Intensified Total Neoadjuvant Therapy in Patients With Locally Advanced Rectal Cancer: A Phase II Trial |
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| Institution: | 1. Department of Radiotherapy, Policlinico Umberto I “Sapienza” University of Rome, Rome, Italy;2. Department of General Surgery, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy;3. Department of Radiological Sciences, Oncology and Pathology, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy;4. Medical Oncology Department, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy;1. Mount Vernon Cancer Centre, Northwood, UK;2. University of Manchester, Manchester, UK;3. Addenbrooke''s Hospital, Cambridge, UK;1. Centre for Trials Research, Cardiff University, Cardiff, UK;2. Addenbrookes Hospital, Cambridge, UK;1. Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK;2. Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK;3. Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, The Christie NHS Foundation Trust, Manchester, UK;4. Department of Critical Care and Anaesthesia, The Christie NHS Foundation Trust, Manchester, UK;5. Christie Patient-Centred Research, Division of Nursing, Midwifery & Social Work, The University of Manchester, The Christie NHS Foundation Trust, Manchester, UK;1. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA;2. Applied Radiation Biology and Radiotherapy Section, Division of Human Health, International Atomic Energy Agency, Vienna, Austria;3. State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Sheikhpura, Patna, India;1. Hall-Edwards Radiotherapy Research Group, Queen Elizabeth Hospital, Birmingham, UK;2. Warwick Clinical Trials Unit, University of Warwick, Coventry, UK;3. Norfolk and Norwich University Hospitals, Norwich, UK;4. Velindre University NHS Trust, Cardiff, UK;5. Addenbrooke''s Hospital, Cambridge, UK;6. Castle Hill Hospital, Cottingham, UK;7. Royal Marsden Hospital, London, UK;11. Weston Park Hospital, Sheffield, UK;12. St James'' Institute of Oncology, Leeds, UK;8. Bristol Haematology and Oncology Centre, Bristol, UK;9. Institute of Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK |
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| Abstract: | AimsWe assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer.Materials and methodsThis was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin–5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%.ResultsBetween October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases.ConclusionFOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies. |
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| Keywords: | BRAF induction chemotherapy oxaliplatin radiotherapy rectal cancer total neoadjuvant therapy |
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