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© 2002 American Society for Clinical Oncology Increasing Single Epirubicin Doses in Advanced Soft Tissue SarcomasByFrom the Division of Medical Oncology B, Regina Elena Institute for Cancer Research, Rome, Italy. Address reprint requests to Massimo Lopez, MD, Division of Medical Oncology B, Regina Elena Institute for Cancer Research, Via E. Chianesi, 53, 00144, Rome, Italy; email: lopez{at}ifo.it
PURPOSE: To evaluate the maximum-tolerated dose and the clinical efficacy of epirubicin in patients with advanced soft tissue sarcoma. PATIENTS AND METHODS: Sixty-one patients were treated at three different epirubicin dose levels: 140 mg/m2 (six patients), 160 mg/m2 (52 patients), and 180 mg/m2 (three patients). Cycles were repeated every 3 weeks for a maximum of eight cycles. The first two dose levels proved to be feasible and safe without dose-limiting toxicity (DLT). Because the first three patients entering the third dose level experienced DLT, subsequent patients received the next lower dose level.
RESULTS: The overall response rate was 44% (95% confidence interval, ± 12%), with six complete (10%) and 21 partial (34%) responses. Responses seemed related to epirubicin dose level, because the response rate was 17%, 44%, and 100% for the three dose levels ( CONCLUSION: The third epirubicin dose level (180 mg/m2) was the maximum-tolerated dose. The recommended drug dose for clinical use is 160 mg/m2 every 3 weeks with hematopoietic support. Single high-dose epirubicin is effective as first-line treatment and should be preferentially used whenever a high response rate is important to allow the resection of an otherwise unresectable disease or whenever it might result in a significant symptomatic benefit.
ALTHOUGH SIGNIFICANT improvements have been made in the overall management of localized soft tissue sarcomas (STS), 40% to 60% of patients still develop metastatic disease after curative local therapy, thus requiring systemic treatment. Unfortunately, only a few drugs have activity in this disease. Doxorubicin still remains the most active single agent, with response rates of 20% to 25%; other active single agents include ifosfamide and dacarbazine.1 In an effort to improve results, many combination regimens have been investigated as first-line treatment in advanced STS.2-8 Despite higher response rates reported in some studies,3,4,7 no multidrug regimen has yet been proven superior to single-agent doxorubicin in terms of overall survival. A possible reason for the lack of superiority of combination regimens could be that the toxicity of the combination precluded the use of high doses of doxorubicin. In fact, a dose-response relationship for doxorubicin in STS has been repeatedly reported.9,10
When used at doses of Epirubicin has been used in the treatment of advanced STS either as single agent or in combination chemotherapy regimens.12-17 In single-agent regimens, epirubicin has produced response rates of 14% to 19%, with no increase in response rate with a modest increase in dose-intensity from standard doses.12,13,16 In combination regimens, however, a dose-response effect has been reported by progressively increasing epirubicin dose from 50 mg/m2 to 140 mg/m2 every 3 weeks.18 Indeed, although a threshold effect at lower anthracycline dose levels has been observed with underdosed patients experiencing a worse outcome, less attention has been devoted to identifying a possible threshold effect at higher dose levels. Because the contribution of other active drugs to an anthracycline as a single agent is questionable in the treatment of advanced STS, this study was carried out with epirubicin alone. We sought to evaluate the maximum-tolerated dose and the clinical efficacy of this agent in patients with STS.
Eligibility Criteria Patients between the ages of 14 and 75 years with histologically confirmed locally advanced STS, metastatic STS, or both were eligible for this study. They were required to have bidimensionally measurable disease; World Health Organization performance status  2; no prior chemotherapy; no history of active cardiac disease, including myocardial infarction, congestive heart failure, or angina pectoris; and a resting left-ventricular ejection fraction (LVEF)  45%. No concurrent therapy was allowed. Other baseline eligibility criteria were adequate renal (serum creatinine 1.5 mg/dL), liver (serum bilirubin 1.5 mg/dL), and bone marrow (absolute WBC 4,000/µL, platelet count 100,000 µL) functions. Exclusion criteria were a history of other malignancies (except adequately treated carcinoma in situ of the cervix or basal cell carcinoma), CNS involvement, and prior radiotherapy on parameter lesions. Patients with mesothelioma, neuroblastoma, Ewing’s sarcoma, chondrosarcoma, osteosarcoma, embryonal rhabdomyosarcoma, and dermatofibrosarcoma were excluded. Written informed consent was obtained from all patients.
