Adjuvant Chemotherapy For Soft Tissue Sarcoma Research Articles

SY9-1 - Standard Therapy for Localized Soft Tissue Sarcomas

Soft tissue sarcomas (STS) are very rare malignant tumors. Because of the rareness, it is difficult to develop new standard therapies for STS. According to the Soft Tissue Tumor Registry by the Japanese Orthopaedic Association, approximately 75% of the patients with STS exhibit the localized disease at first presentation. All localized STS should be treated by definitive surgery with appropriate margin as standard treatment. The low-grade, superficial or small STS can be cured by surgery alone. Insufficient surgical margin, including marginal or intra-lesional resection, may require adjuvant radiation therapy. On the other hand, high-grade, deep-seated and large, i.e., high-risk STS result in poor prognosis when they are treated by surgery alone. To establish the effective adjuvant chemotherapy for high-risk STS, a number of randomized clinical trials have been carried out. All the randomized studies, except one, failed to demonstrate the superiority of adjuvant chemotherapy in overall survival (OS) of the patients with localized STS in comparison with surgery alone. However, meta-analyses of the randomized trials have confirmed the significant improvement of OS by adjuvant chemotherapy for STS. Recently, a randomized study comparing neo-adjuvant full-dose epirubicin (EPI)+ifosfamide (IFM) and histology-tailored chemotherapy for high-risk STS conducted by the Italian Sarcoma Group has clearly showed the significantly better OS in EPI+IFM group. The result was comparable with that in a phase II trial, JCOG0304, using neo-adjuvant chemotherapy with doxorubicin (DOX)+IFM carried out by the Japan Clinical Oncology Group (JCOG). Thus, the current standard therapy for high-grade, deep-seated and large STS is the neo-adjuvant chemotherapy with full-dose DOX+IFM. We are currently conducting a randomized phase II/III study comparing the efficacy of neo-adjuvant DOX+IFM and gemcitabine+docetaxel for high-risk localized STS, JCOG1306.

Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials

The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy (CT) in localized high-grade soft tissue sarcoma (STS). Both studies failed to demonstrate any benefit on overall survival (OS). The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT. Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS (large resection, R0/marginal resection, R1) were pooled. Prognostic factors were assessed by univariate and multivariate analyses. Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor. A total of 819 patients had been enrolled with a median follow-up of 8.2 years. Tumor size, high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival (RFS) and OS. Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS. A significant interaction between benefit of adjuvant CT and age, gender and R1 resection was observed for RFS and OS. Males and patients >40 years had a significantly better RFS in the treatment arms, while adjuvant CT was associated with a marginally worse OS in females and patients <40 years. Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms. Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS. Based on these data, we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine standard of care.

Patterns of chemotherapy administration in soft tissue sarcoma (STS) and impact on overall survival (OS): A National Cancer Database (NCDB) analysis.

10566 Background: Patients with AJCC stage III STS (large, deep, high grade) have an expected OS of approximately 50% at 5 years. A meta-analysis of adjuvant chemotherapy in STS showed an absolute benefit in OS for the chemotherapy group. Despite these results, patterns of care and opinions with regard to adjuvant chemotherapy vary. Our aims were to identify factors associated with receipt/non-receipt of chemotherapy, and their impact on OS in patients with high risk STS. Methods: Individuals diagnosed with stage III STS between 1998-2010 were identified from the NCDB. Excluded from the analysis were patients who did not undergo surgery for the primary tumor and histologies considered resistant to chemotherapy. Chi-square tests and multivariate logistic regression were used to compare sociodemographic and tumor factors between the groups receiving and not receiving chemotherapy. All-cause mortality was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. The survival analysis co...

Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: A study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931

BackgroundWe conducted a retrospective study, pooling data from two clinical trials in high risk soft tissue sarcoma (STS) patients, with the objective of comparing two different age groups: 15–29years (adolescents and young adults (AYA) population) and ⩾30years. The aim was to determine prognostic factors for the AYA population. MethodsPatients selected for analysis were treated in two randomised trials of adjuvant chemotherapy in STS (European Organisation for Research and Treatment of Cancer (EORTC) 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74years (AYA population: n=161, median FU 9.46years; patients ⩾30years: n=632, median FU 8.62years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumour size and localisation (limb versus other), absence or presence of local recurrence and treatment (control arm versus adjuvant chemotherapy). ResultsPatients’ characteristics were globally similar with two exceptions, histological subtype (p=0.0043) and tumour size (p<.0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29%), whereas leiomyosarcoma (18%), malignant fibrous histiocytoma (MFH, presently being termed undifferentiated pleomorphic sarcoma (UPS), 16%) and liposarcoma (15%) were more frequent in patients ⩾30years. For OS, independent favourable prognostic factors were low grade and small tumour size for both groups; radical resection and MFH or liposarcoma subtype were favourable factors for patients ⩾30years only. For RFS, favourable prognostic factors were small tumour size and low grade for both groups; tumour location in the extremities was a favourable factor for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favourable factors for patients ⩾30years only. ConclusionsSignificant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ⩾30years. The results may have further implications for the treatment of STS patients in different age groups, as well as the design of future clinical trials.

