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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

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, and Department of Medical Oncology, University Hospital Radboud, Nijmegen, the Netherlands; Department of Medical Oncology, Christie Hospital, Manchester, Department of Oncology, Weston Park Hospital, Sheffield, and Department of Medical Oncology, Royal Marsden Hospital, Sutton, United Kingdom; Department of Surgery, Cancer Center M. Sklodowska Curie, Warsaw, Poland; Department of Medical Oncology, Hospital General de Asturias, Oviedo, Spain; European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; and Rhône-Poulenc Rorer, Antony, France.

Address reprint requests to Jaap Verweij, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email verweij{at}onch.azr.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess antitumor response and time to progression (TTP) with docetaxel compared with doxorubicin in first-line treatment of advanced and/or metastatic soft tissue sarcoma.

PATIENTS AND METHODS: Patients with measurable soft tissue sarcoma lesions and adequate bone marrow, liver, and renal function were entered onto the study. They were randomized to either docetaxel 100 mg/m² given as a 1-hour intravenous infusion every 3 weeks or doxorubicin 75 mg/m² given as a bolus injection every 3 weeks. A maximum of seven cycles of treatment were scheduled. The study was designed as a randomized phase III study evaluating TTP by log-rank model. There was a clause for premature closure of the trial if fewer than five responses were observed among the first 25 assessable patients in the docetaxel treatment arm.

RESULTS: Eighty-six patients were entered onto the study; 85 were assessable for toxicity and 83 for response. The rate of severe granulocytopenia was not significantly different between the two arms. Nausea (P = .001), vomiting (P < .001), and stomatitis (P = .005) were more common with doxorubicin therapy, whereas neurotoxicity was more frequent with docetaxel treatment. The response rate to doxorubicin therapy was 30% (95% confidence interval, 17% to 46%), whereas no responses to docetaxel therapy were seen (P < .001). In view of this, the trial was closed prematurely and the phase III study part was not conducted.

CONCLUSION: Docetaxel is inactive in soft tissue sarcomas and cannot be recommended for further use in treatment of this disease.

	INTRODUCTION

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SOFT TISSUE SARCOMAS represent 1% of adult malignancies and are a heterogeneous group of neoplasms whose only common denominator is their derivation from mesenchymal tissue.

Local surgery is usually the first line of treatment for soft tissue sarcoma. In the case of extremity lesions, the standard of either radical resection or limb-sparing surgery plus radiotherapy has dramatically improved local control of the disease.^1-4 Radiation therapy as a single primary modality is used only in patients with lesions that are not amenable to surgery because of tumor size.⁵ Despite improved rates of local control, many patients still die from metastatic disease.

Chemotherapy is currently used for the treatment of advanced and/or metastatic soft tissue sarcomas, but only a few cytotoxic drugs have demonstrated activity in this disease. Doxorubicin is the most active single agent, with an associated response rate of approximately 20% to 25%.⁶ Ifosfamide and dacarbazine have also demonstrated activity in soft tissue sarcomas.^6,7 Although some studies suggested that combination chemotherapy has higher response rates than does single-agent doxorubicin therapy,^8,9 the largest such study, performed by the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group and accruing more than 700 patients, showed that there was significantly more myelosuppression with the combinations of doxorubicin and ifosfamide and of cyclophosphamide, vincristine, doxorubicin, and dacarbazine, but response rates were not significantly different.¹⁰ In all studies, there was no benefit in terms of survival for patients receiving combination chemotherapy. Therefore, conventional-dose single-agent chemotherapy can still be considered standard treatment for metastatic soft tissue sarcomas.

Docetaxel is a semisynthetic derivative of a precursor extracted from needles of the European yew. It enhances microtubule assembly and inhibits the depolymerization of tubulin. This can lead to the presence of bundles of microtubules in the cell, which block the cell in the M phase of the cell cycle and thus stop cell division. Docetaxel therapy was tested as second-line chemotherapy by the EORTC Soft Tissue and Bone Sarcoma Group and yielded a response rate of 17% (95% confidence interval [CI], 6% to 34%).¹¹

In another phase II study, no responses occurred,¹² but this result could be related in part to dose-intensity. Because of the uncertainty regarding the activity of docetaxel in this disease, we conducted a randomized phase II/III trial comparing docetaxel with doxorubicin in first-line treatment for advanced and/or metastatic soft tissue sarcoma with a specific stopping rule.