Prestudy and Follow-up Investigations Standard World Health Organization criteria19 were used for evaluating response. The duration of partial response (PR) or no change was measured from the date of registration to the date of documented progression, and the duration of complete response (CR) was calculated from the moment the CR was documented to the documentation of progression. Time to progression was measured from the date of registration to progression or last contact. Duration of survival was calculated from the date of registration to the date of death. Overall survival and time to progression were estimated by the Kaplan-Meier method; differences between curves were assessed with the log-rank test. Toxicity was evaluated according to the National Cancer Institute common toxicity criteria. Clinical signs of cardiac toxicity were graded via the New York Heart Association functional classification of cardiac status.20
Treatment Treatment was postponed by 1 week (maximum of 2 weeks) if the absolute neutrophil count on the day of scheduled retreatment was less than 1,500/µL or the platelet count was less than 100,000/µL. Granulocyte colony-stimulating factor (G-CSF), 300 µg per day subcutaneously days 8 to 13 (or until a neutrophil count > 1,000/µL after recovery from nadir), was administered only to patients who had previously experienced hematologic DLT. In cases of grade 3 mucositis or serum bilirubin levels between 1.5 mg/dL and 3.0 mg/dL, or in cases of grade 4 neutropenia notwithstanding the use of G-CSF, the epirubicin dose was reduced by 25%.
Patients who demonstrated either a LVEF decrease Antiemetic treatment consisted of an antiserotonin agent plus dexamethasone in a 15-minute infusion before chemotherapy. Patients received no more than eight cycles of epirubicin, and treatment was discontinued in case of progressive disease, unacceptable toxicity, or patient refusal.
Patient Characteristics Between April 1991 and September 1996, 61 patients were treated. Sixteen of these patients given epirubicin alone entered a randomized trial of epirubicin with or without dexrazoxane.21 The pretreatment characteristics of the patients are listed in Table 1. Forty-nine patients (80%) had metastatic disease. The median number of metastatic sites was one (range, zero to three sites), and lung was the most common distant site (44% of the patients). The three most frequent histologic types (Table 2) were liposarcoma, synovial sarcoma, and malignant fibrous histiocytoma.
Only six patients were treated with the first epirubicin dose level (140 mg/m2) because this level proved to be feasible without relevant toxicity. After treating a subsequent cohort of six patients with the second dose level (160 mg/m2) without DLT, patients were given the third level (180 mg/m2). Because the first three patients entering this dose level experienced DLT, subsequent patients received the next lower dose level. Overall, six, 52, and three patients entered the three epirubicin dose levels, respectively.
Response Remissions occurred either in patients with locally advanced (one CR and four PR) and in those with metastatic (five CR and 17 PR) disease. Stable disease was observed in 21 patients (34%). Responses were obtained for the full range of metastatic sites, with lung metastases being the most responsive site of disease (at this level, the response rate was 52%). Objective tumor remissions occurred in 54.5% of patients with synovial sarcomas, in 47% with liposarcomas, in 40% with malignant fibrous histiocytoma, and in 28% with leiomyosarcomas. Noteworthy is the case of a 51-year-old man with a synovial sarcoma of the left foot removed on November 1992 that recurred as multiple lung metastases on September 1993. After only one course of epirubicin, the patient experienced a complete remission. Treatment was continued for six courses, and at the last follow-up examination, the patient was alive and free of disease more than 7 years after completion of chemotherapy. The median duration of response in the 61 assessable patients was 10 months, and the median time to progression was 8 months. The median duration of overall survival (Fig 1) was 15 months; it was 18 and 13 months, respectively, for responding and nonresponding patients. Although this difference is statistically significant (P = .002), it should be remembered that there may not be a direct causal relationship between response and survival.