Prognostic factors in adolescents and young adults (AYA) with high-risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: A study based on two pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials

10573 Background: We conducted a retrospective study pooling data from two clinical trials in high risk STS patients with the objective to compare two different age groups: 15 - 29 years (AYA population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population. Methods: Patients selected for analysis were treated in two randomized trials of adjuvant chemotherapy in STS (EORTC 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n = 161, median FU 9.46 years; patients ≥ 30 years: n = 632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumor size and localization (limb vs. other), absence or presence of local recurrence and treatment (control arm vs. adjuvant chemotherapy). Results: Patients’ characteristics were globally similar with two exceptions, histological subtype (p = 0.0043) and tumor size (p &lt; .0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29 %), whereas leiomyosarcoma (18 %), malignant fibrous histiocytoma (MFH, 16 %) and liposarcoma (15 %) were more frequent in patients ≥ 30 years. For OS, independent favorable prognostic factors were low grade and small tumor size for both groups; radical resection and MFH or liposarcoma subtype were factors of favorable prognosis for patients ≥ 30 years only. For RFS, favorable prognostic factors were small tumor size and low grade for both groups; tumor location in the extremities was a factor of favorable prognosis for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favorable factors for patients ≥ 30 years only. Conclusions: On the basis of these data, significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications on the treatment of STS patients in different age groups as well as the design of future clinical trials. No significant financial relationships to disclose.

856 Intensified adjuvant chemotherapy for extremity soft tissue sarcomas (STS)

Adjuvant chemotherapy for STS still remains a matter of debate, since just few randomized studies have indicated a small advantage in terms of disease free interval or overall survival at preliminary reports. However, the majority of those trials have not included adequate doses of anthracyclines nor the today most active agent Ifosfamide (IFO). To re-evaluate the role of adjuvant chemotherapy in extremity STS, we started in June ‘92, a co-operative randomized prospective adjuvant study comparing a control arm to an intensified chemotherapy arm. Treatment consisted of Epirubicin 60 mg/m2, day 1&2, Ifosfamide 1.8 g/m2 × 5days as 1 hr infusion, MESNA 60% of the daily IFO dose fractionated in 3 separated doses, fluids 1.5–2.0 litres/day and G–CSF 300 μg/day from + 8 to + 15; treatment was scheduled every 3 weeks for a total of 5 cycles. Of the 37 up to now randomized pts to the chemotherapy arm, 25 are evaluable (5 cycles completed + two months follow-up) for the toxicity and dose intensity evaluation purpose (12 pts not yet evaluable). The median nadir of WBC and PLTS was 1300/μ1 (range: 200–8000/μ1); and, 120000/μ1 (range: 10000–250000/μ1), respectively. Overall, a G4 leukopenia and thrombocytopenia was noted in 30% and 5% of cycles respectively. Anemia progressively worsened and the median HB fall from basal values to the nadir of the 5th cycle was of 4 g/dl (range 0–9.8 g/dl); in 12 of 25 pts (48%) PRBC transfusions were given to prevent symptoms from anemia. Nevertheless, an optimal recovery to pre-treatment values was obtained after 2 months from end of treatment (median HB 13.5; range: 12.7–14.8). Neutropenic fever was observed in 15% of the cycles, prophylactic antibiotics were administered in further 3% of cycles. No pts received pits support. The median average received dose intensity (ARDI) was of 91% (range: 67–100%) and 19/25 pts (76%) received an ARDI > 80%. Causes of reduction in dose intensity were delay in retreatment in 24 cycles and reduction of the dose in 40 cycles. Even through the toxicity was substantial (anemia and leukopenia) it was possible to give an adequate dose intensity to the majority of pts. All but one pt (3 cycles received) completed the forseen 5 cycles employing the predefined dose reduction schema.

Adjuvant chemotherapy for soft-tissue sarcoma: review and meta-analysis of the published results of randomised clinical trials

Fifteen published randomised trials comparing adjuvant chemotherapy with no chemotherapy in soft-tissue sarcoma (STS) were identified (1546 patients). A qualitative review and a meta-analysis of this published literature were performed. With the qualitative review it was not possible to synthesise the apparently conflicting results of individual trials. The meta-analysis of the published data suggests an improvement in survival at 2 years (OR = 0.73, 95% CI = 0.53-0.99, P = 0.044) and at 5 years (OR = 0.59, 95% CI = 0.45-0.78, P = 0.0002) in favour of chemotherapy. However, the assumptions and approximations required to conduct this quantitative summary demand that the results are interpreted with caution. The only reliable means of assessing the current evidence on whether adjuvant chemotherapy has a role in the treatment of patients with STS, is to collect, check and reanalyse individual patients data (IPD) from each trial centrally, and formally combine the results in a stratified time-to-event analysis. Such an IPD analysis is currently being undertaken by an international collaborative group.

Adjuvant Therapy Of Soft-Tissue Sarcomas

Combination surgery and radiation therapy is currently the standard of care for primary treatment of soft-tissue sarcomas. The practice of complete muscle group excision has been replaced by that of achieving a 3- to 4-cm circumferential margin or adding either pre- or postoperative radiation to the surgical therapy. The surgeon can limit the margins to preserve the optimum tissue function but at the same time achieve maximum local control. Investigations continue to define the role of brachytherapy. Achieving therapeutic radiation doses while significantly limiting the treatment time has obvious advantages. Failure to irradiate a field wide enough, however, could result in marginal relapses. The demonstration of Brennan et al that the very high complication rate associated with this technique can be limited by delaying the delivery of radiation through the surgically placed catheters until 5 days after a surgical resection has significant implications for further protocols. The role of adjuvant chemotherapy in the multimodal management of patients with soft-tissue sarcomas is still investigational. Although a few of the randomized trials showed definite disease-free and overall survival benefit in those patients receiving adjuvant chemotherapy, most did not. In general, many authors believe that adjuvant chemotherapy for soft-tissue sarcoma cannot be recommended outside the context of a clinical trial.(ABSTRACT TRUNCATED AT 250 WORDS)