	PATIENTS AND METHODS

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Eligibility Criteria
Eligibility criteria included histologically proven advanced and/or metastatic soft tissue sarcoma, graded according to the system of Trojani et al¹³ and incurable by surgery or radiotherapy, excluding malignant mesothelioma, chondrosarcoma, neuroblastoma, osteosarcoma, Ewing’s sarcoma, and embryonal rhabdomyosarcoma; at least one bidimensionally measurable target lesion with a minimum size on computed tomographic scan of at least one diameter 2 cm, on x-ray (ie, lung lesion) of 1 cm, or determined by physical examination (ie, skin nodules, superficial lymph nodes) of 1 cm; no previous chemotherapy; no previous radiation therapy to the only site being used to assess response; age greater than 18 years and less than 75 years; World Health Organization performance status 2; absolute neutrophil count more than 2 x 10⁹/L; platelet count more than 100 x 10⁹/L; total bilirubin level less than 1.25 times the upper limits of normal (UNL); AST and ALT levels less than three times UNL; alkaline phosphatase level less than six times UNL (unless bone metastases were present and liver metastases were absent); and serum creatinine level less than 140 µmol/L. All patients gave written informed consent. Histologic data were centrally reviewed.

Prestudy and Follow-Up Investigations
Before the first and all subsequent treatment courses, a physical examination including a neurologic examination was performed. Electrocardiography and chest radiography were performed at baseline and repeated every two courses. Left ventricular ejection fraction (LVEF) was evaluated at baseline and before cycle 7.

Before the study and every 3 weeks thereafter, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, sodium, potassium, creatinine, and total protein levels were measured. WBC, neutrophil, and platelet counts were performed weekly, and hemoglobin levels were also determined each week. Tumor assessments were performed every two cycles, at the end of treatment, and every 3 months thereafter (in patients going off study for other reasons than progression). Standard World Health Organization criteria¹⁴ were used for evaluating response, and all responses were subject to independent review. The duration of partial response or no change was calculated from the date of registration to the date of documented progression, and the duration of complete remission was calculated from the moment the complete response was documented to the documentation of progression. Time to progression (TTP) was calculated 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.

Toxicity was graded using National Cancer Institute common toxicity criteria.

Treatment and Dose Modifications
Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) was administered as a 1-hour intravenous infusion at a dose of 100 mg/m². Doxorubicin was given intravenously at a dose of 75 mg/m² over 5 minutes. Cycles of both drugs were to be repeated every 3 weeks. Patients given docetaxel also received oral corticosteroids. The choice of corticosteroid was left to the discretion of the investigator. However, it was mandatory to use a dose, route, schedule, and duration equivalent to that recommended for methylprednisolone (32 mg 12 and 3 hours before and 12 hours after docetaxel administration and 64 mg daily on days 2 through 4). All patients were scheduled to receive a maximum of seven cycles of doxorubicin or docetaxel therapy. In the case of progression, eligible patients were to be treated with the alternative treatment drug for a maximum of seven cycles.

If the neutrophil count on the day of scheduled retreatment was less than 1.5 x 10⁹/L or the platelet count was less than 100 x 10⁹/L, treatment was delayed by 1 week (maximum of 2 weeks). In the case of a neutrophil count nadir of less than 0.5 x 10⁹/L lasting for more than 7 days or complicated with fever, or a platelet count nadir of less than 25 x 10⁹/L, the subsequent dose of docetaxel was reduced to 75 mg/m² or the subsequent dose of doxorubicin was reduced to 60 mg/m².