Toxicity Patients received a median of six cycles (range, two to eight cycles) of chemotherapy. Grade 3 or 4 noncardiac toxicity in the 52 patients receiving epirubicin 160 mg/m2 is listed in Table 3. This table is based on the lowest value of blood counts and the worst toxicity encountered during the whole treatment. Apart from alopecia, myelosuppression was the most frequent side effect, with grade 3 or 4 neutropenia occurring in 79% of the patients; it was febrile in 16 patients (31%). G-CSF was administered to 11 of these patients. Overall, a drug dose reduction was required in 12 patients, and in 10 of these, treatment was also delayed by 1 week at least once. Grade 3 or 4 thrombocytopenia was infrequently observed, and no patient experienced grade 4 anemia.
The median cumulative epirubicin dose was 820 mg/m2 (range, 280 to 1,280 mg/m2). The dose-intensity was computed according to method of Hryniuk and Bush.22 The mean dose-intensity of epirubicin was 49 mg/m2 per week, and 71% of the patients received the planned dose-intensity. The most common nonhematologic toxicity was mild to moderate nausea and vomiting, which occurred in 32 patients (52%). Mucositis/stomatitis occurred in 19 patients (31%).
Laboratory cardiac toxicity was assessable in 36 patients. A
During the last two decades, different drug combinations have been compared with single-agent doxorubicin in several randomized trials as first-line chemotherapy for advanced STS. In all these studies, single-agent treatment has been demonstrated to be as effective as multidrug regimens in terms of overall survival, although higher response rates were achieved with combination chemotherapy in some studies.3,4,7,8 Among the various factors that could explain these results, the use of inadequate doses of doxorubicin has been frequently advocated.3,8 Unfortunately, attempts at exploiting the reported dose-response relationship with this agent have been hampered because of its myelotoxicity and cumulative cardiotoxicity. Data indicate that epirubicin may be less toxic than doxorubicin, allowing a safer dose escalation that could lead to a greater antineoplastic effect. However, the dose-response for epirubicin is less well defined in comparison to the parent compound. In our experience in a similar patient population,16 the response rate to single-agent epirubicin at a dose of 120 mg/m2 every 3 weeks was only 14%, almost identical to the 15% response rate obtained with lower doses (75 mg/m2) in a randomized study that compared equimolar doses of epirubicin and doxorubicin.12 Similar results were achieved in a French study that used epirubicin doses of 100 to 130 mg/m2,13 suggesting that a dose-response effect may be lacking in this dose range. This was the reason why, in the present trial, a starting epirubicin dose of 140 mg/m2 every 3 weeks was selected. This dose level was clearly feasible because toxicity was not significant. Instead, considerable toxicity was encountered in the first three patients receiving the third epirubicin dose level (180 mg/m2), which was mainly represented by grade 4 mucositis/stomatitis and neutropenic fever. Therefore, this level was defined as the maximum-tolerated dose, and the second epirubicin level (160 mg/m2), which was sufficiently safe and feasible when conventional supportive measures were used, was selected as the optimal dosing. The most prominent side effect in this trial was myelosuppression, with grade 3 or 4 neutropenia occurring in 79% of the patients. Because systematic hematopoietic support was not planned, it is likely that this toxicity could be substantially minimized by routine administration of G-CSF. Apart from mucositis/stomatitis, which was related to dose to some extent, the other toxic effects were generally mild to moderate. Although high-dose epirubicin given as a bolus injection may result in high peak serum levels of the drug, cardiotoxicity was not a problem because it occurred as a decrease in LVEF only in a minority of patients, and only rarely was it accompanied by moderate and reversible clinical cardiac events. The 44% (95% confidence interval, ± 12%) response rate observed in this study suggests good clinical activity, although the relatively small number of patients precluded the achievement of adequate confidence intervals. To our knowledge, until now, no trial has been reported that used doses of epirubicin as high as 160 mg/m2 in patients with advanced STS. In two studies, epirubicin doses of 140 to 150 mg/m2 were administered.18,23 In a large European Organization for Research and Treatment of Cancer (EORTC) phase III trial,23 epirubicin given at 150 mg/m2 as a single agent produced similar results in comparison to single agent doxorubicin, 75 mg/m2. However, response rates (14%) in this study were disappointing and substantially lower than previously reported. In a phase I/II trial,18 epirubicin was escalated from 100 mg/m2 to 140 mg/m2 and was given in combination with fixed doses of