Adjuvant Chemotherapy for STS
There is an urgent need to determine the role of adjuvant chemotherapy for STS since up to half of high-risk patients will eventually relapse or develop distant metastasis. Over 20 studies on adjuvant therapy for STS have been performed. Unfortunately, these trials reported conflicting data. Most of them have been small, enrolled different risk patients and treated with different chemotherapy regimens. Two meta-analyses conducted on the randomized controlled trials regarding adjuvant chemotherapy for STS by Sarcoma Meta-analysis Collaboration (SMAC) have further explored the potential benefit of adjuvant chemotherapy for resected STS in adults. The first meta-analysis was published in 1997 including 14 studies which involved 1,568 adults with postoperative STS (extremities and others) to receive or not receive adjuvant doxorubicin-containing chemotherapy. After a median follow-up of 9.4 years, it was demonstrated a significantly lower risk for relapse, either local or distant metastatic, in chemotherapy arm than in observation arm, but the overall survival (OS) was not statistically significant although there was a trend towards improved [hazard ratio (HR) for death 0.89, 95% confidence interval (CI): 0.76–1.03]. Five recent studies using ifosfamide as part of adjuvant therapy were added to the SMAC updated meta-analysis in 2008. The odds ratios (OR) for local recurrence was 0.73 (95% CI: 0.56–0.94; P=0.02), for distant and overall recurrence was 0.67 (95% CI: 0.56–0.82; P=0.0001), all in favor of chemotherapy, consistent with those found in the earlier meta-analysis. In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI: 0.68–1.03; P=0.09), which was not statistically significant. However, when doxorubicin combined with ifosfamide, it can translate into a gain in OS (OR 0.77, P=0.01) and absolute risk reduction of death of 6%, which implies the role of ifosfamide in the adjuvant treatment of sarcomas.
The first large study to incorporate ifosfamide as part of adjuvant therapy for STS is from the Italian Sarcoma Study Group which was designed on relatively restricted enrollment criteria. A total of 104 high-risk postoperative patients (grade 3–4, primary diameter ≥5 cm or any size recurrent tumor) in extremities or girdles were randomized to the dose intensive chemotherapy group (5 cycles of epirubicin 60 mg/m2 over 2 days and ifosfamide 1.8 g/m2 over 5 days) or control group. After a median follow-up of 59 months, median disease-free survival (DFS) (48 vs. 16 months) and median OS (75 vs. 46 months) were significantly better in the chemotherapy arm. These data imply a survival advantage of high-dose intensified chemotherapy for patients with high-risk extremity STS.
Although there was a significant survival benefit for the trial of the Italian Sarcoma Group, no difference in the recurrence-free survival (RFS) or OS were demonstrated in the European Organization for Research and Treatment of Cancer (EORTC) trials. The largest phase III randomized study of adjuvant chemotherapy was EORTC-62931. A total of 351 grade 2–3 completely resected patients were recruited to 5 cycles of doxorubicin 75 mg/m2 and ifosfamide 5 g/m2 per cycle versus observation. However, this study was negative which showed no statistically significant difference in terms of DFS or OS. The estimated 5-year RFS was 52% in both arms and OS was 69% (control arm) and 64% (chemotherapy arm), respectively. To explain the difference between Italian Sarcoma Study Group and EORTC 62931 is the latter study included a heterogeneous group of high and low risk patients (67% extremity tumors, 60% high-grade, 40% ≥10 cm) and its suboptimal dosage of ifosfamide. In another earlier large EORTC study, postoperative 486 patients were randomized to combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CyVADIC) for 8 cycles or observation. While DFS and local control were both better in the chemotherapy arm, OS was not significantly different between the two arms.
Even in the prospective randomized trials, the role of adjuvant chemotherapy cannot be defined if the population of patients is unselected. Most trials have involved relatively small patient population, with heterogenous groups of recurrence risk. The criteria used to select patients for adjuvant chemotherapy should be based upon who will truly benefit. How to define high-risk patients depends on several factors, including tumor grade, size, histological type, primary location and the quality of surgery. However, there is no universally accepted definition for high-risk patients in STS. The most widely accepted grading system is proposed by the Sarcoma Group of the French Federation of Cancer Centers (FNCLCC). Tumors are classified according to three parameters: the mitotic index, the presence of necrosis, and cell differentiation. This classification has demonstrated prognostic value, with 5-year survival rates of 95%, 75%, and 45% in patients with grade 1, 2, or 3 tumors, respectively.
A recent pooled analysis of the above mentioned two large EORTC studies aimed to evaluate whether adjuvant chemotherapy benefited any particular subgroup patients. However, RFS and OS were only improved in the R1 resection group. It failed to demonstrate any other factors (size, histology, grade) as predictors of improved survival on multivariate analysis.
Adjuvant chemotherapy has failed so far to consistently improve OS. The reason for that may be the criteria now used to select patients for adjuvant treatment (usually high grade, primary tumor ≥5 cm, deeply seated or locally recurrent extremity sarcomas) are not optimal. We need a clear risk stratification for patient selection for adjuvant therapy. Several prognostic nomograms have been developed to predict OS and risk of distant metastasis in patients undergoing resection of STS of the extremities, but all of them have some limitations.[8,9] In the future, clinical design for adjuvant chemotherapy should incorporate these tools for accurate risk stratification.
Moreover, it should be recognized that chemosensitivity is another important factor for consideration in selection patients for adjuvant therapy. It is well known from studies in the metastatic sarcomas that myxoid/round cell liposarcomas and synovial sarcomas are relatively chemosensitive subtypes of STS.
To make some sense of who will be given adjuvant therapy, it is useful to bear in mind that it needs to be discussed on an individual case by case basis, taking into consideration site of disease (extremity/retroperitoneal/trunk), size, grade, histological subtypes, chemosensitivities as well as PS of the patient, comorbidities, and age. Recently, a mobile device called "Sarculator" which may predict 10-year probability of OS and incidence of distant metastasis in STS patients that can help us to identify high-risk STS patients who fit for adjuvant chemotherapy.
Chin Clin Oncol. 2018;7(4) © 2018 AME Publishing Company