imbalance between arms in terms of natural history of advanced/metastatic sarcoma. Because a rapid progression of disease before entry onto the study was not a requirement of the protocol, patients with relatively indolent disease (not entirely dependent on tumor grade) could be more represented in the intensive arm. By contrast, intensive chemotherapy could only have a positive impact in a minor subgroup of patients with rapidly progressing tumors and might account for the lengthening of the PFS in the absence of a dose-intensity effect on response rate. In addition, the well-known discrepancy between clinical and histologic response in locally advanced soft tissue sarcoma treated with preoperative chemotherapy28-30 can be easily applied to metastatic sarcomas. Histologic responses could be more accurate predictors of chemosensitivity than clinical responses, making it difficult to evaluate the actual impact of front-line high-dose but nonmyeloablative chemotherapy regimens on disease-free and overall survival in patients with metastatic sarcoma. A careful analysis of all patient files where a partial response was only mentioned once and therefore, in accordance with WHO criteria, classified as a unconfirmed partial response (stable disease) was performed in both arms. Seven and 20 patients in the standard arm and rhGM-CSF arm, respectively, exhibited a partial response where the absence of confirmation of response was not because of medical reasons but because of inappropriate tumor evaluation policies (no radiologic assessments after partial response). If we added these probable objective responses to the confirmed partial responses, we observed 26% and 34.7% partial responses in the standard and high-dose arms, respectively. Because the difference of response rates remained statistically not significant, these results are more consistent with the actual antitumor activity of both regimens and more in accordance to those obtained in prior studies using the same schedules.7,12 The potential underestimation of tumor response in both therapeutic arms can thus be partly explained by the economic difficulties in some western countries to perform iterative radiologic assessments and the general design of phase III studies, which mostly favors overall survival estimation over that of response rate. However, in a context of palliative therapeutic approaches, should we not favor a remission or stable disease achieved without major toxicity over transient partial responses achieved at the cost of life-threatening side effects? In a recent randomized phase III trial of the Southwest Oncology Group, the addition of ifosfamide to doxorubicin and dacarbazine (MAID), compared with only doxorubicin plus dacarbazine, increased the response rate (32% v 17%, respectively) and the time to progression, but patients receiving the latter regimen had a survival advantage, particularly for those older than 50 years.31 These results can be explained in part by the 5% treatment-related deaths observed in the MAID arm, a rate unacceptably high for a regimen with no influence on the outcome of the disease. Because dose-intensified combinations of chemotherapy fail to achieve high complete remission rates, which presumably is a requirement for improving survival,32 this strategy for inoperable advanced/metastatic soft tissue sarcomas should be considered as investigational. With the emergence of inhibitors of angiogenesis33 and new cellular targets for gene therapy programs34 and cancer vaccines, one of the objectives of the next century will undoubtedly be to significantly prolong the life of these patients, by maintaining a dormancy state in nonsymptomatic lesions. The favorable outcome of patients with nonevolutive tumoral lesions after six cycles of chemotherapy in the present study would favor such a strategy. The situation considerably differs in case of potentially operable metastases (lung lesions, only one tumor site involved, young patients, high-grade tumors, and good performance status). In these highly selected patients, dose-intensified combinations that integrate optimal doxorubicin doses and fractionated schedules of high-dose ifosfamide consistently result in higher response rates.24,35-37 This strategy combined with a radical surgery of lung lesions38-40 aiming to cure metastatic patients justifies more aggressive therapeutic approaches but still as part of study protocols. Future designs of randomized trials in ASTS possibly should separate these two subgroups of metastatic patients to obtain a more realistic assessment of response rate and overall survival achieved with dose-intensified chemotherapy regimens. In a climate of controversy and pessimism regarding the role of high-dose chemotherapy in ASTS, the development of novel concepts is urgently needed.
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ABSTRACT
INTRODUCTION
2 test. Those results were confirmed by the use of stratified tests; the Cochran-Mantel-Haenszel test for response, and the Wald test confirmed time to event analysis. 
