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Safety and Feasibility of Additional Tumor Debulking to First-Line Palliative Combination Chemotherapy for Patients with Multiorgan Metastatic Colorectal Cancer.

ABSTRACT: INTRODUCTION:Local treatment of metastases is frequently performed in patients with multiorgan metastatic colorectal carcinoma (mCRC) analogous to selected patients with oligometastatic disease for whom this is standard of care. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multiorgan mCRC. Here, we report the preplanned safety and feasibility evaluation after inclusion of the first 100 patients. METHODS:Patients were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. In case of clinical benefit after three or four cycles of respectively 5-fluorouracil/leucovorin or capecitabine and oxaliplatin ± bevacizumab patients were randomized to tumor debulking followed by chemotherapy in the intervention arm, or standard treatment with chemotherapy. RESULTS:Twelve patients dropped out prior to randomization for various reasons. Eighty-eight patients were randomized to the standard (n =?43) or intervention arm (n =?45). No patients withdrew after randomization. Debulking was performed in 82% (n =?37). Two patients had no lesions left to treat, five had progressive disease, and one patient died prior to local treatment. In 15 patients (40%) 21 serious adverse events related to debulking were reported. Postoperative mortality was 2.7% (n =?1). After debulking chemotherapy was resumed in 89% of patients. CONCLUSION:Tumor debulking is feasible and does not prohibit administration of palliative chemotherapy in the majority of patients with multiorgan mCRC, despite the occurrence of serious adverse events related to local treatment. IMPLICATIONS FOR PRACTICE:This first prospective randomized trial on tumor debulking in addition to chemotherapy shows that local treatment of metastases is feasible in patients with multiorgan metastatic colorectal cancer and does not prohibit administration of palliative systemic therapy, despite the occurrence of serious adverse events related to local treatment. The trial continues accrual, and overall survival (OS) data and quality of life assessment are collected to determine whether the primary aim of >6 months OS benefit with preserved quality of life will be met. This will support evidence-based decision making in multidisciplinary colorectal cancer care and can be readily implemented in daily practice.

SUBMITTER: Gootjes EC

PROVIDER: S-EPMC7418352 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Safety and Feasibility of Additional Tumor Debulking to First-Line Palliative Combination Chemotherapy for Patients with Multiorgan Metastatic Colorectal Cancer.

Gootjes Elske C EC van der Stok Eric P EP Buffart Tineke E TE Bakkerus Lotte L Labots Mariette M Zonderhuis Barbara M BM Tuynman Jurriaan B JB Meijerink Martijn R MR van de Ven Peter M PM Haasbeek Cornelis J A CJA Ten Tije Albert J AJ de Groot Jan-Willem B JB Hendriks Mathijs P MP van Meerten Esther E Nuyttens Joost J M E JJME Grunhagen Dirk J DJ Verhoef Cornelis C Verheul Henk M W HMW

The oncologist 20200616 8

<h4>Introduction</h4>Local treatment of metastases is frequently performed in patients with multiorgan metastatic colorectal carcinoma (mCRC) analogous to selected patients with oligometastatic disease for whom this is standard of care. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multiorgan mCRC. Here, we report the preplanned safety and feasibility evaluation after inclusion o ...[more]

PMID: 32490570

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Project description:BACKGROUND:Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer. MATERIALS AND METHODS:Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14?days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS. RESULTS:Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy. CONCLUSION:Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control. IMPLICATIONS FOR PRACTICE:Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.

Dataset Information

Safety and Feasibility of Additional Tumor Debulking to First-Line Palliative Combination Chemotherapy for Patients with Multiorgan Metastatic Colorectal Cancer.

Publications

Safety and Feasibility of Additional Tumor Debulking to First-Line Palliative Combination Chemotherapy for Patients with Multiorgan Metastatic Colorectal Cancer.

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