Prediction of Poor Response to Neoadjuvant Chemoradiation in Patients With Rectal Cancer Using a DNA Repair Deregulation Score: Picking the Losers Instead of the Winners.

BACKGROUND: Patients with rectal cancer may undergo neoadjuvant chemoradiation even in early stages in an attempt to achieve complete clinical response and undergo organ preservation. However, prediction of tumor response is unavailable. In this setting, accurate identification of poor responders could spare patients with early stage disease from potentially unnecessary chemoradiation. OBJECTIVE: This study focused on development/test of a score based on DNA repair gene expression to predict response to neoadjuvant chemoradiation in patients with rectal cancer. DESIGN: Pretreatment biopsy samples from patients with rectal cancer undergoing neoadjuvant chemoradiation were collected and underwent gene expression analysis using RNA-Seq (test cohort). A score was constructed using 8 differentially expressed DNA repair genes between good (complete clinical) and poor responders (incomplete clinical) to treatment. The score was validated in 2 independent cohorts of patients undergoing similar treatment strategies and using quantitative polymerase chain reaction and microarray gene expression data. SETTINGS: This was a retrospective analysis of gene expression data from 3 independent institutions. PATIENTS: Patients with rectal cancer undergoing neoadjuvant chemoradiation (50.4-54.0 Gy and 5-fluorouracil-based chemotherapy) were eligible. Patients with complete clinical response, complete pathological response, or ≤10% residual cancer cells were considered good responders. Patients with >10% residual cancer cells were considered poor responders. The test cohort included 25 patients (16 poor responders). Validation cohort 1 included 28 patients (18 poor responders), and validation cohort 2 included 46 patients (22 poor responders). MAIN OUTCOMES MEASURES: Response was correlated with the DNA repair score calculated using the expression levels of 8 DNA repair genes. DNA repair score sensitivity, specificity, and positive and negative predictive values were determined in test and validation cohorts. RESULTS: Poor responders had significantly lower DNA repair scores when compared with good responders across all 3 cohorts, regardless of the gene expression platform used. A low score correctly predicted poor response in 93%, 90%, and 71% in test, validation 1, and validation 2 cohorts. LIMITATIONS: This study was limited by its small sample size, different gene expression platforms, and treatment regimens across different cohorts used. CONCLUSIONS: A DNA repair gene score may predict patients likely to have poor response to chemoradiation. This score may be a relevant tool to be investigated in future studies focused on chemoradiation used in the context of organ preservation. See Video Abstract at http://links.lww.com/DCR/B104. PREDICCIÓN DE RESPUESTA DEFICIENTE A LA RADIO-QUIMIOTERAPIA NEOADYUVANTE EN PACIENTES CON CÁNCER RECTAL UTILIZANDO UNA PUNTUACIÓN DE DESREGULACIÓN DE REPARACIÓN DE ADN: ESCOGER LOS PERDEDORES EN LUGAR DE LOS GANADORES: Los pacientes con cáncer rectal pueden someterse a radio-quimioterapia neoadyuvante incluso en estadios tempranos en el intento por lograr una respuesta clínica completa y permitir una preservación de órgano. Sin embargo, aun no existen herramientas disponible para la prediccion de la respuesta tumoral al tratamiento. En este contexto, la identificación precisa de los tumores con mala respuesta al tratamiento podría evitar que los pacientes con enfermedad en estadio temprano sean sometidos a radio-quimioterapia potencialmente innecesaria.Desarrollo / testeo de una puntuación basada en la expresión genes reparadores del ADN para predecir la respuesta a la nCRT en pacientes con cáncer rectal.Se recogieron muestras de biopsia de pre-tratamiento de pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante y se les realizó un análisis de expresión génica utilizando RNAseq (cohorte de prueba). Se construyó una puntuación utilizando 8 genes de reparación de ADN expresados diferencialmente entre buenos (respuesta clinica completa) y pobres respondedores (respuesta clinica incompleta) al tratamiento. La puntuación se validó en 2 cohortes independientes de pacientes sometidos a estrategias de tratamiento similares y utilizando qPCR y datos de expresión de genes en chips ADN (biotecnología -microarrays).Análisis retrospectivo de los datos de expresión génica de 3 instituciones independientes.Fueron incluidos aquellos pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante (50,4-54 Gy y quimioterapia basada en 5FU). Los pacientes con respuesta clínica completa, respuesta patológica completa o ≤10% de células cancerosas residuales se consideraron buenos respondedores. Los pacientes con> 10% de células cancerosas residuales se consideraron de respuesta deficiente. La cohorte de prueba incluyó a 25 pacientes (16 respondedores pobres). La cohorte de validación n. ° 1 incluyó a 28 pacientes (18 respondedores pobres) y la cohorte de validación n. ° 2 incluyó a 46 pacientes (22 respondedores pobres).La respuesta se correlacionó con la puntuación de reparación de ADN calculada utilizando los niveles de expresión de 8 genes de reparación de ADN. La sensibilidad del puntaje de reparación del ADN, la especificidad, los valores predictivos positivos y negativos se determinaron en las cohortes de prueba y validación.Los malos respondedores tuvieron puntuaciones de reparación de ADN significativamente más bajas en comparación con los buenos respondedores en las 3 cohortes, independientemente de la plataforma de expresión génica utilizada. Una puntuación baja predijo correctamente una respuesta pobre en el 93%, 90% y 71% en las cohortes de prueba, validación n. ° 1 y validación n. ° 2, respectivamente.Pequeño tamaño de la muestra, diferentes plataformas de expresión génica y regímenes de tratamiento en diferentes cohortes utilizadas.La puntuacion basada en genes de reparación del ADN puede predecir los pacientes con respuesta pobre a la radio-quimioterapia. Esta puntuación puede ser una herramienta relevante para investigar en futuros estudios centrados en la radio-quimioterapia utilizada en el contexto de la preservación de órganos. Consulte Video Resumen en http://links.lww.com/DCR/B104. (Traducción-Dr. Xavier Delgadillo and Dr. Laura Melina Fernandez).

