|Year : 2020 | Volume
| Issue : 3 | Page : 598-602
Sarcoma and gastrointestinal stromal tumor update: Lessons from the American Society of Clinical Oncology 2020 and implications for practice
Azgar Abdul Rasheed1, Ankur Varshney1, Sameer Rastogi2
1 Department of Medical Oncology, AIIMS, New Delhi, India
2 Sarcoma Medical Oncology Clinic, AIIMS, New Delhi, India
|Date of Submission||13-Jul-2020|
|Date of Decision||26-Jul-2020|
|Date of Acceptance||09-Aug-2020|
|Date of Web Publication||19-Sep-2020|
Sarcoma Medical Oncology Clinic, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Rasheed AA, Varshney A, Rastogi S. Sarcoma and gastrointestinal stromal tumor update: Lessons from the American Society of Clinical Oncology 2020 and implications for practice. Cancer Res Stat Treat 2020;3:598-602
|How to cite this URL:|
Rasheed AA, Varshney A, Rastogi S. Sarcoma and gastrointestinal stromal tumor update: Lessons from the American Society of Clinical Oncology 2020 and implications for practice. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 31];3:598-602. Available from: https://www.crstonline.com/text.asp?2020/3/3/598/295497
| Introduction|| |
Sarcomas are a family of rare tumors, encompassing nearly 100 subtypes with distinct clinical, histological, and molecular characteristics. Owing to their differing clinical behaviors, the treatment of sarcomas demands precision and is driven by histology and molecular markers. Considering their rarity, the management plan benefits from pooling together the experiences of a multidisciplinary team of medical, surgical, and radiation oncologists; orthopedic surgeons; pathologists; radiologists; and palliative care specialists. However, despite the high levels of collaboration, the management of sarcomas is not quite standardized. It is hoped that the recent development of more effective molecular diagnostic techniques, and newer trial designs that permit a more efficient study of rare diseases will help in advancing sarcoma research. The annual conference of the American Society of Clinical Oncology (ASCO) provides an opportunity for oncology professionals to present their pathbreaking studies. In this article, we aim to discuss a few of the potentially practice-changing presentations at the ASCO 2020, as summarized in [Table 1]. While the details are still awaited, these studies are likely to have an impact on the treatment of sarcomas.
|Table 1: Selected studies on sarcoma and gastrointestinal stromal tumor from the American Society of Clinical Oncology, 2020 and their implications on practice|
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| Ewing Sarcoma – Reecur and Euro Ewing 2012|| |
First-line chemotherapy for Ewing sarcoma (ES) comprises vincristine, doxorubicin, actinomycin-D, ifosfamide (IFOS), and etoposide in varying schedules. The use of dose-dense therapies and the improvement in supportive care have resulted in 5-year overall survival (OS) rates of up to 78%. The rEECur trial, of the Euro Ewing Consortium (EEC) and the EURO EWING 2012 trial (EE2012), both aim to distinguish the best among the current therapies for the management of ES. While the rEECur study deals with treatment protocols for relapsed ES, EE2012 was intended to compare the contrasting management approaches on either side of the Atlantic.
Relapsed ES has an extremely poor prognosis with a 5-year OS ranging from 7% to 30%, depending on the time to relapse., The optimum option for second-line therapy is not clear. The rEECur study is an ongoing Phase II/III multi-arm, multistage adaptive trial, in which 366 patients aged 4–50 years with recurrent and primary refractory Ewing sarcoma (RR-ES) are randomly assigned to one of four chemotherapy regimens: gemcitabine/docetaxel (GD), topotecan/cyclophosphamide, irinotecan/temozolomide (IT), or high-dose IFOS. The primary outcome is the objective response rate (ORR) after four cycles according to the response evaluation criteria in solid tumors (RECIST 1.1). There were two preplanned interim analyses, at each of which the arm with the least ORR would be terminated. Accrual in the GD arm was closed after the first interim assessment because of an inferior ORR of 11.5% (95% confidence interval [CI], 4.4%–23%), and a median progression-free survival (PFS) of 3 months (95% CI, 1.6–8.0). At the ASCO 2020, the results of the second interim assessment were reported. Accrual in the IT arm has now been terminated due to an inferior ORR as compared to the other two arms. The IT arm had a response rate of 20%, a median PFS of 4.7 months (95% CI, 3.4–5.7), and a median OS of 13.9 months (95% CI, 10.6–18.1) at a median follow-up of 9.2 months. With continuing accrual in the remaining two arms, the final results of this first randomized trial in RR-ES are eagerly awaited.
