Oncology – Bone and Sarcomas
RCT: Pembrolizumab with Preoperative Radiotherapy Shows Potential in Stage III Soft Tissue Sarcoma
2 Jan, 2025 | 09:00h | UTCBackground: Patients with locally advanced, high-grade soft tissue sarcomas of the extremity often face a high risk of metastatic disease, despite curative-intent surgery and radiotherapy. Traditional doxorubicin-based chemotherapy provides variable benefits and can cause considerable toxicity, prompting investigations into alternative strategies. Emerging data from smaller trials hinted that immune checkpoint inhibitors might offer targeted benefit in sarcomas, but robust evidence in the neoadjuvant setting remains limited.
Objective: To assess whether adding neoadjuvant and adjuvant pembrolizumab to preoperative radiotherapy and surgical resection could enhance disease-free survival (DFS) in individuals with resectable grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or liposarcoma of the extremity and limb girdle.
Methods: This open-label, randomized trial (SU2C-SARC032) enrolled 143 participants at 20 academic centers in Australia, Canada, Italy, and the USA. Eligible patients were 12 years or older, presented with primary tumors >5 cm, and did not receive chemotherapy as part of this protocol. Participants were randomized 1:1 to standard preoperative radiotherapy (50 Gy/25 fractions) plus surgery (control) or the same radiotherapy combined with pembrolizumab (200 mg every three weeks) in the neoadjuvant setting, followed by up to 14 adjuvant cycles. The primary endpoint was disease-free survival, analyzed in a modified intention-to-treat cohort of 127 evaluable patients, with a median follow-up of 43 months.
Results: The pembrolizumab group demonstrated a higher 2-year DFS rate (67%) compared with controls (52%), suggesting a favorable hazard ratio (0.61) for recurrence or death. Nonetheless, grade 3 or higher adverse events were more common in the pembrolizumab arm (56% vs 31%). Secondary endpoints, including distant disease-free survival and overall survival, also appeared to favor the pembrolizumab arm, but these comparisons were not powered for definitive conclusions.
Conclusions: Neoadjuvant and adjuvant pembrolizumab in combination with radiotherapy and surgery demonstrated a DFS advantage in stage III undifferentiated pleomorphic sarcoma or liposarcoma, reinforcing the potential role of immunotherapy in high-risk settings. However, given the increased incidence of adverse events and the relatively short follow-up for overall survival, cautious interpretation is warranted. Further evidence is required to determine long-term benefits and confirm whether these findings extend to other sarcoma subtypes.
Implications for Practice: These data suggest that incorporating pembrolizumab could be considered in selected patients, particularly those with large, high-grade tumors unresponsive to or unsuitable for traditional chemotherapy. Clinicians must balance the incremental risk of immunotherapy-induced side effects against the observed gains in disease-free survival and the ongoing need for extended follow-up.
Study Strengths and Limitations: Strengths include a multicenter randomized design, focus on a high-risk population, and a robust primary endpoint. Limitations encompass a relatively small sample size, inherent to rare cancers, underpowered subgroup analyses, and absence of long-term survival data. Confirmation of these early signals in larger cohorts and over more extended follow-up periods remains necessary.
Future Research: Additional trials should explore optimal radiotherapy fractionation, potential synergies with cytotoxic or targeted agents, and predictive biomarkers of response. Understanding immune correlates, including circulating tumor DNA and tumor microenvironmental factors, may refine treatment selection and enhance therapeutic outcomes.
Reference: Mowery YM, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. The Lancet. 2024;404(10467). DOI: http://doi.org/10.1016/S0140-6736(24)01812-9
Consensus Paper | Ten recommendations for sarcoma surgery
14 Jul, 2023 | 12:49h | UTC
RCT | Ganitumab added to chemotherapy did not improve outcomes in patients with metastatic Ewing sarcoma
30 Mar, 2023 | 14:16h | UTCRandomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children’s Oncology Group – Journal of Clinical Oncology (link to abstract – $ for full-text)
Commentary: Ganitumab Provides No Benefit in Metastatic Ewing Sarcoma – Cancer Therapy Advisor
RCT | Nirogacestat for desmoid tumors
15 Mar, 2023 | 14:57h | UTCNirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors – New England Journal of Medicine (link to abstract – $ for full-text)
News Release: Nirogacestat Improves Outcomes for Patients With Desmoid Tumors – Memorial Sloan Kettering Cancer Center
Commentary on Twitter
In a randomized, placebo-controlled trial, oral nirogacestat twice daily led to 41% of patients having a tumor response, and 2-year progression-free survival was 76%. Most adverse events were low grade. https://t.co/wtt7solTHW pic.twitter.com/qkRchfnXU2
— NEJM (@NEJM) March 10, 2023
Consensus Recommendations | Spinal tumors
9 Mar, 2023 | 14:15h | UTC
Review | Morbidity and mortality after surgery for retroperitoneal sarcoma
28 Feb, 2023 | 13:35h | UTCMorbidity and Mortality after Surgery for Retroperitoneal Sarcoma – Current Oncology
German Guidelines on Sarcoma of the Uterus.
