Limits of Clinical Restaging in Detecting Responders After Neoadjuvant Therapies for Rectal Cancer

BACKGROUND: Accurate clinical restaging is required to select patients who respond to neoadjuvant chemoradiotherapy for locally advanced rectal cancer and who may benefit from an organ preservation strategy. OBJECTIVE: The purpose of this study was to review our experience with the clinical restaging of rectal cancer after neoadjuvant therapy to assess its accuracy in detecting major and pathological complete response to treatment. DESIGN: This was a retrospective cohort study. SETTING: This study was conducted at 2 high-volume Italian centers for Colorectal Surgery. PATIENTS: Data were included from all consecutive patients who underwent neoadjuvant therapy and surgery for locally advanced rectal cancer from January 2012 to July 2020. Criteria to define clinical response were no palpable mass, a superficial ulcer <2 cm (major response), or no mucosal abnormality (complete response) at endoscopy and no metastatic nodes at MRI. MAIN OUTCOME MEASURES: The main outcome measures were sensitivity, specificity, positive predictive values, and negative predictive values of clinical restaging in detecting pathological complete response (ypT0) or major pathological response (ypT0-1) after neoadjuvant therapy. RESULTS: A total of 333 patients were included; 81 (24.3%) had a complete response whereas 115 (34.5%) had a pathological major response. Accuracy for clinical complete response was 80.8% and for major clinical response was 72.9%. Sensitivity was low for both clinical complete response (37.5%) in detecting ypT0 and clinical major response (59.3%) in detecting ypT0-1. Positive predictive value was 68.2% for ypT0 and 60.4% for ypT0-1. LIMITATIONS: The main limitation of the study its retrospective nature. CONCLUSION: Accuracy of actual clinical criteria to define pathological complete response or pathological major response is poor. Failure to achieve good sensitivity and precision is a major limiting factor in the clinical setting. Current clinical assessments need to be revised to account for indications for rectal preservation after neoadjuvant chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/C63. LÍMITES DE LA REESTADIFICACIÓN CLÍNICA EN LA DETECCIÓN DE RESPONDEDORES DESPUÉS DE TERAPIAS NEOADYUVANTES PARA EL CÁNCER DE RECTO ANTECEDENTES: Se requiere una nueva reestadificación clínica precisa para seleccionar pacientes que respondan a la quimiorradioterapia neoadyuvante para el cáncer de recto localmente avanzado y que puedan beneficiarse de una estrategia de preservación de órganos. OBJETIVO: El propósito de este estudio fue revisar nuestra experiencia con la reestadificación clínica del cáncer de recto después de la terapia neoadyuvante para evaluar su precisión en la detección de una respuesta patológica importante y completa al tratamiento. DISEÑO: Estudio de cohorte retrospectivo. AJUSTE: Este estudio se realizó en dos centros italianos de alto volumen para cirugía colorrectal. PACIENTES: Incluimos datos de todos los pacientes consecutivos que se sometieron a terapia neoadyuvante y cirugía por cáncer de recto localmente avanzado desde enero de 2012 hasta julio de 2020. Los criterios para definir la respuesta clínica fueron ausencia de masa palpable, úlcera superficial <2 cm (respuesta mayor) o ausencia de anomalías en la mucosa. (respuesta completa) en la endoscopia, y sin ganglios metastásicos en la resonancia magnética. PRINCIPALES MEDIDAS DE RESULTADO: Exploramos la sensibilidad, la especificidad, los valores predictivos positivos y negativos de la reestadificación clínica para detectar una respuesta patológica completa (ypT0) o mayor (ypT0-1) después de la terapia neoadyuvante. RESULTADOS: Se incluyeron 333 pacientes; 81 (24,3%) tuvieron una respuesta completa mientras que 115 (34,5%) tuvieron una respuesta patológica mayor. La precisión de la respuesta clínica completa y la respuesta clínica importante fue del 80,8 % y el 72,9 %, respectivamente. La sensibilidad fue baja tanto para la respuesta clínica completa (37,5 %) en la detección de ypT0 como para la respuesta clínica mayor (59,3 %) en la detección de ypT0-1. El valor predictivo positivo fue del 68,2 % para ypT0 y del 60,4 % para ypT0-1. LIMITACIONES: Nuestro estudio tiene como principal limitación su carácter retrospectivo. CONCLUSIÓNES: La precisión de los criterios clínicos reales para definir una respuesta patológica completa o mayor es pobre. El hecho de no lograr una buena sensibilidad y precisión es un factor limitante importante en el entorno clínico. La indicación para la preservación rectal después de la quimiorradioterapia neoadyuvante necesita una mejora de la evaluación clínica actual. Consulte Video Resumen en http://links.lww.com/DCR/C63. (Traducción—Dr. Mauricio Santamaria)

