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A phase I dose escalation study of oxaliplatin plus oral S-1 and pelvic radiation in patients with locally advanced rectal cancer (SHOGUN trial).

ABSTRACT: The objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer.Patients received radiotherapy in a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy consisted of a fixed oral dose of S-1 (80 mg/m(2)/day) on days 1-5, 8-12, 22-27, and 29-33, plus escalated doses of oxaliplatin as an intravenous infusion on days 1, 8, 22, and 29. Oxaliplatin was initially given in a dose of 40 mg/m(2)/week to three patients. The dose was then increased in a stepwise fashion to 50 mg/m(2)/week and the highest dose level of 60 mg/m(2)/week until the MTD was attained.Thirteen patients were enrolled, and 12 received CRT. Dose-limiting toxicity (DLT) occurred in two of six patients (persistent grade 2 neutropenia, delaying oxaliplatin treatment by more than 3 days) at dose level 3; there were no grade 3 or 4 adverse events defined as DLT. The RD was 60 mg/m(2)/week of oxaliplatin on days 1, 8, 22, and 29. Twelve patients underwent histologically confirmed R0 resections, and two out of six patients (33%) given dose level 3 had pathological complete responses.The RD for further studies is 80 mg/m(2) of S-1 5 days per week plus 60 mg/m(2) of oxaliplatin on days 1, 8, 22, and 29 and concurrent radiotherapy. Although our results are preliminary, this new regimen for neoadjuvant chemoradiotherapy is considered safe and active.This trial was registered with Clinicaltrials.gov (identifier: NCT01227239 ).

SUBMITTER: Ishihara S

PROVIDER: S-EPMC4312451 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A phase I dose escalation study of oxaliplatin plus oral S-1 and pelvic radiation in patients with locally advanced rectal cancer (SHOGUN trial).

Ishihara Soichiro S Matsusaka Satoshi S Kondo Keisaku K Horie Hisanaga H Uehara Keisuke K Oguchi Masahiko M Murofushi Keiko K Ueno Masashi M Mizunuma Nobuyuki N Shinbo Taijyu T Kato Daiki D Okuda Junji J Hashiguchi Yojiro Y Nakazawa Masanori M Sunami Eiji E Kawai Kazushige K Yamashita Hideomi H Okada Tohru T Ishikawa Yuichi Y Nakajima Toshifusa T Watanabe Toshiaki T

Radiation oncology (London, England) 20150123

<h4>Background</h4>The objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer.<h4>Methods</h4>Patients received radiotherapy in a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy consisted of a fixed oral dose of S-1 (80 mg/m(2)/day) on days 1-5, 8-12, 22-27, and 29-33, plus escalated doses of oxaliplatin as an intrav ...[more]

PMID: 25612635

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Project description:BackgroundCurrent standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer.MethodsThe study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression.DiscussionRecent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC.Trial registrationTrial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.

Project description:PurposeTo evaluate the cost-effectiveness of preoperative short-course radiotherapy (SCRT, 5 × 5 Gy) plus FOLFOX4 versus long-course oxaliplatin and bolus of fluorouracil based preoperative long-course chemoradiotherapy (LCCRT, 50.4 Gy in 28 fractions) in the management of cT4 or advanced cT3 rectal cancer (RC), both of which have been reported to achieve similar clinical effect in the NCT00833131 trial.Materials and methodsA Markov decision-analytic model compared SCRT plus chemotherapy and LCCRT, by simulating three health states (disease-free survival (DFS), progressive disease (PD) and death). The primary outcomes were quality-adjusted life months (QALMs), costs, and incremental cost-effectiveness ratios (ICERs). Transition probabilities were based on the NCT00833131 trial. The costs were calculated from a Chinese payers' perspective. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $2370.47 (3 × GDP) per QALM gained. Sensitivity analysis was performed to model uncertainty in these parameters.ResultsThe overall costs for SCRT plus chemotherapy and LCCRT were $78,937 and $38,140 with effectiveness of 29.92 QALMs and 22.99 QALMs, respectively. SCRT plus chemotherapy increased costs and QALM by $40,797.34 and 6.93 compared to LCCRT, resulting in an ICER of $5884.56/QALM gained. In the DFS state, the whole cost for SCRT plus chemotherapy and LCCRT were $11,490.03 and $10,794.06 with an effectiveness of 21.70 QALMs and 19.65 QALMs, respectively. SCRT plus chemotherapy increased cost and QALM by $695.97 and 2.05 compared to LCCRT, resulting in a ICER of $339.50/QALM gained, which below the WTP. The utility associated with the DFS state was the most influential factor on the cost-effectiveness of SCRT plus chemotherapy. When the cost of PD state below $1920, the ICER of SCRT compared with LCCRT below the WTP.ConclusionCompared with LCCRT, SCRT plus chemotherapy is a more cost-effective strategy for locally advanced resectable RC in the DFS state as well as in the all states when the cost of PD state below $1920.

Dataset Information

A phase I dose escalation study of oxaliplatin plus oral S-1 and pelvic radiation in patients with locally advanced rectal cancer (SHOGUN trial).

Publications

A phase I dose escalation study of oxaliplatin plus oral S-1 and pelvic radiation in patients with locally advanced rectal cancer (SHOGUN trial).

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