The EE2012 was planned to compare the European and American standards of chemotherapy in ES. Oncologists in the United States of America prefer dose-intense induction therapy with alternating two-weekly cycles of vincristine, doxorubicin, cyclophosphamide (VDC) and IFOS/etoposide (IE) in nonmetastatic disease. On the other hand, the standard in Europe is induction with vincristine, IFOS, doxorubicin, and etoposide (VIDE). Consolidation strategies with autologous transplant also differ between the two regions, with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) used more aggressively in Europe, especially in localized, poor-risk disease, based on the results of the EURO-E.W.I.N.G.99 trial. EE2012 was a multicenter, Phase III, open-label Bayesian design randomized trial with two randomizations and event-free survival (EFS) as the primary outcome. At randomization R1, patients were allocated to Arm A (induction with six cycles of VIDE) or Arm B (induction with nine cycles of alternating VDC and IE). For consolidation in Arm A, patients with good-risk localized disease received one cycle of vincristine, actinomycin-D, and IFOS (VAI), followed by seven cycles of vincristine, actinomycin-D, and cyclophosphamide; patients with poor-risk localized disease received one cycle of VAI, followed by busulfan/melphalan (BuMel); and patients with poor-risk localized disease with contraindication to BuMel, regional lymph node involvement, or metastatic disease received eight cycles of VAI. For consolidation in Arm B, patients with good-risk localized disease, regional lymph node involvement, metastatic disease, or poor-risk localized disease with contraindication to BuMel received five cycles of alternating IE and vincristine/cyclophosphamide (VC), whereas patients with poor-risk localized disease were given one cycle VAI plus BuMel. Both arms included radiotherapy for lung metastases. At randomization R2, patients were allocated to either receive nine cycles of zoledronic acid after the first cycle of consolidation chemotherapy or no zoledronic acid.
A total of 640 patients aged 5–50 years with newly diagnosed localized or metastatic ES were enrolled in the study. Each arm comprised 320 patients, including 26% cases of metastatic disease. At a median follow-up of 1.7 years, patients in Arm B had a better EFS (hazard ratio [HR] 0.66; 95% CI, 0.49–0.90) and OS (HR 0.64; 95% CI, 0.43–0.94), with posterior probabilities of 98% each that EFS and OS were better in Arm B. Acute toxicity was experienced by two-thirds of the patients in each arm. Grade 3 or higher adverse events were documented in 91% of the patients in Arm A and 90% in Arm B during induction chemotherapy and in 65% of the patients in both the arms during consolidation chemotherapy. However, the Arm A (VIDE) had six treatment-related deaths, whereas Arm B had none. The Children's Oncology Group AEWS0031 trial had already shown the dose-dense therapy with the two-weekly VDC/IE/VC to be superior in non-metastatic ES, with higher EFS (73% vs. 65%, P = 0.048) and OS (83% vs. 77%, P = 0.056) compared to the standard arm and no increase in toxicity. The results of the EE2012 trial re-establish the superiority of dose-dense VDC-IE as the current first-line therapy in non-metastatic ES. However, since this trial incorporated HDCT/ASCT consolidation for the poor-risk Arm B patients, which is not the standard of care in the US, the comparison between the American and European strategies is not entirely accurate. It is uncertain as to how much benefit is gained by adding HDCT/ASCT consolidation to the standard dose-dense American regimen. Zoledronic acid was chosen for this trial based on preclinical data, without any preceding clinical trials. This is reminiscent of a previous Phase III trial of zoledronic acid in osteosarcoma, which showed no benefit with its addition to chemotherapy. Therefore, Phase I/II studies are needed for the use of zoledronic acid in sarcomas.
| Soft-Tissue Sarcoma – Leader and Jcog1306|| |
Leiomyosarcoma (LMS) and liposarcoma (LPS) account for nearly a fourth of all soft-tissue sarcoma (STS) cases, and advanced cases have poor prognosis even with therapy. Eribulin was approved for use in LPS based on the results of a Phase III trial which compared eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8) with dacarbazine in patients with advanced LMS or LPS who were previously exposed to an anthracycline. In the LPS subgroup, the patients had an OS and PFS of 15.6 and 2.9 months, respectively, whereas in the dacarbazine group, the OS and PFS were 8.4 and 1.7 months, respectively.