ifosfamide, 9 g/m2, and routine hematopoietic support. The objective response rate was 54% and was clearly related to the dose level of epirubicin, being 17%, 33%, and 100% for the three epirubicin dose levels 100 mg/m2, 120 mg/m2, and 140 mg/m2, respectively. A similar finding was observed in our study, in which the response rates increased from 17% to 44% and 100% with increasing dose levels of epirubicin. Whether these dose increments translate in a true higher response rate or prolongation of survival can only be determined by prospective randomized comparative trials, which should be preferentially performed in the most chemosensitive histologic subtypes. However, because of the rarity of STS, it is unlikely that these studies will ever be carried out. Discrepancies between results of noncontrolled studies and randomized studies in the treatment of advanced STS may be found also when doxorubicin has been used. In a recent randomized EORTC study24 that compared conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus granulocyte-macrophage colony-stimulating factor, despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen did not demonstrate any superiority in terms of objective response and overall survival, although a dose-response relationship of doxorubicin, when given in combination with an identical standard dose of ifosfamide, has been suggested by several nonrandomized studies.5,25-27 In rare and heterogeneous diseases such are STS, these conflicting results may be partly explained by patient selection. Despite the heterogeneity of STS, historically, they have been considered together and managed as if they were a single entity. However, it is now clear that certain histologic types are more responsive to chemotherapy. Although liposarcoma28 and synovialsarcoma7 are usually sensitive to chemotherapy, malignant fibrous histiocytoma is less sensitive to cytotoxic drugs, and leiomyosarcomas are generally rather drug resistant, especially when they arise from the gastrointestinal tract.24,29 The incidence of leiomyosarcoma was high in both the EORTC studies,23,24 and this may in part explain the low objective response rate. In contrast, in our study, 46% of tumors were liposarcomas and synovial sarcomas, and together, they accounted for 14 out of 27 responses observed. In addition, almost all CRs were achieved in these histologic subtypes. A recent EORTC retrospective analysis of 2,185 sarcoma patients treated with anthracycline-containing regimens indicated that liver metastases are an independent unfavorable factor for chemotherapy response.28 The increased proportion of patients with liver involvement included in recent EORTC trials evaluating the activity of high-dose anthracycline regimens30 may have therefore contributed to the disappointing results observed by this collaborative group. In the present study, lung lesions were the most frequent metastatic site of disease, and as already reported by other investigators,18 they were the most responsive to chemotherapy. Because dose-intensified chemotherapy regimens have not been demonstrated to impart a survival benefit, standard-dose chemotherapy should be the preferred treatment in advanced STS. An exception may be represented by those patients from whom a cytoreduction may allow the resection of an otherwise unresectable disease or may result in a significant symptomatic benefit. In this patient population, higher response rates have been consistently reported when high-dose chemotherapy is used with an anthracycline and ifosfamide.18,31 The results of our study suggest that also high-dose epirubicin may be an appropriate first-line treatment in these instances, with the additional advantage of saving other active agents to be effectively administered in second-line treatment.
1. Peters PW, Brennan MF: Sarcomas of soft tissue, in Abeloff MD, Armitage JO, Lichter AS, et al (eds): Clinical Oncology (ed 2). Philadelphia, PA, Churchill Livingstone, 2000, pp 2273-2313 2. Yap BS, Baker LH, Sinkovics JG, et al: Cyclophosphamide, vincristine, Adriamycin and DTIC (CyVADIC) combination chemotherapy for the treatment of advanced sarcomas. Cancer Treat Rep 64: 93-98, 1980[Medline] 3. Schoenfeld D, Rosenbaum C, Horton J, et al: A comparison of Adriamycin versus vincristine, Adriamycin and cyclophosphamide versus vincristine, actinomycin-D and cyclophosphamide for advanced sarcomas. Cancer 50: 2757-2762, 1982[CrossRef][Medline]
4.
Borden EC, Amato DA, Rosenbaum C, et al: Randomized comparison of three Adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 5: 840-850, 1987 5. Elias A, Ryan L, Sulkes A, et al: Response to mesna, doxorubicin, ifosfamide and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7: 1208-1216, 1989[Abstract] 6. Weh H, Agarwal K, Zorning C, et al: Treatment results obtained in metastatic soft tissue sarcoma with a combination of doxorubicin and dacarbazine or doxorubicin and ifosfamide. Cancer Chemother Pharmacol 31: 189-193, 1993
7.