Organ Preservation Among Patients With Clinically Node-Positive Rectal Cancer: Is It Really More Dangerous?

BACKGROUND: Select patients with complete clinical response to chemoradiation have been managed without radical surgery. The presence of radiologic evidence of nodal metastases at baseline could be a risk factor for local tumor regrowth, more advanced stage at the time of recurrence, and worse distant metastases-free survival. OBJECTIVE: The purpose of this study was to compare the outcomes of patients with baseline node-positive and node-negative cancer after neoadjuvant chemoradiation and complete clinical response managed nonoperatively. DESIGN: This was a retrospective review of consecutive patients with nonmetastatic distal rectal cancer undergoing neoadjuvant chemoradiation. PATIENTS: Consecutive patients with clinical and radiologic evidence of complete clinical response at 8 to 10 weeks were managed nonoperatively and enrolled in a strict follow-up program (watch and wait). Patients with incomplete clinical response or tumor regrowth after initial complete clinical response were referred to surgery. MAIN OUTCOMES MEASURES: Surgery-free and distant metastases-free survival were compared between patients according to nodal status at baseline. RESULTS: A total of 117 patients with node-positive and 218 with node-negative cancer at baseline were reviewed. Overall, 62 (53.0%; node positive) and 135 (61.9%; node negative) achieved a complete clinical response and were managed nonoperatively (p = 0.13). Patients with baseline node-positive cancer had similar rates of pathologic nodal metastases at the time of recurrence. Five-year surgery-free (39.7% vs 46.8%; p = 0.2) and distant metastases-free survival (77.5% vs 80.5%; p = 0.49) were similar between baseline node-positive and node-negative patients. LIMITATIONS: This was a retrospective study with a small sample size and possible inaccurate nodal staging. CONCLUSIONS: Patients with rectal cancer with node-positive cancer at baseline who develop a complete clinical response after neoadjuvant chemoradiation are not at increased risk for local tumor regrowth or development of more advanced disease at the time of recurrence. These patients seem to be safe candidates for organ-preserving strategies after achieving complete clinical response. See Video Abstract at http://links.lww.com/DCR/A902.

Achieving a Complete Clinical Response After Neoadjuvant Chemoradiation That Does Not Require Surgical Resection: It May Take Longer Than You Think!

