Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal sarcomas: A 10-year single institution retrospective study

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Abstract

Background

Patients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen.

Methods

We retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed.

Results

Sixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46 months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence-free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS.

Conclusions

For a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity.

Introduction

Contemporary management of extremity and truncal soft tissue sarcomas (STS) revolves around wide local excision in combination with the judicious use of pre- or post-operative radiation therapy1, 2, 3, 4, 5, 6 to promote limb salvage, and thereby, to optimise quality of life. This strategy reliably achieves local control in 85–92% of patients.7 However, the risk of distant metastasis remains a major concern, and this risk is intimately related to tumour grade and size.8 Thus, there is obvious motivation to include chemotherapy in the treatment approach in an effort to improve metastasis-free and overall survival.9, 10 In addition, in the neoadjuvant setting, chemotherapy may work synergistically with radiation therapy to decrease the extent of the required surgical resection and, consequently, to promote better functional outcomes.11

At Massachusetts General Hospital (MGH), we have previously reported high rates of local and distant control in our pilot study of an aggressive regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with 44 Gy external beam radiation therapy (EBRT) and followed by resection and post-operative chemotherapy with or without additional radiation.12 This pilot study prompted a multi-institutional Phase II study (Radiation Therapy Oncology Group (RTOG) 9514) to evaluate high-risk (⩾8 cm, intermediate or high grade) extremity and truncal STS amenable to complete surgical resection and limb preservation.13 At a median follow-up of 7.7 years, rates of distant disease-free and overall survival were quite favourable at 64.1% and 71.2%, respectively.14 We subsequently reported the long-term follow-up of our pilot study of high-risk extremity sarcomas treated from 1989 to 1999, demonstrating significantly higher 7-year disease-specific (81%) and overall (79%) survival rates when compared to a historical matched control group of patients managed with alternate treatment regimens.15

However, this aggressive chemoradiotherapy regimen has been associated with noteworthy toxicity, particularly in the multi-institutional phase II study, in which the dose of ifosfamide was 25% higher than in the MGH study and large radiation therapy fields, extending 9 cm proximal and distal to gross disease, were employed. Three (5%) treatment-related deaths, 5 (9.4%) amputations and a 97% early rate of significant toxicity were reported, although the latter strikingly decreased after 5 years of follow-up.14 We have not seen such high rates of toxicity in the patients whom we have treated at MGH on this regimen over the past 20 years, and given the encouraging long-term survival data, we currently recommend it for those patients with large, high-grade extremity sarcomas who are deemed fit to tolerate the regimen. In this retrospective study, we report the outcomes of patients with high-risk extremity and truncal STS who participated in this protocol at MGH since completion of the pilot study in 1999.

Section snippets

Patients and methods

This study was approved by the Institutional Review Board of Partners Healthcare/Massachusetts General Hospital.

Patient and tumour characteristics

Clinicopathologic features of the patients in this series are shown in Table 1. Sixty-six patients were included, of whom 50 (76%) patients were male. The median age at diagnosis was 53 years. The most prevalent histological type was undifferentiated high grade pleomorphic sarcoma (35%), and the most common location at presentation was the thigh (55%). The pre-treatment median tumour size was 10 cm (range, 4.1–35 cm), and all tumours were of histological grade 2 (50%) or 3 (50%). Only 1 patient’s

Discussion

In this update to our original pilot study of patients with high-risk extremity and truncal STS treated with an intensive regimen of neoadjuvant chemoradiotherapy, we report promising 5-year rates of overall survival (86%) and disease-specific survival (89%). Although this regimen has been slow to gain wide acceptance due to its toxicity and potential for secondary myelodysplasias, this analysis of the most recent 66 patients at MGH over the past 10 years confirms the modest toxicities that we

Financial support

Biostatistics Core of Dana-Farber/Harvard Cancer Center supported by NCI Cancer Center Support Grant # NIH 5 P30 CA06516.

Conflict of interest statement

None declared.

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