The Phase Ib/II Lenvatinib and Eribulin Advanced Soft-Tissue Sarcoma (LEADER) trial used a Simon two-stage minimax design, with ORR according to RECIST 1.1 as the primary outcome. A total of 22 patients with advanced or recurrent disease (15 LMS and 7 LPS) were enrolled and followed up over a median period of 6 months. The recommended Phase II dose was 14 mg per day for lenvatinib and 1.1 mg/m2 on days 1 and 8 for eribulin in three-weekly cycles. The ORR was 28.5% (95% CI, 11.2%–52.1%) according to RECIST 1.1 and 71.4% (95% CI, 47.8%–88.7%) according to the Choi criteria. The median PFS was 37 months (95% CI, 24 weeks– not reached). Although these values compare favorably with the efficacies of more established drugs in LMSs and LPSs (L-sarcomas), such as doxorubicin ± IFOS, GD, trabectedin, dacarbazine, and pazopanib, the results are not interpretable due to the heterogeneity of the tumor histologies, the small sample size, and the resultant wide confidence intervals. It is also unclear why lenvatinib was chosen when a combination of eribulin and pazopanib might perhaps have been the logical choice. Furthermore, nearly half of the patients (10 of 22) were chemotherapy-naïve and had received only the standard of care, doxorubicin, in the first line. However, this serves well as a pilot study, and the promising results justify the further exploration of this combination in future trials to evaluate its efficacy and its place in the sequence of therapy.
A study by the Japan Clinical Oncology Group study (JCOG1306), compared perioperative therapy with IFOS (10 g/m2)/adriamycin (60 mg/m2) (IA) with gemcitabine (1.8 g/m2)/docetaxel (70 mg/m2) (GD) in Phase III, noninferiority trial with OS as the primary endpoint. After a median follow-up of 2.3 years, the estimated HRs for the 3-year PFS and 3-year OS were 2.32 (95% CI, 1.22–4.39) and 2.55 (95% CI, 0.80–8.14), respectively, decidedly favoring the IA arm. However, the GD arm was less toxic. A Phase III trial by Gronchi et al. has also shown that neoadjuvant IA has a superior efficacy in high-risk STS compared to histology-tailored therapy. These results reinforce the superiority of IA in the perioperative setting in STS.
| Gastrointestinal Stromal Tumor – Imatinib/binimetinib in Advanced Gastrointestinal Stromal Tumor and Guadecitabine in Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor|| |
Neoadjuvant and adjuvant imatinib have become the standard of care in advanced gastrointestinal stromal tumors (GISTs). A single-arm, Phase II study by Chi et al. tested a combination of imatinib with the mitogen-activated protein kinase 1/2 inhibitor, binimetinib, in treatment-naïve patients with advanced GISTs, with ORR as the primary outcome. The ORR was 68.4% (95% CI, 51%–83%), and the median PFS was 29.9 months. Previous studies have reported an ORR of 45%–68.1% and a median PFS of 18–25 months with imatinib alone.,,, The improved survival seen with the new combination could be due to better patient selection, a more favorable mutation profile in the study population, or improvements in supportive care. Nonetheless, a Phase III trial with imatinib as the control arm and long-term follow-up would be justified based on the current trial results.
Another interesting Phase II study was presented by Wedekind et al. in the rare subset of succinate dehydrogenase (SDH)-deficient GIST. The DNA methyltransferase inhibitor, guadecitabine, was tested in hypermethylated tumors such as SDH-deficient GIST, pheochromocytoma/paraganglioma, and hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma. It was hoped that the tumors would respond due to the reversal of methylation by guadecitabine, but none of the nine patients enrolled in the study responded to therapy. A Phase II trial of temozolomide in advanced SDH-deficient GISTs is currently under way. If successful, it would be an enlightening example of treatment based on tumor biology.
| Conclusion|| |
The rEECur and EE2012 trials will bring clarity to the current treatment standards in upfront and relapsed refractory ES, respectively. Uniformity of treatment across centers may also help with further collaboration, data interpretation, and refinements in therapy. The JCOG1306 trial firmly establishes the superiority of perioperative IA in patients with STS. While the initial results with the combinations of lenvatinib/eribulin in L-sarcomas and imatinib/binimetinib in GISTs do show promise, further research is needed to ascertain their benefits. Generating data regarding the efficacy of alkylators in SDH-deficient GISTs is also an unmet need.
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Conflicts of interest
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