BACKGROUND: Patients with rectal cancer who achieve complete clinical response after neoadjuvant chemoradiation have been managed by organ-preserving strategies and acceptable long-term outcomes. Controversy still exists regarding optimal timing for the assessment of tumor response after neoadjuvant chemoradiation. OBJECTIVE: The purpose of this study was to estimate the time interval for achieving complete clinical response using strict endoscopic and clinical criteria after a single neoadjuvant chemoradiation regimen. DESIGN: This was a retrospective review of consecutive patients managed by 54-Gy and consolidation 5-fluorouracil-based chemotherapy. Assessment of response was performed at 10 weeks after radiation. Patients with suspected complete clinical response were offered watch-and-wait strategy and reassessment every 6 to 8 weeks until achievement of strict criteria of complete clinical response or overt residual cancer. SETTINGS: This study was conducted at a single tertiary care center. PATIENTS: Patients with complete clinical response who underwent a successful watch-and-wait strategy until last follow-up were eligible. Dates of radiation completion and achievement of strict endoscopic and clinical criteria (mucosal whitening, teleangiectasia, and no ulceration or irregularity) were recorded. Patients with incomplete response or with initial complete clinical response followed by local recurrence or regrowth were excluded. MAIN OUTCOMES MEASURES: The distribution of time intervals between completion of radiation and achievement of strict complete clinical response was measured. Patients who achieved early complete clinical response (≤16 wk) were compared with late complete clinical response (>16 wk). RESULTS: A total of 49 patients achieved complete clinical response and were successfully managed nonoperatively. A median interval of 18.7 weeks was observed for achieving strict complete clinical response. Only 38% of patients achieved complete clinical response between 10 and 16 weeks from radiation completion. Patients with earlier cT status (cT2/T3a) achieved a complete clinical response significantly earlier when compared with those patients with more advanced disease (T3b-d/4; 19 vs 26 wk; p = 0.03). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSIONS: Assessment at 10 to 16 weeks may detect a minority of patients who achieve complete clinical response without additional recurrence after neoadjuvant chemoradiation. Patients suspected for a complete clinical response should be considered for reassessment beyond 16 weeks before definitive management when considered for a watch and wait strategy. See Video Abstract at http://links.lww.com/DCR/A901.

Intratumoral Genetic Heterogeneity in Rectal Cancer: Are Single Biopsies representative of the entirety of the tumor?

OBJECTIVE: Demonstrate intratumoral genetic heterogeneity in rectal cancer. BACKGROUND: Several clinical management decisions in rectal cancer may be influenced by pretreatment biopsy information. However, in the setting of significant intratumoral heterogeneity, biopsies may not be representative of the entirety of the tumor and limit the reliability of the information provided from them for clinical decision management. METHODS: Three fragments from a single rectal adenocarcinoma were chosen for whole-exome sequencing followed by mutation detection analysis. About 25 Gb of unambiguously mapped sequences were generated for each sample resulting in a median fold-coverage of 35x. Captured sequences mapped to the reference human genome were then used for the detection of somatic point mutations. RESULTS: Overall, 193 unique somatic point mutations were identified. Only 53 (27%) of these were shared by all three fragments, including known genes involved in early phases of the adenoma-carcinoma sequence (such as, APC). Approximately, 115 (59%) mutations were exclusively present in only one of the fragments, including mutations in "driver" genes (DNAH12). Jaccard distances showed a median distance of 0.603 for pair-wise comparison of fragments indicating significant heterogeneity between them. CONCLUSIONS: Considerable intratumoral heterogeneity is present among naive rectal cancers. The majority of point mutations detected in different fragments from rectal cancers are frequently unique to a single fragment. These findings support that gene mutations found on single pretreatment biopsies will not necessarily be representative of mutations present in the entirety of the tumor and therefore may limit the utility of the biological information provided by single biopsy fragments for clinical management decisions.

Baseline T Classification Predicts Early Tumor Regrowth After Nonoperative Management in Distal Rectal Cancer After Extended Neoadjuvant Chemoradiation and Initial Complete Clinical Response.