[1]  G. Spolverato,et al.  Association of Delayed Surgery With Oncologic Long-term Outcomes in Patients With Locally Advanced Rectal Cancer Not Responding to Preoperative Chemoradiation. , 2021, JAMA surgery.

[2]  L. Collette,et al.  Timing to achieve the highest rate of pCR after preoperative radiochemotherapy in rectal cancer: a pooled analysis of 3085 patients from 7 randomized trials. , 2020, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[3]  G. Spolverato,et al.  18F-FDG PET/MRI for Rectal Cancer TNM Restaging After Preoperative Chemoradiotherapy: Initial Experience , 2019, Diseases of the colon and rectum.

[4]  H. Aerts,et al.  Radiomics performs comparable to morphologic assessment by expert radiologists for prediction of response to neoadjuvant chemoradiotherapy on baseline staging MRI in rectal cancer , 2019, Abdominal Radiology.

[5]  P. Neary,et al.  Meta‐analysis of the effect of extending the interval after long‐course chemoradiotherapy before surgery in locally advanced rectal cancer , 2019, The British journal of surgery.

[6]  M. Morino,et al.  Individual participant data pooled-analysis of risk factors for recurrence after neoadjuvant radiotherapy and transanal local excision of rectal cancer: the PARTTLE study , 2019, Techniques in Coloproctology.

[7]  H. Grabsch,et al.  Response assessment after (chemo)radiotherapy for rectal cancer: Why are we missing complete responses with MRI and endoscopy? , 2019, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[8]  S. Saito,et al.  Endoscopic criteria to evaluate tumor response of rectal cancer to neoadjuvant chemoradiotherapy using magnifying chromoendoscopy. , 2018, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[9]  Huadan Xue,et al.  Can Endorectal Ultrasound, MRI, and Mucosa Integrity Accurately Predict the Complete Response for Mid-Low Rectal Cancer After Preoperative Chemoradiation? A Prospective Observational Study from a Single Medical Center , 2018, Diseases of the colon and rectum.

[10]  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.

[11]  M. Weiser,et al.  AJCC 8th Edition: Colorectal Cancer , 2018, Annals of Surgical Oncology.

[12]  P. Delrio,et al.  Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study , 2017, Techniques in Coloproctology.

[13]  G. Casula,et al.  Risk of complications and long-term functional alterations after local excision of rectal tumors with transanal endoscopic microsurgery (TEM) , 2016, International Journal of Colorectal Disease.

[14]  L. Stassen,et al.  Assessment of Clinical Complete Response After Chemoradiation for Rectal Cancer with Digital Rectal Examination, Endoscopy, and MRI: Selection for Organ-Saving Treatment , 2015, Annals of Surgical Oncology.

[15]  M. Marzola,et al.  Value of (18)F-FDG PET for Predicting Response to Neoadjuvant Therapy in Rectal Cancer: Systematic Review and Meta-Analysis. , 2015, AJR. American journal of roentgenology.

[16]  G. Casula,et al.  Limits of Endorectal Ultrasound in Tailoring Treatment of Patients with Rectal Cancer , 2015, Digestive Surgery.

[17]  M. Gollub,et al.  Multiparametric MRI of Rectal Cancer in the Assessment of Response to Therapy: A Systematic Review , 2014, Diseases of the colon and rectum.

[18]  J. Gama-Rodrigues,et al.  Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. , 2014, International journal of radiation oncology, biology, physics.

[19]  M. Kalady,et al.  Clinical Criteria Underestimate Complete Pathological Response in Rectal Cancer Treated With Neoadjuvant Chemoradiotherapy , 2014, Diseases of the colon and rectum.