If LVEF decreased by 10% or to an absolute level of less than 0.50, treatment with doxorubicin was to be stopped. With regard to docetaxel, dose reductions were prescribed by protocol in the case of cutaneous toxicity (excluding nail changes), peripheral neuropathy, and liver function abnormalities. With regard to fluid retention, no dose reduction was planned, but treatment with oral spironolactone 50 mg every day or every other day was recommended.

Statistical Analysis
The study was designed as a randomized phase III study evaluating TTP by log-rank model. To detect a difference in TTP corresponding to an increase in 1-year disease-free survival rate from 15% (doxorubicin therapy) to 25% (docetaxel therapy), a total of 203 patients had to be accrued in each arm (alpha = 0.05, beta = 0.2, two-sided test, Freedman’s method).¹⁵ At the beginning of the study, the two-step Simon design¹⁶ was applied to ensure that the response rate was adequate. The hypothesis was P0 = 10%, P1 = 30%; where P0 is the largest response probability, which, if true, implies that the therapeutic activity does not warrant further investigation of the drug, and where P1 is the lowest response probability, which, if true, implies that the therapeutic activity does warrant further investigation of the drug (alpha = 0.1, beta = 0.1).

Under this hypothesis, the trial was to be discontinued if fewer than five responses were observed among the first 25 assessable patients in the docetaxel treatment arm.

Comparisons of response rate and toxicity were performed using the log-rank test for trend. Overall survival and TTP were estimated using the Kaplan-Meier method. TTP was censored at the start of a new antitumor therapy if this new therapy occurred before progression of the disease. The log-rank test was used for comparison. The intent-to-treat population was defined as all randomized patients.

	RESULTS

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Patient Characteristics
Eighty-six patients were entered onto the first part of the study. Patient characteristics are listed in Table 1. Two patients were considered ineligible because of low LVEF (this patient never received chemotherapy) and active infection. The characteristics were evenly distributed over both groups. The analysis was performed on an intent-to-treat basis. Eighty-five patients were assessable for toxicity and 83 for response. Three patients were not evaluated for response because of treatment refusal after course 1 (one patient), intercurrent radiotherapy after course 1 (one patient), and treatment with expired docetaxel (one patient).

Toxicity
Only three patients discontinued therapy because of toxicity: two receiving docetaxel (one because of edema and one because neurotoxicity) and one receiving doxorubicin (because of a decrease in LVEF). Side effects are listed only for the first part of the study. After cross-over, the pattern was similar. Hematologic side effects are listed in Table 2. The rate of severe granulocytopenia was not significantly different between groups. The median granulocyte level nadir was 0.4 x 10⁹/L in the doxorubicin treatment arm and 0.5 x 10⁹/L in the docetaxel treatment arm. Severe thrombocytopenia occurred only with doxorubicin therapy. Neutropenic fever was seen in 13 patients (15%), equally distributed over both treatments.

View larger version (16K): [in this window] [in a new window]   Fig 1. TTP after first-line chemotherapy.

Because of the lack of responses after first-line docetaxel chemotherapy, and according to study protocol, the study was discontinued after completion of the phase II part.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The treatment of metastatic soft tissue sarcomas continues to be difficult because of a paucity of active agents. The only two agents with proven activity are doxorubicin and ifosfamide.^6,7 Also, in various phase III studies, single-agent therapy has been shown to be as effective as combination chemotherapy as far as survival is concerned,^8-10 although a higher response rate was achieved with combination chemotherapy in one study.⁹ For this reason, the EORTC Soft Tissue and Bone Sarcoma Group is using single-agent doxorubicin therapy as the comparator in its randomized studies.