BACKGROUND: Selected patients with rectal cancer and complete clinical response after neoadjuvant chemoradiation have been managed nonoperatively with acceptable outcomes. However, ≈20% of these patients will develop early tumor regrowth. Identification of these patients could select candidates for more intensive follow-up. OBJECTIVE: The purpose of this study was to investigate the influence of baseline radiological T classification on recurrences after a complete clinical response managed nonoperatively after chemoradiation. DESIGN: This was a retrospective review of a prospective collected database. SETTINGS: The study was conducted at a single center. PATIENTS: Patients with distal rectal cancer (cT2-4N0-2M0) undergoing extended chemoradiation (54 Gy + 5-fluorouracil-based chemotherapy) were eligible. Patients were reassessed for tumor response at 10 weeks after radiation completion. Patients with complete clinical response (clinical, radiological, and endoscopic) were managed nonoperatively and strictly followed. MAIN OUTCOMES MEASURES: Complete clinical response rates, early tumor regrowth rates (<12 mo), local recurrence-free survival, and distant metastases-free survival were measured. RESULTS: A total of 91 consecutive patients with rectal cancer underwent extended chemoradiation. Sixty-one patients developed initial complete clinical response (67%). cT2 patients developed similar initial complete clinical response rates compared with cT3/T4 (72% vs 63%; p = 0.403). Early tumor regrowths were more frequent among baseline cT3/4 when compared with cT2 patients (30% vs 3%; p = 0.007). There were no differences in late local recurrences (p = 0.593) or systemic recurrences (p = 0.387). Local recurrence-free survival was significantly better for cT2 patients at 1 year (96% vs 69%; p = 0.009). After Cox regression analysis, baseline T stage was an independent predictor of improved local recurrence-free survival at 1 year (p = 0.03; OR = 0.09 (95% CI, 0.01-0.81)). LIMITATIONS: This study was limited by its small sample size, retrospective nature, and short follow-up. CONCLUSIONS: cT2 patients who develop complete clinical response after extended chemoradiation managed nonoperatively are less likely to develop early tumor regrowths when compared with cT3/4 patients. cT3/4 patients should undergo more intensive follow-up after a complete clinical response to allow for early detection of early regrowths.

Extralevator Abdominal Perineal Excision Versus Standard Abdominal Perineal Excision: Impact on Quality of the Resected Specimen and Postoperative Morbidity.

BACKGROUND: Abdominal perineal excision (APE) has been associated with a high risk of positive circumferential resection margin (CRM+) and local recurrence rates in the treatment of rectal cancer. An alternative extralevator approach (ELAPE) has been suggested to improve the quality of resection by avoiding coning of the specimen decreasing the risk of tumor perforation and CRM+. The aim of this study is to compare the quality of the resected specimen and postoperative complication rates between ELAPE and "standard" APE. METHODS: All patients between 1998 and 2014 undergoing abdominal perineal excision for primary or recurrent rectal cancer at a single Institution were reviewed. Between 1998 and 2008, all patients underwent standard APE. In 2009 ELAPE was introduced at our Institution and all patients requiring APE underwent this alternative procedure (ELAPE). The groups were compared according to pathological characteristics, specimen quality (CRM status, perforation and failure to provide the rectum and anus in a single specimen-fragmentation) and postoperative morbidity. RESULTS: Fifty patients underwent standard APEs, while 22 underwent ELAPE. There were no differences in CRM+ (10.6 vs. 13.6%; p = 0.70) or tumor perforation rates (8 vs. 0%; p = 0.30) between APE and ELAPE. However, ELAPE were less likely to result in a fragmented specimen (42 vs. 4%; p = 0.002). Advanced pT-stage was also a risk factor for specimen fragmentation (p = 0.03). There were no differences in severe (Grade 3/4) postoperative morbidity (13 vs. 10%; p = 0.5). Perineal wound dehiscences were less frequent among ELAPE (52 vs 13%; p < 0.01). Despite short follow-up (median 21 mo.), 2-year local recurrence-free survival was better for patients undergoing ELAPE when compared to APE (87 vs. 49%; p = 0.04). CONCLUSIONS: ELAPE may be safely implemented into routine clinical practice with no increase in postoperative morbidity and considerable improvements in the quality of the resected specimen of patients with low rectal cancers.