6 Dec, 2022 | 13:50h | UTCSingle-arm P2 study | Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas.
9 Nov, 2022 | 12:24h | UTCHypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial – The Lancet Oncology (link to abstract – $ for full-text)
RCT | Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma.
9 Nov, 2022 | 12:12h | UTCComparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial – The Lancet (link to abstract – $ for full-text)
SR | Efficacy and safety of stereotactic body radiotherapy for painful bone metastases.
8 Nov, 2022 | 12:00h | UTC
Single-arm phase 2 study | Activity of Cabazitaxel in metastatic or inoperable locally advanced dedifferentiated liposarcoma.
22 Aug, 2022 | 11:53h | UTCActivity of Cabazitaxel in Metastatic or Inoperable Locally Advanced Dedifferentiated Liposarcoma: A Phase 2 Study of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) – JAMA Oncology (free for a limited period)
Invited Commentary: Optimizing Histology-Specific Clinical Trials in Soft-Tissue Sarcoma—Are We There Yet? – JAMA Oncology (free for a limited period)
Single-center phase 2 trial | Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas.
11 Aug, 2022 | 11:52h | UTCDurvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial – The Lancet Oncology (link to abstract – $ for full-text)
Commentary on Twitter
Online first: #Durvalumab plus #tremelimumab in advanced or metastatic soft tissue and bone #sarcomas: a single-centre phase 2 trial https://t.co/Zt9vTFzBOK pic.twitter.com/BP7fz9FWRw
— The Lancet Oncology (@TheLancetOncol) August 5, 2022
RCT | Doxorubicin alone vs. doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma.
20 Jul, 2022 | 11:36h | UTCDoxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomised, multicentre, open-label phase 3 trial – The Lancet Oncology (link to abstract – $ for full-text)
RCT: Efficacy and safety of TRC105 plus pazopanib vs. pazopanib alone for treatment of patients with advanced angiosarcoma.
27 May, 2022 | 11:15h | UTCCommentaries:
Addition of Carotuximab to Pazopanib in Advanced Angiosarcoma – The ASCO Post
Commentaries on Twitter
A phase III trial in 123 patients with advanced-stage angiosarcoma reveals no significant difference in mPFS with pazopanib plus the anti-endoglin (CD105) mAb carotuximab vs pazopanib alone: https://t.co/TPPFRNCOoC #scmsm #caxtx
— NatureRevClinOncol (@NatRevClinOncol) April 5, 2022
First randomized trial in angiosarcoma demonstrates no signif difference in progression-free survival for combo of novel angiogenesis inhibitor carotuximab + pazopanib vs. pazopanib alone in advanced angiosarcoma. https://t.co/f1Z5EjOdK2 pic.twitter.com/qf3Tez9VU2
— JAMA Oncology (@JAMAOnc) March 31, 2022
RCT: Selinexor in advanced, metastatic dedifferentiated liposarcoma.
12 Apr, 2022 | 08:24h | UTC
Guidelines for diagnosing incidental solitary bone lesions on CT and MRI in adults: bone reporting and data system (Bone-RADS).
4 Apr, 2022 | 00:45h | UTC
Commentary on Twitter (article and images under a http://creativecommons.org/licenses/by-nc/4.0/)
https://twitter.com/AdamSingerMD/status/1509949481969668098
Educational Review: Multiparametric MRI evaluation of bone sarcomas in children.
3 Mar, 2022 | 07:54h | UTCMultiparametric MRI evaluation of bone sarcomas in children – Insights into Imaging
RCT: Prolonging prophylactic intravenous antibiotic regimens not beneficial after endoprosthetic reconstruction for lower extremity bone tumors.
19 Jan, 2022 | 08:37h | UTCCommentary: No Benefit Seen With Longer Antibiotic Course After Surgery for Bone Tumors – Cancer Therapy Advisor
Bone sarcomas: ESMO–EURACAN–GENTURIS–ERNPaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up.
1 Oct, 2021 | 09:57h | UTC
ASTRO Guideline: Radiation therapy for treatment of soft tissue sarcoma in adults.
29 Jul, 2021 | 10:54h | UTCNews release: Astro Issues Clinical Guideline on Radiation Therapy for Soft Tissue Sarcoma in Adults
ESMO Guidelines: Soft tissue and visceral sarcomas.
29 Jul, 2021 | 10:53h | UTC
Meta-analysis: Bisphosphonates or RANK‐ligand‐inhibitors for men with prostate cancer and bone metastases
20 Jan, 2021 | 01:09h | UTC