A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma

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Abstract

The aim of this study was to examine the strategy, feasibility and outcome of neo-adjuvant chemotherapy, with doxorubicin and ifosfamide, in adult patients with ‘high-risk’ soft-tissue sarcomas. Patients with ‘high-risk’ soft-tissue sarcomas, defined as tumours ⩾8 cm of any grade, or grade II/III tumours <8 cm, or grade II/III locally recurrent tumours, or grade II/III tumours with inadequate surgery performed in the previous 6 weeks and therefore requiring further surgery, were randomised between either surgery alone or three cycles of 3-weekly doxorubicin 50 mg/m2 intravenous (i.v.) bolus and ifosfamide 5 g/m2 (24 h infusion) before surgery. The type of surgery had to be planned at randomisation. Tumours were to be amenable to surgery by amputation, compartmental resection, wide or marginal excision. If chemotherapy was given, surgery had to be performed within 21 days after the last chemotherapy. Patients received postoperative radiotherapy in cases of marginal surgery, microscopically incomplete resection and no further possibility for surgery, and in cases of surgery because of local recurrence. 150 patients were entered into the study and 134 were eligible, 67 in each arm. The most frequent side-effects of chemotherapy were alopecia, nausea and vomiting (95%), and leucocytopenia (32%). One patient died of neutropenic fever after the first cycle of chemotherapy. Chemotherapy did not interfere with planned surgery and did not affect postoperative wound healing. Limb-salvage was achieved in 88%, amputation was necessary in 12% (all according to the plan at randomisation). The trial was closed after completion of phase II, since accrual was too slow to justify expanding the study into the scheduled phase III study. At a median follow-up of 7.3 years, the 5 year disease-free survival is estimated at 52% for the no chemotherapy and 56% for the chemotherapy arm (standard error: 7%) (P=0.3548). The 5 year overall survival for both arms is 64 and 65%, respectively (standard error 7%) (P=0.2204). Neo-adjuvant-chemotherapy with doxorubicin and ifosfamide at these doses and with this schedule was feasible and did not compromise subsequent treatment, surgery with or without radiotherapy. Although not powered to draw definitive conclusions on benefit, but with an at least 7 year median follow-up, the results render it less likely that major survival benefits will be achieved with this type of chemotherapy.

Introduction

Patients with a ‘high-risk’ soft-tissue sarcoma [1] have a 50% risk of developing distant metastases with subsequent poor survival.

Several prospective randomised trials, comparing adjuvant chemotherapy after surgery to surgery alone, have produced controversial results [2]. Zalupski and colleagues [3] concluded from a meta-analysis that was performed on data from publications, that there was a statistically significant improvement in disease-free and overall survival in favour of chemotherapy. An international collaborative group [4] concluded from their meta-analysis performed on the actual study data (a more valid way of performing meta-analysis) comprising 1568 patients from 14 trials that adjuvant doxorubicin-based chemotherapy significantly increased the time to local and distant recurrence and recurrence-free survival. However, there was only a trend towards improved overall survival with the result that adjuvant chemotherapy is still not regarded by many as standard treatment.

The timing of chemotherapy as an adjuvant to surgery is a topic for ongoing debate. In several other malignancies, e.g. head and neck cancers, bladder cancer, osteosarcomas and inflammatory breast cancer, neo-adjuvant-chemotherapy preceding surgery is now preferred. Such chemotherapy is associated with better patient compliance and has no negative impact on the potential of local treatment.

In view of this the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) designed a study to investigate the feasibility and outcome of neo-adjuvant-chemotherapy in adult soft-tissue sarcomas.

As the possibility that disease progression during chemotherapy might render patients inoperable was a major concern, the study was designed as a phase II/III trial. Only if progression during chemotherapy was infrequent and accrual appeared to be appropriate would the study proceed to phase III. Due to limited accrual, however, the study was terminated at the end of phase II. Preliminary results have been presented in abstract previously [5]. This is presently still the only randomised trial of neo-adjuvant-chemotherapy in soft-tissue sarcoma and here we report the results after a median follow-up of 7.3 years.

Section snippets

Patients and methods

The design of the trial is shown in Fig. 1.

Patient characteristics

150 patients were entered into this study by 23 centres. Seventy percent of all patients were entered by five centres. The accrual rate was initially extremely low. It thereafter varied considerably over time, in some periods tending to increase to such an extent that with a further increase extension into the phase III study would have become possible. However, despite various efforts to further increase accrual, it finally dropped again to such unacceptably low rates that continuation could

Discussion

The concept of neo-adjuvant chemotherapy is a topic for ongoing debate. The outcome of non-randomised phase II studies of neo-adjuvant chemotherapy suggest that chemotherapy given at this stage of the disease gives a higher response rate than chemotherapy given for distant metastases 7, 8, 9. This suggestion would be consistent with similar data available from treatment in tumours such as osteosarcoma, head and neck cancer, breast cancer 9, 10, bladder cancer and various other types of

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1

Present address: Istituto Clinico Humanitas, Rozzano, Milano, Italy.

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