Transanal Endoscopic Microsurgery (TEM) Following Neoadjuvant Chemoradiation for Rectal Cancer: Outcomes of Salvage Resection for Local Recurrence.

BACKGROUND: Transanal endoscopic microsurgery (TEM) has been considered an alternative for selected patients with rectal cancer following neoadjuvant chemoradiation (CRT). Immediate total mesorectal completion for all patients with unfavorable pathological features would result in unnecessary protectomies in a significant proportion of patients. Instead, salvage total mesorectal excision (TME) could be restricted for patients developing local recurrence. The aim of the present study is to determine oncological outcomes of salvage resection for local recurrences following CRT and TEM. METHODS: Consecutive patients undergoing TEM following neoadjuvant CRT for rectal cancer were reviewed. Patients with "near" complete response to CRT (≤3 cm; ycT1-2N0) were offered TEM. Salvage surgery was attempted in the event of a local recurrence. RESULTS: A total of 53 patients were managed by CRT followed by TEM. Unfavorable pathological features were present in 36 patients (68 %). None of the patients underwent immediate completion TME. There were 12 patients who developed local recurrence resulting in a 2-year local recurrence-free survival of 77 % (95 % CI, 53-100 %). Of these patients, 9 developed exclusively local recurrences, and all had at least 1 unfavorable pathological feature in the specimen after TEM (100 %). Eight patients (8 of 9) underwent salvage resection (abdominoperineal resection [APR] in 87 %) with CRM+ in 7 of 8 patients (87 %). Four patients developed local re-recurrence after a median 36 months of follow-up. The 2-year local re-recurrence free survival was 60 %. CONCLUSIONS: Salvage resection for local recurrence following CRT and TEM is associated with high rates of R1 resection (CRM+) and local re-recurrence. Immediate completion of TME should be considered for patients with unfavorable pathological features after TEM.

Impact of Organ-Preserving Strategies on Anorectal Function in Patients with Distal Rectal Cancer Following Neoadjuvant Chemoradiation.

BACKGROUND: Organ-preserving strategies have been considered for patients with distal rectal cancer and complete or near-complete response to neoadjuvant chemoradiation to avoid the functional consequences of radical surgery. Transanal endoscopic microsurgery and no immediate surgery (watch and wait) have been considered in selected patients. OBJECTIVE: The aim of this study is to compare anorectal function following these 2 organ-preserving strategies (transanal endoscopic microsurgery and watch and wait) for rectal cancer with complete or near-complete response to neoadjuvant chemoradiation. DESIGN: This study is based on the comparison of prospectively collected data. SETTINGS: This study was conducted at a single center. PATIENTS: Consecutive patients with distal rectal cancer undergoing neoadjuvant chemoradiation (50.4-54 Gy and 5-fluorouracil-based chemotherapy) were prospectively studied. Patients with complete clinical response were managed by watch and wait. Patients with near-complete response (≤3 cm, ycT1-2N0) were managed by transanal endoscopic microsurgery. MAIN OUTCOME MEASURES: Functional outcomes were determined by anorectal manometry and Fecal Incontinence Index and Quality of Life assessment. RESULTS: Two groups of patients were included in the study. Twenty-nine patients with near-complete response undergoing transanal endoscopic microsurgery and 53 with complete response after watch and wait were assessed. Baseline features were similar between groups. Patients undergoing transanal endoscopic microsurgery had worse resting/squeeze pressures (p = 0.004) and rectal capacity (p = 0.002). In addition, their incontinence scores (2.3 vs. 6.5; p < 0.001) and quality-of-life questionnaire responses (in all domains; p ≤ 0.01) were significantly worse in comparison with patients undergoing watch and wait. LIMITATIONS: This study was limited by the small sample size and the absence of baseline anorectal function information. CONCLUSIONS: Nonoperative management of patients with complete clinical response following chemoradiation results in better anorectal function in comparison with patients with near-complete response managed by transanal endoscopic microsurgery. In the absence of clinically detectable residual cancer, this latter approach may result in significant worsening of anorectal function.

Transanal local excision for distal rectal cancer and incomplete response to neoadjuvant chemoradiation - does baseline staging matter?

