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10.1245/s10434-006-9168-8
Annals of Surgical Oncology 14:1254-1256 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Controversies in Surgical Oncology: Routine Anthracycline-based Adjuvant Chemotherapy for Stage III Extremity Soft Tissue Sarcoma

Vivien H. C. Bramwell

Department of Medicine, Division of Medical Oncology, University of Calgary, 1331, 29 Street N.W., Calgary, AB T2N 4N2, Canada

Correspondence: Address correspondence and reprint requests to: Vivien H. C. Bramwell; E-mail: vivienbr{at}cancerboard.ab.ca

For adult soft tissue sarcomas (ASTS), stage III encompasses tumors larger than 5 cm, high grade (3 or 4), located deep to the superficial fascia, that have no evidence of distant metastasis.1 After definitive locoregional treatment only, approximately 50% of these patients will develop a recurrence, and 45% will die of sarcoma within 5 years.1 Adjuvant systemic treatment is of proven benefit in a number of tumors, notably breast cancer,2 and in other sarcomas such as osteosarcoma3 and Ewing’s sarcoma.4 While acknowledging that current adjuvant chemotherapy has undoubted biological effects on ASTS, in this article I will argue against its routine, as opposed to selective use in stage III extremity tumors, based on concerns about long-term efficacy and morbidity.

The highest quality evidence of the effects of adjuvant chemotherapy comes from an individual patient data meta-analysis of 1,568 patients included in 14 randomized controlled trials (RCTs) of adjuvant doxorubicin-based chemotherapy versus control. This was published by the Sarcoma Meta-Analysis Collaboration (SMAC) in 1998,5 and the results are summarized in Table 1Go. The benefits were modest, although greatest in extremity ASTS, with a hazard ratio (HR) for overall survival (OS) of 0.80 (P = 0.029), following chemotherapy, equivalent to a 7% absolute OS benefit at 10 years. The SMAC analysis included RCTs that completed patient accrual by December 1992, and less than 5% of patients received a chemotherapy regimen that included if-osfamide, a drug accepted as having significant activity in ASTS. Thus, publication in 2001 of the early promising results from an Italian cooperative group RCT,6 which evaluated an optimal intensive high-dose epirubicin/ifosfamide regimen versus control in patients most likely to benefit (i.e., stage III extremity ASTS), generated considerable interest. Based on an early stopping rule, the study was closed after accruing 104 patients, half the intended recruitment goal. With a median follow-up of 59 months, an intent-to-treat analysis showed median disease free survival (DFS) times of 48 versus 16 months (P = 0.04) and median OS times of 75 versus 46 months (P = 0.03) for chemotherapy and control groups, respectively. In an accompanying editorial,7 I discussed some of the hazards of interpreting data from a small RCT after short follow-up, recognizing the substantial heterogeneity of ASTS. As early as 4 years, there was a convergence in relapse rates (28 and 32 in chemotherapy and control groups, respectively). One late relapse occurred in the chemotherapy arm and, at a median follow-up of 89.6 months, a small numerical difference in the number of deaths (22 vs. 29) did not translate into a statistically significant difference in OS, 56.9 versus 41.5%.8 The 5-year DFS results (69 vs. 44%, P = 0.01) of another small Italian RCT9 also favored adjuvant chemotherapy, and there was a trend for OS benefit (72 vs. 47%, P = 0.06). However, the study included a heterogeneous group of 88 patients (extremity, 52%; grade 3, 41%; >5 cm, 49%) and adjuvant regimens (epirubicin 58%; epirubicin and ifosfamide 42%). In contrast, an Austrian study of adjuvant doxorubicin/dacarbazine/ifosfamide, given to 31 patients (vs. 28 controls), reported at 41 (8–84) months follow-up, showed no differences in DFS or OS.10 Both studies were underpowered for efficacy endpoints.