[20]  V. Canzonieri,et al.  Local Excision After Preoperative Chemoradiotherapy for Rectal Cancer: Results of a Multicenter Phase II Clinical Trial , 2013, Diseases of the colon and rectum.

[21]  J. Stoker,et al.  Patients who undergo preoperative chemoradiotherapy for locally advanced rectal cancer restaged by using diagnostic MR imaging: a systematic review and meta-analysis. , 2013, Radiology.

[22]  K. Bujko,et al.  Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders: a prospective multicentre study. , 2013, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[23]  K. Sheahan,et al.  The surgical significance of residual mucosal abnormalities in rectal cancer following neoadjuvant chemoradiotherapy , 2012, The British journal of surgery.

[24]  S. Harries,et al.  A single‐centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management? , 2012, Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland.

[25]  W. Hohenberger,et al.  Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Geerard L Beets,et al.  Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  J. Gama-Rodrigues,et al.  Complete Clinical Response After Neoadjuvant Chemoradiation Therapy for Distal Rectal Cancer: Characterization of Clinical and Endoscopic Findings for Standardization , 2010, Diseases of the colon and rectum.

[28]  D. Winter,et al.  Rectum‐conserving surgery in the era of chemoradiotherapy , 2010, The British journal of surgery.

[29]  Karin Haustermans,et al.  Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. , 2010, The Lancet. Oncology.

[30]  Roberto Orecchia,et al.  Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. , 2010, European journal of cancer.

[31]  J. Skibber,et al.  Local Excision After Preoperative Chemoradiation Results in an Equivalent Outcome to Total Mesorectal Excision in Selected Patients with T3 Rectal Cancer , 2010, Annals of Surgical Oncology.

[32]  P. Pattyn,et al.  Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: A systematic review and meta‐analysis , 2009, International journal of cancer.

[33]  A. Crucitti,et al.  Locally advanced rectal cancer: MR imaging in prediction of response after preoperative chemotherapy and radiation therapy. , 2009, Radiology.

[34]  T. Yeatman,et al.  Long-Term Results of Transanal Excision After Neoadjuvant Chemoradiation for T2 and T3 Adenocarcinomas of the Rectum , 2008, Journal of Gastrointestinal Surgery.

[35]  T. Junginger,et al.  Neoadjuvant Chemoradiation and Local Excision for T2-3 Rectal Cancer , 2008, Annals of Surgical Oncology.

[36]  J. Gama-Rodrigues,et al.  Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy , 2006, Journal of Gastrointestinal Surgery.

[37]  M. Mazumdar,et al.  Clinical examination following preoperative chemoradiation for rectal cancer is not a reliable surrogate end point. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  Fábio Guilherme Campos,et al.  Operative Versus Nonoperative Treatment for Stage 0 Distal Rectal Cancer Following Chemoradiation Therapy: Long-term Results , 2004, Annals of surgery.

[39]  M. Guerrieri,et al.  Long-term Results of Patients with pT2 Rectal Cancer Treated with Radiotherapy and Transanal Endoscopic Microsurgical Excision , 2002, World Journal of Surgery.

[40]  J. Vauthey,et al.  Transanal excision of locally advanced rectal cancers downstaged using neoadjuvant chemoradiotherapy. , 2002, Journal of the American College of Surgeons.

[41]  J. Guillem,et al.  Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. , 2002, Journal of the American College of Surgeons.

[42]  T. Yeatman,et al.  Local Excision of T2 and T3 Rectal Cancers After Downstaging Chemoradiation , 2001, Annals of surgery.

[43]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.

[44]  J. Gérard,et al.  Can we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: lessons from a systematic review of recent randomized trials. , 2012, Critical reviews in oncology/hematology.

[45]  E. Lezoche,et al.  A prospective randomized study with a 5-year minimum follow-up evaluation of transanal endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant therapy , 2007, Surgical Endoscopy.

[46]  J. Guillem,et al.  Preoperative radiation with or without chemotherapy and full-thickness transanal excision for selected T2 and T3 distal rectal cancers , 2002, International Journal of Colorectal Disease.

[47]  M. Mohiuddin,et al.  High-dose preoperative radiation and full thickness local excision: a new option for selected T3 distal rectal cancers. , 1994, International journal of radiation oncology, biology, physics.