In an expanded cohort of patients with primary localised high-grade myxoid liposarcoma of the extremities and trunk wall from a phase III randomised study that compared different regimens of neoadjuvant chemotherapy, disease-free survival (DFS) of patients in the trabectedin neoadjuvant arm was not inferior to the DFS of those in the neoadjuvant anthracycline plus ifosfamide chemotherapy arm. Additionally, in a non-Bayesian analysis, the DFS and overall survival (OS) curves were not significantly different in the two treatment groups in both intention-to-treat and per-protocol populations.
The study met the prespecified hypothesis of non-inferiority of histotype-tailored chemotherapy for DFS according to Dr. Alessandro Gronchi of the Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and colleagues from Italian, Spanish, French, and Polish Sarcoma Groups, who published the findings on 17 January 2023 in the JCO.
The authors wrote in the background that in recent years, neoadjuvant chemotherapy for high-risk extremity and trunk wall soft tissue sarcoma (STS) has been investigated in two prospective randomised studies.
The first study included patients with high-risk STS (defined as tumours ≥5 cm and malignancy grade of 3) of the extremity and trunk wall and compared the administration of 3 neoadjuvant cycles of full-dose anthracycline plus ifosfamide chemotherapy to the administration of the same 3 neoadjuvant cycles of full-dose anthracycline plus ifosfamide chemotherapy with the addition of 2 cycles of anthracycline plus ifosfamide postoperatively. After enroling of 328 patients and a median follow-up of 5 and 10 years, the study demonstrated that the administration of 3 cycles of full-dose anthracycline plus ifosfamide chemotherapy in the neoadjuvant setting was not inferior to the administration of 5 cycles.
The second study compared the administration of 3 cycles of standard full-dose anthracycline plus ifosfamide to a histotype-tailored neoadjuvant chemotherapy in 5 most frequent STS histologic types. Histotype-tailored regimens were selected based on findings in the metastatic setting, where histology-specific sensitivities to drugs different from anthracycline were demonstrated.
After the third prespecified futility analysis and after enroling 287 of the planned 350 patients, this randomised study was terminated slightly early because of the observation at a median follow-up of 1 year of a hazard ratio (HR) of 2.0 for DFS and 2.7 for OS for histotype-tailored approach. This observation was confirmed at the final analysis after observing 132 events and reaching a median follow-up of 52 months with an HR of 1.23 for DFS and 1.77 for OS (p = 0.02).
The superior outcome of patients treated by standard chemotherapy was consistent across all histologic types, except for high-grade myxoid liposarcoma, where an equivalence between the administration of standard and histotype-tailored chemotherapy (HR 1.03 for DFS) was observed and confirmed at the final analysis (HR 1.05 for OS).
Because of this finding, while the overall study was closed to randomisation, the high-grade myxoid liposarcoma cohort was reopened and randomisation continued to test the non-inferiority between the two study arms. In the latest article published in the JCO, the study team reports the final results for efficacy and toxicity of this expanded high-grade myxoid liposarcoma cohort.
Patients had localised high-grade (defined as cellular component >5%, size ≥5 cm, deeply seated) myxoid liposarcoma of extremities or trunk wall. The primary endpoint was DFS. The secondary endpoint was OS. The study used a non-inferiority Bayesian design, wherein histotype-tailored would be considered not inferior to standard regimen if the posterior probability of the true HR being >1.25 was <5%.
From May 2011 to June 2020, 101 patients with high-grade myxoid liposarcoma were randomly assigned, 45 to the histotype-tailored arm and 56 to the standard arm. The median follow-up was 66 months (IQR, 37-89 months). Median size was 107 mm (IQR, 84-143 mm), 106 mm (IQR, 75-135 mm) in the histotype-tailored arm and 108 mm (IQR, 86-150 mm) in the standard arm.
At 60 months, the DFS and OS probabilities were 0.86 and 0.73 (HR 0.60, 95% confidence interval [CI] 0.24 to 1.46; log-rank p = 0.26) for DFS and 0.88 and 0.90 (HR 1.20, 95% CI 0.37 to 3.93; log-rank p = 0.77) for OS in the histotype-tailored and standard arms. The posterior probability of HR being >1.25 for DFS met the Bayesian monitoring cut-off of <5% (4.93%). This result confirmed the non-inferiority of trabectedin to anthracycline plus ifosfamide suggested in the original study cohort.
The authors concluded that in the expanded cohort of high-grade myxoid liposarcoma, neoadjuvant trabectedin was not inferior to anthracycline plus ifosfamide and confirmed a better toxicity profile. While the study was randomised, appropriate caution must be taken with the data, since it is difficult to specify type 1 and 2 errors for this patient cohort due to the change in design over the study course.
Pointing out to the limitations, they stated that one might argue that data from the final analysis of this expanded cohort support the choice of trabectedin, possibly in combination with radiation therapy, when neoadjuvant treatment is a consideration for high-grade myxoid liposarcoma. According to the authors, it is essential to further explore the prognostic correlation of current pathologic grading of high-grade myxoid liposarcoma to improve prognostic risk stratification for these patients.
In an accompanied editorial, Dr. Robert G. Maki of the Memorial Sloan Kettering Cancer Center in New York, NY, US wrote that in the case of rare cancers, outcomes are poorer and randomised studies are still feasible, but designs should be customised to account for the challenges of accrual and expectations of outcomes. Setting a high bar for outcomes and including enough sites to complete a study are two important considerations to make rare cancer therapeutic studies as efficient as possible.
The study was previously presented at the ASCO 2022 Annual Meeting (3-7 June 2022, Chicago, IL, US).
It was supported in part by EU grant (EUROSARC FP7 278472). The French sites were supported by NETSARC, LYRICAN, and DEPGYN. PharmaMar provided trabectedin for the high-grade myxoid liposarcoma cohort.
References
- Gronchi A, Palmerini E, Quagliuolo V, et al. Neoadjuvant Chemotherapy in High-Grade Myxoid Liposarcoma: Results of the Expanded Cohort of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish Sarcoma Groups (PSG). JCO; Published online 17 January 2024. DOI: https://doi.org/10.1200/JCO.23.0090
- Maki RG. Trials and Tribulations in Rare Cancer Clinical Research. JCO; Published online 17 January 2024. DOI: https://doi.org/10.1200/JCO.23.02137