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  		TABLE 1. SMAC meta-analysis
 
In the RCTs described above, adjuvant chemotherapy was delivered in the postoperative setting, and usually after completion of radiotherapy, if needed. There is an extensive literature describing neoadjuvant chemotherapy11–17 or chemoradiotherapy18–21 in patients with high-risk extremity ASTS. Local control rates have usually been excellent, but significant rates of relapse and death are documented in large series with long-term follow-up.11,18 An EORTC RCT,22 comparing neoadjuvant doxorubicin/ifosfamide versus control in high-risk ASTS (82% extremity), failed to show any differences in 5-year DFS (56 vs. 52%) or OS (65 vs. 64%). This study was closed early because of poor accrual, and thus was underpowered for survival endpoints. However, it is worth noting that it is larger than the positive Italian study6 of postoperative chemotherapy described earlier. Although neoadjuvant treatment has the theoretical benefit of early delivery of chemotherapy to micrometastases, the 6–12 week time difference may only be important in a minority of rapidly proliferating tumors. It can also play a role in facilitating limb salvage and improving local control in selected locally-advanced ASTS. Clinical/radiological response to neoadjuvant chemotherapy does not correlate well with survival outcomes.11 By contrast, in a series of 496 patients receiving neoadjuvant chemo-radiation, Eilber et al.18 found that 5- and 10-year survival rates were significantly higher for patients whose primary tumors showed ≥ 95% pathological necrosis. However, the significance of this finding is debatable. Despite data from cohort studies that "good" pathological response correlates with favorable outcomes, RCTs in breast23 and osteosarcoma24 have not shown improved survival for neoadjuvant versus adjuvant chemotherapy.

An interesting cohort analysis may also shed some light on the limitations of adjuvant chemotherapy. Cormier et al.25 evaluated treatment and outcomes for 674 patients with stage III primary extremity STS treated in two specialized sarcoma centers. Pre- or post-operative doxorubicin-based chemotherapy was used in a non-randomized fashion in approximately half of the cases. Five-year disease specific survival (DSS) was 61%. Cox regression analysis showed a time-varying effect of chemotherapy. During the first year, the HR for DSS for patients treated with chemotherapy versus no chemotherapy was 0.37 (P = 0.002) but thereafter it was 1.36 (P = 0.04), suggesting delay in the development, but not prevention of distant metastases.

The potential benefits of adjuvant chemotherapy need to be carefully balanced against its established toxicities and risks. Short-term toxicities of anthracycline/ifosfamide combinations may include alopecia, nausea/vomiting, diarrhea, mucositis, fatigue, hematuria, confusion. Myelosuppresion is usually significant, e.g., Frustaci et al.6 reported that, despite the routine use of G-CSF, 35% of their patients had grade 4 leukopenia, and 13% experienced neutropenic fever. Long-term side-effects are poorly documented in most adjuvant/neoadjuvant chemotherapy series, but may include heart failure and nephrotoxicity. Wound complications and bone fractures are significant sequelae of neoadjuvant chemoradiotherapy protocols. It is worth noting that patients ≥ 65 years, or with major co-morbidities are excluded from most intensive adjuvant/neoadjuvant chemotherapy protocols, and may represent 20–30% of patients with ASTS.

In an editorial,7 written in 2001, I concluded that it was premature to state that adjuvant systemic therapy should be the standard of care for ASTS. I suggested that "the option of adjuvant chemotherapy with the purpose of delaying distant recurrence and perhaps prolonging survival should certainly be discussed with younger patients who have large high-grade extremity sarcomas, as should the option of any available RCT’s." Since that time, as no additional data from RCT’s have been published, I do not see any reason to change that conclusion. EORTC protocol 62931, comparing 5 cycles of doxorubicin/ ifosfamide chemotherapy versus control in patients with high-risk ASTS, completed accrual at the end of 2003, and first results are expected 2007. At that time, updating the SMAC analysis with data from more recent RCTs may be more helpful in guiding us how to manage our patients. Molecular and pathological redefinition of some soft tissue and bone sarcomas, using chromosome analysis and microarray technology,26–29 has facilitated more appropriate targeted therapies in some sarcomas. However, as specific molecular markers have yet to be identified for the majority of ASTS, it may be some time before these studies assist us in developing more appropriate adjuvant systemic treatments.

Received for publication December 6, 2005. Accepted for publication April 27, 2006.


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