BACKGROUND: Local excision may offer the possibility of organ preservation for the management of select patients after neoadjuvant chemoradiation. The oncological outcomes of this strategy have been largely associated with the risk of nodal metastases. Therefore, in addition to final ypT status, baseline staging has been suggested to potentially influence the outcomes of this treatment modality. OBJECTIVE: The aim of this study is to compare the pathological and oncological outcomes of patients following neoadjuvant chemoradiation and incomplete clinical response managed by transanal endoscopic microsurgery according to baseline staging. DESIGN: This study is a retrospective review of prospectively collected data. SETTINGS: The study was conducted at a single center. PATIENTS: Forty-six patients with distal rectal cancer cT2-4N0-2M0 underwent 5-fluorouracil-based neoadjuvant chemoradiation. Assessment of response was performed at least 8 weeks from radiotherapy completion. Patients with a complete clinical response were not operated on immediately. Patients with an incomplete clinical response were managed by surgery. Those with small (≤3 cm) residual cancers (ycT1-2N0M0) were managed by transanal endoscopic microsurgery. MAIN OUTCOME MEASURES: Patients undergoing local excision following chemoradiation were compared according to baseline staging. RESULTS: Fifteen patients (32%) were cT2N0 at baseline. Final ypT status was ypT0 in 3 (20%) patients, ypT1 in 2 (13%) patients, ypT2 in 9 (60%) patients, and ypT3 in 1 (7%) patient. There were no differences in final ypT status in comparison with patients with baseline cT3-4 or cN+ undergoing chemoradiation followed by transanal endoscopic microsurgery (p = 0.38). Local recurrence was observed in 1 patient with baseline cT2N0 (7%) and in 7 patients (23%) with stage II and III (p = 0.18). LIMITATIONS: This study was limited by the short follow-up, its limited sample size, and its retrospective and nonrandomized nature. CONCLUSIONS: Patients with baseline cT2N0 that do not develop complete response to chemoradiation (ycT0-2N0; ≤3 cm) frequently present unfavorable pathological features for transanal local excision (ypT2 or 3 in >66%). In the presence of incomplete clinical response following chemoradiation, patients with baseline cT2N0 have pathological and oncological outcomes similar to patients with baseline stage II or III and are probably not ideal candidates for local excision (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A159).

Fragmented pattern of tumor regression and lateral intramural spread may influence margin appropriateness after TEM for rectal cancer following neoadjuvant CRT.

BACKGROUND: The main tenets of local excision of rectal cancer following neoadjuvant chemoradiation (CRT) are that the mucosal scar represents the main focus of residual disease and a solid conglomerate around this rather than being scattered (fragmented) through the bowel wall. METHODS: Retrospective review of a prospective cohort of patients with residual rectal ycT1-2N0 adenocarcinoma with small residual tumors (≤3 cm) following CRT who underwent transanal endoscopic microsurgery (TEM) with 1-cm margins around the residual mucosal abnormality was performed. Distribution and morphology (solid vs. fragmented) of tumor spread were studied and correlated to postoperative oncological outcomes. RESULTS: Thirty patients were included. Twenty percent (n = 6) were ypT1, 60% (n = 18) were ypT2, and 20% (n = 6) were ypT3 tumors. Fragmentation was present in 37%. The mean distance between foci of residual scattered tumor was 3.6 ± 2.0 mm. Lateral spread under normal mucosa was present in 19 specimens (53%; mean extension 4.8 ± 2.4 mm). With a median follow up of 32 months, none of these findings impacted upon development of recurrence. CONCLUSIONS: Both occult lateral spread and fragmented tumor patterns are common findings after CRT. Despite the potential of occult spread to mislead surgeon choice of resection margin, its presence did not influence oncological outcome in this series.

Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we getting closer to anal cancer management?

