Departments of 1 Surgery, 2 Medicine and 3 Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY; 4 Department of Medicine, Dana Farber Cancer Institute, Boston, MA, USA
* Correspondence to: Dr S. Singer, The Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. Tel: +1-212-639-2940; Fax: +1-646-422-2300; Email: singers{at}mskcc.org
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Abstract |
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Patients and methods: Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors.
Results: NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.530.71) for patients not receiving NAC and 0.83 (95% CI: 0.720.95) for patients receiving NAC.
Conclusion: NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.
Key words: chemotherapy, doxorubicin, ifosfamide, neo-adjuvant, sarcoma
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Introduction |
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Despite these inconsistent data, adjuvant or neo-adjuvant chemotherapy (NAC) is commonly used at many centers as part of a treatment plan for patients with primary extremity STSs. Proponents have suggested several potential benefits including an ability to assess sarcoma response to a given chemotherapeutic regimen, earlier treatment of microscopic metastatic disease and facilitation of tumor removal [5, 6
]. In spite of these theoretical benefits, the value of NAC in improving survival of patients with STS remains unproven. This study was undertaken to retrospectively determine the association of NAC with survival and recurrence in a group of patients with high risk (large, high-grade) extremity STS.
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Patients and methods |
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Patients treated with NAC consisting of doxorubicin/ifosfamide/mesna (AIM) followed by surgery for their primary disease were identified. Chemotherapy was not administered in the setting of a protocol. Patients were treated by a heterogeneous group of physicians at two institutions who individually made treatment decisions. Doxorubicin was typically given at 75 mg/m2/cycle as divided doses i.v. bolus over 3 days and ifosfamide was given as a dose of 69 g/m2/cycle, in divided doses over 3 days, usually over 3 h with mesna as a urothelial protectant. Among those who received chemotherapy, the mean number of cycles of pre-operative chemotherapy given was 3 ± 0.4 (standard deviation). These patients had been diagnosed with STS of the extremity between March 1985 and July 2001. All patients with large, high-grade, deep, extremity STS who received surgery during this same time period, but did not receive any chemotherapy (neo-adjuvant or adjuvant) for their primary disease were also identified. Since only two patients were treated with NAC during the 1980s (both from DFCI, one diagnosed in 1985, the other in 1989), we restricted our cohort to all patients treated with NAC and surgery or surgery alone from 1990 to 2001. Seventy-four patients were treated with NAC and surgery (30 from DFCI and 44 from MSKCC), and 282 patients were treated with surgery alone (21 from DFCI and 261 from MSKCC). Patient records were reviewed to confirm data collected in the databases.
The purpose of the study was to determine the association of NAC with survival and recurrence in a group of patients with high-risk extremity STS. The primary end points for the analysis were disease-specific survival (defined as time from diagnosis to death due to disease or last follow-up) and recurrence-free survival (defined as time from diagnosis to first recurrence, either local or distant). Secondary end points included time to distant recurrence (defined as time from diagnosis to development of metastatic disease), and time to local recurrence (defined as time from surgery to development of local recurrence). Three-year estimates of disease-specific survival and the recurrence end points are presented since the median follow-up time for survivors was 37 months (Table 1).
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Approval for this study was obtained from the Institutional Review Boards of MSKCC and DFCI.
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Results |
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Overall disease-specific survival was 73% at 3 years, with a 95% confidence interval (CI) of 6878% (Table 2; Figure 1). The unadjusted hazard ratio for the effect of NAC on disease-specific survival was 0.75 (95% CI: 0.451.2). Using the Cox proportional hazards model stratified by histology, size of primary tumor and age, NAC was associated with a significant improvement in disease-specific survival, P=0.02 (Table 3). The hazard ratio (HR) for the effect of NAC on disease-specific survival was 0.52 (95% CI: 0.300.92). In order to investigate whether the effect of NAC varied among different prognostic groups, the effect of NAC was examined within strata. However since the number of patients was small in many strata when stratifying by the combination of histology, size and age, the effect of NAC was examined by stratifying by each of the three prognostic variables individually. The effect of NAC on disease-specific survival was not significant when stratifying by histology or age (Table 3). However, the effect of NAC did vary significantly when stratification was done by tumor size (Table 3). The benefit of NAC was seen in patients with tumors >10 cm, but not in patients with tumors 510 cm. The disease-specific mortality HR for NAC in patients with tumors 510 cm was 1.4 (95% CI: 0.573.3). Although it appears that NAC has an adverse effect on disease-specific survival in patients with tumors 510 cm, it is important to note that the number of patients in the NAC-treated group was small (n=23) and the 95% CI is very wide. The disease-specific mortality HR for NAC in patients with tumors >10 cm was 0.45 (95% CI: 0.250.83). The 3-year disease-specific survival for tumors >10 cm was 62% (95% CI: 5371%) for patients not receiving NAC and 83% (95% CI: 7295%) for patients receiving NAC. Survival curves demonstrating the effect of NAC on larger tumors are shown in Figure 2 (curves 2 and 4). These results indicate that the overall benefit of NAC on disease-specific survival may be driven by the effect of NAC on those patients with tumors >10 cm.
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Overall probability of local recurrence-free survival was 83% at 3 years (95% CI: 0.780.88). Since the number of local recurrences is very small in the NAC group (nine local recurrences), further analysis was not attempted. The 3-year estimate for freedom from distant recurrence was 57% (95% CI: 5162%) (Table 2). The results for freedom from distant recurrence were similar to the results for recurrence-free survival, as would be expected given that the majority of recurrences occurred distantly (Table 3). Although an overall benefit in freedom from distant recurrence was not seen, a benefit of NAC was seen in those patients with tumors >10 cm (HR: 0.67; 95% CI: 0.390.98).
