Doxorubicin/Adriamycin Monotherapy or Plus Ifosfamide in First-Line Treatment for Advanced Soft Tissue Sarcoma: A Pooled Analysis of Randomized Trials

BackgroundDoxorubicin/Adriamycin (ADM) alone or combined with ifosfamide (IFO) (AI) is available for previously untreated advanced soft tissue sarcoma (ASTS). However, the clinical choice between them remains controversial. In this pooled analysis, we comprehensively compared the efficacy and tolerability of AI versus ADM in patients with ASTS.MethodsPubMed, Web of Science, EMBASE, and Cochrane Library were systematically searched from inception to April 14, 2021. Eligible studies were randomized clinical trials comparing AI to ADM. The primary outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Discontinuation rate (DR) and toxic death (TD) were explored as secondary outcomes.ResultsOverall, three open-label randomized phase 2/3 clinical trials with a total of 1108 newly diagnosed ASTS patients were enrolled. Between AI and ADM, pooled hazard ratios were 0.93 (95% confidence interval 0.58-1.50, p = 0.78) for OS and 0.85 (0.57-1.25, p = 0.41) for PFS. While pooled risk ratios for ORR, DR, and TD were 1.37 (0.94-1.99, p = 0.10), 1.04 (0.74-1.46, p = 0.82), and 0.68 (0.19-2.36, p = 0.54) respectively. No publication bias was observed across the studies.ConclusionIn the first-line setting, adding IFO to ADM failed to benefit ASTS patients against ADM alone, even with comparable tolerability.

Keeping the balance, the true major goal in advanced sarcoma

Achieving a balance between long-term efficacy and good quality of life (QoL) is the main goal of treatment for patients with advanced soft tissue sarcoma, some of whom experience prolonged survival without progression. An awareness of the challenges particular to this complex set of diseases can help preserve patient QoL during treatment. Histology is among the main factors to consider when selecting treatment in advanced disease. Close attention to the toxicity profiles of available regimens is of particular importance, especially in more advanced lines where the population is usually more vulnerable. Surgical outcomes are significantly better in patients managed with expert care, and early referral to sarcoma reference centers is key to improving survival and QoL.

Efficacy and safety of anlotinib combined with liposomal doxorubicin in first-line treatment of advanced soft-tissue sarcoma.

e23530 Background: Anthracycline-based chemotherapy is the main first-line treatment option for advanced soft-tissue sarcoma (STS). Anlotinib has been approved for the treatment of STS by the Chinese agency. This study was performed to evaluate the efficacy and safety of Anlotinib combined with liposomal doxorubicin in first-line treatment of patients with advanced STS. Methods: This is a single-center, retrospective study. Eligible patients were those ≥14 years old, ECOG performance state of 0-1, with histologically confirmed locally advanced, unresectable or metastatic STS, previously untreated, with measurable disease by RECIST v1.1. All patients received Anlotinib (12mg once daily, 2 weeks on and 1 week off) and liposomal doxorubicin (40-50 mg/m2, IV, D1, every 3 weeks) until disease progression or unacceptable adverse events. The primary endpoint was progression-free survival (PFS). Disease control rate (DCR), objective response rate (ORR), and side effects were also calculated. Results: Between April 2019 and December 2020, 8 patients were evaluated, including 2 undifferentiated pleomorphic sarcoma, 1 liposarcoma, 4 fibrosarcomas, and 1 synovial sarcoma. The median age was 42 years. 2 patients (25%) achieved a confirmed partial response (PR) and 3(37.5%) had stable disease (SD). The ORR and DCR were 25% and 62.5% respectively. The median PFS was 11.3 months, and the PFS rate at 4 months was 50%. Treatment-related adverse events included hand-foot syndrome (3/8, 37.5%), pneumothorax (1/8, 12.5%), oral mucositis (2/8, 25%), epistaxis (2/8, 25%), hypertension (2/8, 25%), arrhythmias (1/8, 12.5%), and pharyngeal pain (1/8, 12.5%). Three patients experienced grade 3 or 4 adverse events, 2 hand-foot syndrome (2/8, 25%) and 1 pneumothorax (1/8, 12.5%). Conclusions: This study suggested that the combination of Anlotinib and liposomal doxorubicin might have anti-tumor activity and acceptable toxicity in first-line treatment of patients with advanced STS.

Long-term evaluation of the novel radioenhancer NBTXR3 plus radiotherapy in patients with locally advanced soft tissue sarcoma treated in the phase II/III Act.In.Sarc trial.

11544 Background: NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment, in patients with locally advanced soft tissue sarcoma (LA STS), compared to RT alone. Primary endpoint of pCR rate was 16% vs 8% (p=0.044) and R0 margin rate was 77% vs 64% (p=0.042) (Bonvalot et al. Lancet Oncol. 2019). No modification of the early safety profile of RT was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life. Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT (NCT02379845). Patients were treated with either a single intratumoral injection of NBTXR3 (volume equivalent to 10% of tumor volume, at 53.3g/L) plus EBRT (arm A), or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. The primary and main secondary efficacy endpoints were previously reported. Safety of NBTXR3+RT, as preoperative treatment, was evaluated as secondary endpoint. We present the safety analyses done in the “all treated population”, with data recorded during at least a two-year follow-up. Important parameters related to HR-QoL, including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires. Results: Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Second primary cancer was observed in 1 patient in arm A and 6 patients in arm B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis (4.5% vs 7.7%), arthrosis (2.2% vs 0.0%) and edema (6.7% vs 2.2%) that may alter limb function showed no difference between arms. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. In addition, the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site. Finally, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions. Conclusions: The long-term safety results demonstrate that the addition of NBTXR3 to EBRT neither added toxicity nor modified the bystander effect of RT. The results presented here associated with the efficacy data reported previously reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS. Clinical trial information: NCT02379845.