BACKGROUND: No immediate surgery (Watch and Wait) has been considered in select patients with complete clinical response after neoadjuvant chemoradiation to avoid postoperative morbidity and functional disorders after radical surgery. OBJECTIVE: The purpose of this study was to demonstrate the long-term results of patients who had a complete clinical response following an alternative chemoradiation regimen and were managed nonoperatively. DESIGN: This is a prospective study. SETTINGS: This study was conducted at a single center. PATIENTS: Seventy consecutive patients with T2-4N0-2M0 distal rectal cancer were studied. Neoadjuvant chemoradiotherapy included 54 Gy and 5-fluorouracil/leucovorin delivered in 6 cycles every 21 days. Patients were assessed for tumor response at 10 weeks from radiation completion. Patients with incomplete clinical response were referred to immediate surgery. Patients with complete clinical response were not immediately operated on and were monitored. MAIN OUTCOME MEASURES: The primary outcomes measured were the initial complete clinical response rates after 10 weeks and the sustained complete clinical response rates after 12 months from chemoradiotherapy. RESULTS: One patient died during chemoradiotherapy because of cardiac complications. Forty-seven (68%) patients had initial complete clinical response. Of these, 8 developed local regrowth within the first 12 months of follow-up (17%). Thirty-nine sustained complete clinical response at a median follow-up of 56 months (57%). An additional 4 patients (10%) developed late local recurrences (>12 months of follow-up). Overall, 35 patients never underwent surgery (50%). LIMITATIONS: This study is limited by the short follow-up and small sample size. CONCLUSION: Extended chemoradiation therapy with additional chemotherapy cycles and 54 Gy of radiation may result in over 50% of sustained (>12 months) complete clinical response rates that may ultimately avoid radical rectal resection. Local failures occur more frequently during the initial 12 months of follow-up in up to 17% of cases, whereas late recurrences are less common but still possible, leading to 50% of patients who never required surgery. Strict follow-up may allow salvage therapy in the majority of these patients (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A113.).

Transanal endoscopic microsurgery for residual rectal cancer (ypT0-2) following neoadjuvant chemoradiation therapy: another word of caution.

BACKGROUND: Significant tumor downstaging among patients with rectal cancer following neoadjuvant chemoradiation has raised the issue of offering patients with small residual cancers restricted to the bowel wall an alternative treatment strategy to total mesorectal excision. Transanal endoscopic microsurgery may allow proper primary tumor resection with promising oncological outcomes, less postoperative morbidity, and minimal long-term sexual, urinary, and fecal continence disorders in comparison with radical resection. OBJECTIVE: The aim of this study was to determine the oncological outcomes of patients with residual rectal cancers restricted to the rectal wall (ypT0-2) following neoadjuvant chemoradiation and transanal endoscopic microsurgery. DESIGN: This study considered a prospective cohort of patients with residual rectal cancers following neoadjuvant chemoradiation treated by transanal endoscopic microsurgery and no additional systemic therapy. SETTINGS: This study was a single-institution experience. PATIENTS: Patients with adenocarcinoma of the rectum located no more than 7 cm from the anal verge and endorectal ultrasound- or magnetic resonance-staged cT2-4N0-2M0 treated by neoadjuvant chemoradiation (50.4-54 Gy and 5-fluorouracil-based chemotherapy) were eligible for the study. Patients with small residual tumors (≤3 cm) radiologically staged ycT0-2N0 were treated by transanal endoscopic microsurgery. INTERVENTIONS: Transanal endoscopic microsurgery was performed. MAIN OUTCOME MEASURES: The primary outcome measured was local recurrence. RESULTS: Of the 27 patients treated by transanal endoscopic microsurgery, 3 had ypT0, 6 had ypT1, and 18 had ypT2 cancers. All patients underwent R0 transanal endoscopic microsurgery excision. Local recurrence was observed in 4 (15%) patients after a median follow-up of 15 months. Only lymphovascular invasion was an independent predictive factor for local failure (p = 0.04). Tumor size, ypT status, T-status downstaging, lateral/radial margins, and tumor regression grade were not predictors of local failure. LIMITATIONS: This study was limited by the small sample size and limited follow-up. CONCLUSIONS: A local failure rate of 15% after transanal endoscopic microsurgery for patients with residual rectal cancers restricted to the bowel wall (ypT0-2) may limit the indication of this procedure to highly selected patients as an alternative to standard radical total mesorectal excision.

Accuracy of positron emission tomography/computed tomography and clinical assessment in the detection of complete rectal tumor regression after neoadjuvant chemoradiation: long-term results of a prospective trial (National Clinical Trial 00254683).