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Discussion |
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More recently there has been interest in the combination of doxorubicin and ifosfamide in the management of STS. The combination of doxorubicin, ifosfamide and mesna (AIM) has been reported to be more effective than doxorubicin alone in the treatment of advanced STS [14]. When ifosfamide has been used in the neo-adjuvant setting for STS, response rates ranging from 29 to 62.5% [6
, 15
] have been reported.
Recently published prospective randomized trials of adjuvant and/or neo-adjuvant chemotherapy with anthracycline/ifosfamide combinations for STS have yielded inconsistent results [1517
], and these studies have been criticized for their small sample size and/or heterogeneity of tumor types and sizes [2
, 18
, 19
]. Two trials showed no survival advantage in those patients treated with doxorubicin/ifosfamide-based adjuvant therapy [15
, 16
]. The most encouraging trial to date has been that of Frustaci et al. [17
]. This trial demonstrated a significant survival benefit at 4 years in those patients treated with adjuvant epirubicin, ifosfamide and mesna. The study had been closed for improvement in disease-free survival and overall survival, but over time has shown loss of significance of the benefit of chemotherapy in terms of overall survival [20
]. In addition, the control and treatment groups in this study were not balanced with regard to histologic subtype. It is noteworthy that the incidence of distant failures was equal in the chemotherapy and non-chemotherapy groups at 4 years, consistent with the overall survival data from the recent study update [17
]. There have been two previously published retrospective series of patients receiving NAC containing doxorubicin and ifosfamide [5
, 21
]. Both series reported an improvement in disease-specific survival among those treated with NAC compared to historical controls.
In this study, we retrospectively analyzed the association of NAC with disease-specific survival in patients with high-grade extremity sarcomas from prospectively acquired databases of patients from two separate institutions. NAC was associated with an overall improvement in disease-specific survival for the complete cohort of patients and this improvement appears to be driven by the benefit of NAC in patients with extremity sarcomas >10 cm. In this high-risk group, there was a 21% improvement in disease-specific survival at 3 years. Conversely, no association was seen between improved disease-specific survival in patients with extremity sarcomas between 5 and 10 cm. There was also a trend towards an improvement in recurrence-free survival in patients with tumors >10 cm treated with NAC.
The effect of NAC in these patients has been previously analyzed and presented in abstract form using a case-matched technique [22]. In the previous analysis, we found a significant improvement in 2-year disease-specific survival in those treated with NAC but no improvement in long-term disease-specific survival. Limitations in the design of the previous analysis (a variable matching ratio for each strata and the lack of randomness associated with small group sizes) prompted us to finally perform the stratified analysis presented here. This difference in analytic techniques accounts for the similar but slightly different results and conclusions in the present report. Other changes that should be noted in this analysis include: tightening the study period to 19902001 from 19782001, and removing margin status from the analysis.
Most disease-specific mortality in patients with high-risk extremity sarcomas is related to the development of metastatic disease. Therefore, the finding that NAC was not associated with an improvement in distant recurrence-free survival must be noted as it is seemingly inconsistent with the noted improvement in overall survival. It remains possible that NAC does not delay the appearance of metastatic disease but does slow the progression of metastatic disease thereby improving disease-specific survival.
It should be underscored that this study design has distinct limitations. This is a retrospective cohort study, not a randomized trial. Chemotherapy in this study was not given in a protocol fashion, but rather according to individual physician judgment. We adjusted for several known prognostic variables for STS (age, tumor size and tumor histology). This was especially important given that patients with synovial sarcoma, tumors >10 cm and younger patients were more commonly treated with NAC in the present series indicating potential bias in selection of patients for chemotherapy. However, there could be imbalances in variables that have not been accounted for in the present model. It must be noted that performance status was not compared in the two groups in this series. It is possible that performance status was higher in those selected for NAC and could account for some of the observed benefit of NAC.
While generally well tolerated, AIM chemotherapy may be associated with severe neutropenia, thrombocytopenia and/or anemia in some cases, and in some cases these side-effects of chemotherapy may be fatal [1517
]. The decision to employ NAC containing AIM should be made with these potential toxic effects in mind.
In conclusion, this study suggests an association between improved disease-specific survival (a 21% survival benefit at 3 years) and the use of NAC in patients with high-grade extremity sarcomas >10 cm. However, these data represent a retrospective analysis and can by no means replace a prospective randomized study of chemotherapy. We suggest that, in order to obtain clearer data, consideration should be given to nationwide adjuvant or neo-adjuvant chemotherapy studies restricted to a single well-defined histological subtype, such as leiomyosarcoma or synovial sarcoma. A design to consider that may be more palatable than a study in which there is a no-treatment arm would be a trial designed to identify early biochemical and molecular markers of response to therapy and treatment benefit for individual patients. For the group of patients unresponsive to AIM chemotherapy, there are woefully inadequate options for treatment, underscoring the need to screen and identify new therapeutic targets to enhance response rates and improve survival in patients with high-grade extremity sarcoma. With the development of such agents we hope to find more significant differences in improvement in response rate and survival in the neo-adjuvant setting, which may render moot the argument of whether to give chemotherapy or not.
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Conflict of interest |
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Acknowledgements |
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Received for publication March 12, 2004. Revision received June 10, 2004. Accepted for publication June 18, 2004.
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References |
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