Total neoadjuvant treatment for MRI-stratified high-risk rectal cancer: a single-center, single-arm, prospective Phase II trial (PKUCH-R02)

Abstract Background Induction chemotherapy combined with neoadjuvant chemoradiotherapy has been recommended for patients with high-risk, locally advanced rectal cancer. However, the benefit of more intensive total neoadjuvant treatment (TNT) is unknown. This study aimed to assess the safety and efficacy of induction chemotherapy combined with chemoradiotherapy and consolidation chemotherapy for magnetic resonance imaging-stratified high-risk rectal cancer. Methods This was a single-center, single-arm, prospective Phase II trial in Peking University Cancer Hospital (Beijing, China). Patients received three cycles of induction oxaliplatin and capecitabine (CapeOX) followed by chemoradiotherapy and two cycles of consolidation CapeOX. The primary end point was adverse event rate and the second primary end points were 3-year disease-free survival rate, completion of TNT, and pathological downstaging rate. Results Between August 2017 and August 2018, 68 rectal cancer patients with at least one high risk factor (cT3c/3d/T4a/T4b, cN2, mesorectal fascia involvement, or extramural venous invasion involvement) were enrolled. The overall compliance of receiving the entire treatment was 88.2% (60/68). All 68 patients received induction chemotherapy, 65 received chemoradiotherapy, and 61 received consolidation chemotherapy. The Grade 3–4 adverse event rate was 30.8% (21/68). Nine patients achieved clinical complete response and then watch and wait. Five patients (7.4%) developed distant metastasis during TNT and received palliative chemotherapy. Fifty patients underwent surgical resection. The complete response rate was 27.9%. After a median follow-up of 49.2 months, the overall 3-year disease-free survival rate was 69.7%. Conclusions For patients with high-risk rectal cancer, this TNT regimen can achieve favorable survival and complete response rates but with high toxicity. However, it is necessary to pay attention to the possibility of distant metastasis during the long treatment period.

[1]  Chen Hu,et al.  Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR) , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  T. Friede,et al.  Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. , 2021, JAMA oncology.

[3]  Gong Chen,et al.  Total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: a systematic review and meta-analysis. , 2021, The oncologist.

[4]  T. Conroy,et al.  Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. , 2021, The Lancet. Oncology.

[5]  H. Putter,et al.  Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. , 2020, The Lancet. Oncology.

[6]  F. Petrelli,et al.  Total Neoadjuvant Therapy in Rectal Cancer: A Systematic Review and Meta-analysis of Treatment Outcomes. , 2020, Annals of surgery.

[7]  D. Winter,et al.  Systematic review of outcomes after total neoadjuvant therapy for locally advanced rectal cancer , 2019, The British journal of surgery.

[8]  T. Friede,et al.  Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  I. Petkovska,et al.  Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy , 2019, JAMA oncology.

[10]  J. Gama-Rodrigues,et al.  Achieving a Complete Clinical Response After Neoadjuvant Chemoradiation That Does Not Require Surgical Resection: It May Take Longer Than You Think! , 2019, Diseases of the colon and rectum.

[11]  Matthew P. Goetz,et al.  NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY , 2019 .

[12]  Zongguang Zhou,et al.  Total neoadjuvant treatment (CAPOX plus radiotherapy) for patients with locally advanced rectal cancer with high risk factors: A phase 2 trial. , 2018, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[13]  C. Maurer,et al.  Oncological outcome after MRI‐based selection for neoadjuvant chemoradiotherapy in the OCUM Rectal Cancer Trial , 2018, The British journal of surgery.

[14]  I. Edhemovic,et al.  Induction Chemotherapy, Chemoradiotherapy and Consolidation Chemotherapy in Preoperative Treatment of Rectal Cancer - Long-term Results of Phase II OIGIT-01 Trial , 2018, Radiology and oncology.

[15]  Ahmed Kamel,et al.  Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. , 2018, Journal of the National Comprehensive Cancer Network : JNCCN.

[16]  G. Beets,et al.  Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study , 2018, The Lancet.

[17]  J. Ji,et al.  Pattern and Management of Recurrence of Mid‐Low Rectal Cancer After Neoadjuvant Intensity‐Modulated Radiotherapy: Single‐Center Results of 687 Cases , 2018, Clinical colorectal cancer.

[18]  R. Perez,et al.  Oncological and Survival Outcomes in Watch and Wait Patients With a Clinical Complete Response After Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Systematic Review and Pooled Analysis , 2018, Annals of surgery.

[19]  Lijun Shen,et al.  Predictive value of MRI-detected extramural vascular invasion in stage T3 rectal cancer patients before neoadjuvant chemoradiation. , 2018, Diagnostic and interventional radiology.

[20]  C. Montagut,et al.  MRI assessment and outcomes in patients receiving neoadjuvant chemotherapy only for primary rectal cancer: long-term results from the GEMCAD 0801 trial , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  T. Hothorn,et al.  Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. , 2015, The Lancet. Oncology.

[22]  J. Gu,et al.  Efficacy and Safety of Neoadjuvant Intensity-Modulated Radiotherapy With Concurrent Capecitabine for Locally Advanced Rectal Cancer , 2015, Diseases of the colon and rectum.

[23]  M. Lacouture,et al.  Grading dermatologic adverse events of cancer treatments: the Common Terminology Criteria for Adverse Events Version 4.0. , 2012, Journal of the American Academy of Dermatology.

[24]  Torsten Hothorn,et al.  Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. , 2012, The Lancet. Oncology.

[25]  L. Boni,et al.  Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Hein Putter,et al.  Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. , 2011, The Lancet. Oncology.

[27]  D. Tait,et al.  Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. , 2010, The Lancet. Oncology.

[28]  S. Polo,et al.  Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer d , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. Makuuchi,et al.  The Clavien-Dindo Classification of Surgical Complications: Five-Year Experience , 2009, Annals of surgery.

[30]  Laurence Collette,et al.  Chemotherapy with preoperative radiotherapy in rectal cancer. , 2006, The New England journal of medicine.

[31]  H. Putter,et al.  Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. , 2001, The New England journal of medicine.