Vivien H.C. Bramwell
University of Western OntarioLondon Regional Cancer CentreLondon, Ontario, Canada
For many years, considerable controversy has surrounded the use of adjuvant chemotherapy in adults with soft tissue sarcoma (STS). Improvement in overall survival in the chemotherapy arm was only evident in two of the 13 published randomized trials (RCTs) that completed accrual before 1990. Because of concern that a beneficial effect of chemotherapy was being missed due to the small size of individual studies (median patient accrual, 76; range, 26 to 468), the Sarcoma Meta-Analysis Collaboration (SMAC) performed an individual patient data meta-analysis of outcome for 1,568 patients included in 14 RCTs (one unpublished) of adjuvant doxorubicin–based chemotherapy versus control.Their study showed that for overall survival, the hazard ratio (HR) of 0.89 (95% confidence interval [CI] , 0.76 to 1.03) was not significant (P = .12) but there was a small absolute survival benefit of 4% at 10 years. There were improvements in the local relapse-free interval (HR 0.73, 95% CI, 0.56 to 0.94 P = .016), distant relapse-free interval (HR 0.70, 95% CI, 0.57 to 0.85; P = .0003), and overall recurrence-free survival (HR 0.75, 95% CI, 0.64 to 0.87; P = .0001) corresponded with absolute benefits for adjuvant chemotherapy of 6%, 10%, and 10%, respectively. For 886 patients with STS of the extremities, the HR for overall survival was 0.80 (P = .029), equivalent to a 7% absolute benefit at 10 years. Because of small numbers in the subgroups for other sites (trunk, uterus, other), there was no clear evidence that outcomes of chemotherapy were different across the various tumor locations. In addition, the effects of chemotherapy were not influenced by whether doxorubicin was given alone or in combination.
An RCT reported by Frustaci et al4 in this issue of the Journal of Clinical Oncology, evaluating an intensive anthracycline/ifosfamide chemotherapy regimen in adult patients with high-grade extremity STS, thus has considerable potential to enlighten the debate.
This trial was conducted by an Italian cooperative group. Patients aged 18 to 65 years with high-grade STS of the extremities were randomized, after locoregional treatment, between five cycles of high-dose epirubicin (60 mg/m2 on days 1 and 2) and ifosfamide (1.8 g/m2 on days 1 through 5) with granulocyte colony-stimulating factor (G-CSF), and control (no chemotherapy). A total of 104 patients were entered onto this study, which, based on an early stopping rule, was terminated after half the planned number of patients had been recruited. With a median follow-up of 59 months, an intention-to-treat analysis showed median disease-free survival times of 48 versus 16 months (P = .04) and median overall survival times of 75 versus 46 months (P = .03) for the chemotherapy and control groups, respectively. Despite the routine use of G-CSF, myelosuppression was substantial, with 35% of patients experiencing grade 4 leucopenia and 13% neutropenic fever. There were no toxic deaths and no evidence of cardiotoxicity; other side effects were reversible. The mean relative dose-intensity of delivered chemotherapy was 83%.
Intensive anthracycline/ifosfamide combinations have been evaluated in two other small European RCTs,5,6 but these provide conflicting results. In an Austrian study,5 59 patients with grade 2 or 3 STS (47 extremity, 11 trunk, and one retroperitoneum) underwent primary surgery and then were randomized to receive six cycles of chemotherapy (ifosfamide 1.5 g/m2 on days 1 through 4, dacarbazine 200 mg/m2 on days 1 through 4, and doxorubicin 25 mg/m2 on days 1 and 2, administered at 14-day intervals supported by G-CSF) concurrent with hyperfractionated accelerated radiotherapy, or radiotherapy alone. At a median follow-up of 41 months (range, 8 to 84 months), relapse-free survival (P = .1), time to local failure (P = .09), time to distant failure (P = .17), and overall survival (P = .4) did not differ significantly between the groups. This study failed to meet its accrual target of 100 patients in 48 months, and thus was underpowered for efficacy end points. An abstract report of a second Italian study6 described an improved 5-year disease-free interval (65% v 41%, P = .01) for 42 patients with grade 2 or 3 extremity and retroperitoneal STS who received adjuvant chemotherapy, compared with 39 controls, and a similar trend for survival (72% v 47%, P = .06). It should be noted that only 19 patients received an intensive epirubicin/ifosfamide combination; the remainder in the chemotherapy arm received single-agent epirubicin. Given the available information, the results of this study do not contribute substantially to the debate.
So can we establish a standard of care regarding adjuvant chemotherapy for adult STS? As for breast cancer, at this stage we need to define high-risk groups most likely to benefit from chemotherapy. Most sarcoma specialists would agree that patients with small (< 5 cm) and/or low-grade STS should not receive adjuvant chemotherapy outside a trial setting. Because of concerns about toxicity, and a detrimental effect on outcome, adjuvant chemotherapy for retroperitoneal tumors should also be considered experimental. It is worth noting that patients older than 70 years (> 65 years in the study by Frustaci et al) have been excluded from most adjuvant chemotherapy studies, yet a substantial minority of STS cases occur in these older patients, and chemotherapy should be used with caution, particularly dose-intensive regimens.
Despite the reservations advanced here, this Italian study has substantially added to our knowledge in this field. 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 RCTs. For example, in European Organization for Research and Treatment of Cancer protocol 62931, patients are randomized after definitive surgery between chemotherapy (doxorubicin 75 mg/m2 and ifosfamide 5 g/m2 + G-CSF every 21 days) or no chemotherapy.
It is even more difficult to make recommendations regarding the large numbers of STS patients who do not fit into the "low-risk" or "high-risk" categories. These include, but are not limited to, patients with STS of head, neck, trunk, visceral, and uterine sites, patients with intermediate-grade tumors, and patients with small high-grade tumors.
To return, then, to the issue of standard of care. Meta-analyses are helpful in providing a systematic quantitative summary of the available evidence. Through the development of practice guidelines, this evidence can be translated into practical recommendations that are modified by practitioner feedback7 from the local community in which they may be implemented. In Canada, for example, a practice guideline (no. 11.2) on "Adjuvant chemotherapy following complete resection of soft tissue sarcoma" has been completed (abstract available on http://www.cancercare.on.ca/ccopgi/; manuscript in preparation).
Although a specific standard of care relating to the use of adjuvant chemotherapy in STS may not yet be clear, I will make a general plea that has been made before but is worth reiterating. Patients with these rare tumors should be managed by an experienced team of sarcoma specialists comprising, at a minimum, surgical oncologists, pathologists, radiologists, and radiation and medical oncologists who can ensure that care is optimum at all stages of diagnosis and treatment. It is in this setting that the most informed discussions may be had and decisions made about adjuvant treatments.