Neoadjuvant Chemotherapy for STS
Neoadjuvant chemotherapy is already a well-adopted approach in the management of osteosarcoma. However, as the efficacy of chemotherapy for metastatic STS is relatively low, the role of neoadjuvant chemotherapy in adult STS is ill defined. There are many theoretical advantages for giving neoadjuvant chemotherapy before surgery, such as tumor cytoreduction for limb salvage surgery, elimination of micrometastases as well as prediction of the effectiveness of chemotherapy. However, in STS, there is lack of evidence specifically addressing the role of chemotherapy when used in a neoadjuvant setting. A European phase II trial enrolled 134 patients with resectable high-risk primary and recurrent STS. "High-risk" defined as tumors > or =8 cm of any grade, or grade II/III tumors <8 cm, or grade II/III locally recurrent tumors, or grade II/III tumors with inadequate surgery. These high-risk patients were randomized between either surgery alone or 3 cycles of doxorubicin 50 mg/m2 and ifosfamide 5 g/m2 before surgery. At a median follow-up of 7.3 years, the 5-year DFS is estimated at 52% for the no chemotherapy and 56% for the chemotherapy arm (P=0.3548). The 5-year OS for both arms is 64% and 65%, respectively (P=0.2204). Despite neoadjuvant chemotherapy with doxorubicin and ifosfamide at these doses and with this schedule was feasible and did not compromise subsequent treatment, it was not powered to draw definitive conclusions on benefit of neoadjuvant chemotherapy even in these selected high-risk patients. The low chemotherapy intensity used and patients with a large variety of histologies and varying chemosensitivities in this trial may potentially impact the possible benefit of neoadjuvant chemotherapy.
In light of the dose intense combination of ifosfamide (9 g/m2) plus epirubicin (120 mg/m2) with G-CSF support may improve therapeutic efficacy, a multicenter international phase III study was designed by Italian Sarcoma Group and the Spanish Sarcoma Group (ISG) to compare 3 cycles of preoperative full-dose epirubicin and ifosfamide (arm A) with 5 cycles of the same drugs given perioperatively (3 neoadjuvant cycles followed by surgery and 2 further adjuvant cycles) (arm B). A total of 328 high-risk patients were recruited, with 164 patients in each arm. At a median follow-up of 63 months, 5-year OS probability was 0.70 for the entire group of patients (0.68 in arm A and 0.71 in arm B). The HR of arm A versus arm B was 1.00 (90% CI: 0.72–1.39). It was concluded from this study that 3 cycles of full-dose preoperative chemotherapy were not inferior to 5 cycles of perioperative chemotherapy in terms of survival. In 2016, Gronchi et al. reported on their 10-year long-term follow-up of this trial. The non-inferiority of 3 cycles in comparison to five is confirmed. These results showed that if 3 cycles of full-dose neoadjuvant chemotherapy have been given, it does not need to give further adjuvant cycles. However, this study did not address whether these 3 cycles of full-dose chemotherapy given preoperative is superior or equal to postoperative with long-term survival.
Despite doxorubicin and ifosfamide are the two most active drugs in STS, there is more emerging evidence of different sensitivity to treatment for different histological subtypes. Promising activity has been reported from varying histology-specific regimens in treatment of metastatic STS. In a recently published phase III trial by ISG (ISG-STS-1001), 3 cycles of neoadjuvant histology-tailored chemotherapy were compared to standard chemotherapy with full dose epirubicin and ifosfamide. 287 high-risk patients with five different histological subtypes of STS were randomly assigned to standard chemotherapy or histology-tailored therapy (trabectedin for high-grade myxoid liposarcomas (MLPS) (n=64), high-dose ifosfamide alone for synovial sarcoma (n=70), etoposide plus ifosfamide for malignant peripheral nerve sheath tumors (n=27), gemcitabine plus dacarbazine for leiomyosarcoma (LMS) (n=28), and gemcitabine plus docetaxel for undifferentiated pleomorphic sarcoma (UPS) (n=97). The primary endpoint was DFS. With a median follow-up of 12.3 months, the projected DFS at 46 months was 62% in the standard chemotherapy group, better than 38% in the histotype-tailored chemotherapy group (HR for DFS was 2.0, 95% CI: 1.22–3.26; P=0.006) across various histological subtypes, with the exception of high-grade MLPS, in which DFS was similar between trabectedin and standard chemotherapy. The OS probability at 46 months was 0.89 and 0.64 (log rank, P=0.003) in the standard and in the tailored arm, respectively. An absolute benefit of nearly 20% on PFS translates into an advantage on OS. Although neoadjuvant histotype-tailored chemotherapy regimen did not show any advantage over the standard chemotherapy regimen, the benefit with the standard chemotherapy regimen further confirmed the value of neoadjuvant chemotherapy itself in patients with high-risk STS.
From ESMO guideline, for STS, there is no consensus on the current role of adjuvant chemotherapy. It can be proposed as an option to the high-risk patient (high-grade, deep, >5 cm tumor) for a shared decision-making with the patient or within clinical trials. Adjuvant chemotherapy is not used in histological subtypes known to be insensitive to chemotherapy. If the decision is made to use chemotherapy as upfront treatment, it may well be used preoperatively. From the study of ISG-STS-1001, a benefit may be gained when 3 cycles of full-dose anthracycline-ifosfamide regimen in selected high-risk STS of extremity/trunk wall.
Chin Clin Oncol. 2018;7(4) © 2018 AME Publishing Company