Clearly, there is a need for new and active agents to use in the treatment of this disease, but the search for such agents has not been very successful. We were encouraged by our initial results with docetaxel therapy, which had a response rate of 17% in pretreated patients.¹¹ The National Cancer Institute of Canada (NCIC) meanwhile published the results of its phase II study involving non-pretreated patients, for whom the response rate to docetaxel treatment was only 11%.¹⁷ These results were published after accrual to the present EORTC study had been completed. The results of our randomized study comparing docetaxel therapy with doxorubicin therapy seem to confirm the results of the NCIC study and also the results of a small study performed at the Mayo Clinic that indicate that docetaxel lacks activity in soft tissue sarcomas.¹² The other taxane, paclitaxel, was found to be inactive in this disease in three phase II studies.^18-20

The reason for the discrepancy between the outcome in our initial phase II study involving pretreated patients and that in the present and other studies involving non-pretreated patients remains unclear. There do not seem to be differences in patient characteristics apart from the previous chemotherapy. In our previous study, four of the five responding patients were entered after having progressed within 3 months of completion of adjuvant chemotherapy, and the fifth patient had not responded to first-line chemotherapy for metastatic disease. Frequently debated today is the influence of the number of patients with leiomyosarcomas included in studies, particularly the number of patients with the gastrointestinal stromal tumor (GIST) subtype, which tends to be even less responsive to chemotherapy than other subtypes. However, in our initial phase II study of docetaxel therapy, responses were also noted in patients with leiomyosarcomas, and two of the three responders in the NCIC study also had leiomyosarcomas.¹⁷ In our present study, 30 patients (35%) had leiomyosarcomas. Nine tumors were of gastrointestinal origin (GIST) and were equally distributed over the two treatment arms, seven tumors were uterine, eight were retroperitoneal, and six originated from extremities. None of the patients with leiomyosarcomas treated with docetaxel responded, whereas four (one patient with a tumor near the shoulder, one with a retroperitoneal tumor, and two with uterine tumors) of the 14 patients with leiomyosarcomas treated with doxorubicin responded. None of the patients with GISTs responded to treatment. If leiomyosarcoma patients are excluded from our response analysis, the response rates for doxorubicin therapy and docetaxel therapy are 31% and 0%, respectively.

In contrast to the Mayo Clinic study, in which the achieved dose-intensity was not optimal, presumably because of dose reductions for toxicity,¹² the achieved dose-intensities for both docetaxel and doxorubicin in our present study were close to optimal, discounting the possibility that suboptimal dosing accounts for the lack of docetaxel activity.

All other known prognostic factors for response²¹ were evenly distributed over the two arms. The numbers of patients are too small to permit subset analysis. However, if one combines the results of the NCIC,¹⁷ Mayo Clinic,¹² and EORTC¹¹ studies, in which docetaxel therapy was first-line treatment in a total of 89 patients, the conclusion that docetaxel is likely to be an inactive agent in this tumor type seems to be justified.

Although the common impression is that docetaxel is a myelotoxic agent, in our study doxorubicin was equally myelotoxic at the dose given. Doxorubicin induced significantly more nausea, vomiting, and stomatitis, whereas neurotoxicity and edema were more frequent with docetaxel therapy. Doxorubicin treatment was previously not known to induce peripheral edema but was found to induce mild edema in 23% of our patients. This suggests that specifically focused questions about side effects may reveal additional mild toxicities not reported spontaneously.

In conclusion, given the results of this study, docetaxel should not be used in the treatment of soft tissue sarcomas.

	ACKNOWLEDGMENTS

 
Supported by a research grant from Rhône-Poulenc Rorer, Antony, France.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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7. Benjamin RS, Legha SS, Patel SR, et al: Single agent ifosfamide studies in sarcomas of soft tissue and bone: The MD Anderson experience. Cancer Chemother Pharmacol 31:174-179, 1993 (suppl 2)

8. Schoenfeld DA, Rosenbaum C, Horton J, et al: A comparison of Adriamycin versus vincristine and Adriamycin, and cyclophosphamide versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma. Cancer 50:2757-2762, 1982[Medline]

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11. van Hoesel QGCM, Verweij J, Catimel G, et al: Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult: EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 5:539-542, 1994[Abstract/Free Full Text]

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17. Bramwell V, Blackstein M, Berlanger K, et al: A phase II study of docetaxel in chemotherapy-naive patients with recurrent or metastatic adult soft tissue sarcoma. Sarcoma 2:29-33, 1998

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Submitted September 9, 1999; accepted January 25, 2000.

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