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
8.
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 9. O’Brian RM, Baker LH, Gottlieb JE, et al: Dose response evaluation of Adriamycin in human neoplasia. Cancer 39: 1940-1948, 1977[CrossRef][Medline] 10. Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas: Implications for decision making in the clinic—Sarcomas, part II. Hematol Oncol Clin North Am 9: 765-785, 1995[Medline]
11.
Bonadonna G, Gianni L, Santoro A, et al: Drugs ten years later: Epirubicin. Ann Oncol 4: 359-369, 1993 12. Mouridsen HT, Bastholt L, Somers R, et al: Adriamycin versus epirubicin in advanced soft tissue sarcomas: A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol 23: 1477-1483, 1987[CrossRef][Medline] 13. Chevallier B, Monteuquet P, Fachini T, et al: Phase II study of epirubicin in advanced soft tissue sarcoma. Bull Cancer 77: 991-995, 1990[Medline] 14. Lopez M, Carpano S, Di Lauro L, et al: Epirubicin and DTIC (EDIC) for advanced soft-tissue sarcomas. Oncology 48: 230-233, 1991[CrossRef][Medline] 15. Chevallier B, Leyraz S, Olivier JP, et al: Epirubicin and ifosfamide ai advanced soft tissue sarcoma: A phase II study. Cancer Invest 11: 135-139, 1993[Medline] 16. Lopez M, Carpano S, Di Lauro L, et al: Clinical modulation of epirubicin resistance by lonidamine in patients with advanced soft-tissue sarcomas. Int J Clin Oncol 6: 363-367, 1995
17.
Frustaci S, Foladore S, Buonadonna A, et al: Epirubicin and ifosfamide in advanced soft tissue sarcomas. Ann Oncol 4: 669-672, 1993 18. Frustaci S, Buonadonna A, Galligioni E, et al: Increasing 4'-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A pilot study. J Clin Oncol 15: 1418-1426, 1997[Abstract] 19. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatments. Cancer 47: 207-214, 1981[CrossRef][Medline] 20. Criteria Committee of the New York Heart Association: Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels (ed 8). Boston, MA, Little, Brown, 1979
21.
Lopez M, Vici P, Di Lauro L, et al: Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol 16: 86-92, 1998 22. Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2: 1281-1288, 1984[Medline] 23. Nielsen OS, Dombernowsky P, Mourisden H, et al: High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcoma: A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 78: 1634-1639, 1998[Medline]
24.
Le Cesne A, Judson I, Crowther D, et al: 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 Group. J Clin Oncol 18: 2676-2684, 2000 25. Mansui JL, Fisher C, Wiltschaw E, et al: A phase I-II study of ifosfamide in combination with adriamycin in the treatment of adult soft tissue sarcomas. Eur J Cancer Clin Oncol 4: 1434-1443, 1988 26. Loecher PJ, Sledge GW, Nicaise C, et al: Ifosfamide plus doxorubicin in metastatic adult sarcomas: A multi-institutional phase II trial. J Clin Oncol 11: 1655-1659, 1989 27. 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[Abstract]
28.
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
29.
Verweij J, Lee SM, Ruka W, et al: Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 18: 2081-2086, 2000 30. Van Glabbeke M, van Oosterom AT, Nielsen OS, et al: Prognostic factors for 1st-line high-dose chemotherapy outcome in advanced soft-tissue sarcoma (STS): An overview of 759 patients (pts) included in studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG). Proc Am Soc Clin Oncol 17: 512a, 1998 (abstr 1975) 31. Patel SR, Vadhan-Raj S, Burgess MA, et al: Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 21: 317-321, 1998[CrossRef][Medline] Submitted June 26, 2001; accepted November 12, 2001.
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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
2 test for trend, P = .02). Median response duration, median time to progression, and median overall survival were 10, 8, and 15 months, respectively. Myelosuppression was the most frequent side effect, with grade 3 or 4 neutropenia occurring in 79% of the patients; 31% of patients were febrile. Nonhematologic toxicity was mainly grades 1 and 2. The mean epirubicin dose-intensity was 49 mg/m2 per week. 