BACKGROUND: Neoadjuvant chemoradiation (CRT) therapy may result in significant tumor regression in patients with rectal cancer. Patients who develop complete tumor regression have been managed by treatment strategies that are alternatives to standard total mesorectal excision. Therefore, assessment of tumor response with positron emission tomography/computed tomography (PET/CT) after neoadjuvant treatment may offer relevant information for the selection of patients to receive alternative treatment strategies. METHODS: Patients with clinical T2 (cT2) through cT4NxM0 rectal adenocarcinoma were included prospectively. Neoadjuvant therapy consisted of 54 grays of radiation and 5-fluorouracil-based chemotherapy. Baseline PET/CT studies were obtained before CRT followed by PET/CT studies at 6 weeks and 12 weeks after the completion of CRT. Clinical assessment was performed at 12 weeks after CRT completion. PET/CT results were compared with clinical and pathologic data. RESULTS: In total, 99 patients were included in the study. Twenty-three patients were complete responders (16 had a complete clinical response, and 7 had a complete pathologic response). The PET/CT response evaluation at 12 weeks indicated that 18 patients had a complete response, and 81 patients had an incomplete response. There were 5 false-negative and 10 false-positive PET/CT results. PET/CT for the detection of residual cancer had 93% sensitivity, 53% specificity, a 73% negative predictive value, an 87% positive predictive value, and 85% accuracy. Clinical assessment alone resulted in an accuracy of 91%. PET/CT information may have detected misdiagnoses made by clinical assessment alone, improving overall accuracy to 96%. CONCLUSIONS: Assessment of tumor response at 12 weeks after CRT completion with PET/CT imaging may provide a useful additional tool with good overall accuracy for the selection of patients who may avoid unnecessary radical resection after achieving a complete clinical response. Cancer 2012;3501-3511. © 2011 American Cancer Society.

The need for effective radiosentitizing agents: experience in patients with complete pathological response.

Chemoradiation therapy is now considered the preferred initial treatment strategy for distal rectal cancer because of the observation of better local disease control and significant tumor downstaging. Downstaging has become an important clinical outcome as patients with complete pathological response are associated with improved survival. Even though radiation alone may result in low local recurrence rates, the use of additional radiosensitizing agents may provide an increase in local disease control in addition to improved tumor regression rates. Several compounds have been investigated in the setting of neoadjuvant multimodality treatment of rectal cancer with variable rates of treatment-related toxicity and complete pathological response. The balance between complete pathological response and toxicity should aid in the management decision for the use of radiosensitizing agents in the neoadjuvant setting for the treatment of rectal cancer.

Transanal endoscopic microsurgery for residual rectal cancer after neoadjuvant chemoradiation therapy is associated with significant immediate pain and hospital readmission rates.

BACKGROUND: Transanal endoscopic microsurgery may represent appropriate diagnostic and therapeutic procedure in selected patients with distal rectal cancer following neoadjuvant chemoradiation. Even though this procedure has been associated with low rates of postoperative complications, patients undergoing neoadjuvant chemoradiation seem to be at increased risk for suture line dehiscence. In this setting, we compared the clinical outcomes of patients undergoing transanal endoscopic microsurgery with and without neoadjuvant chemoradiation. METHODS: Thirty-six consecutive patients were treated by transanal endoscopic microsurgery at a single institution. Twenty-three patients underwent local excision after neoadjuvant chemoradiation therapy for rectal adenocarcinoma, and 13 patients underwent local excision without any neoadjuvant treatment for benign and malignant rectal tumors. Chemoradiation therapy included 50.4 to 54 Gy and 5-fluorouracil-based chemotherapy. All patients underwent transanal endoscopic microsurgery with primary closure of the rectal defect. Complications (immediate and late) and readmission rates were compared between groups. RESULTS: Overall, median hospital stay was 2 days. Immediate (30-d) complication rate was 44% for grade II/III complications. Patients undergoing neoadjuvant chemoradiation therapy were more likely to develop grade II/III immediate complications (56% vs 23%; P = .05). Overall, the 30-day readmission rate was 30%. Wound dehiscence was significantly more frequent among patients undergoing neoadjuvant chemoradiation therapy (70% vs 23%; P = .03). Patients undergoing neoadjuvant chemoradiation therapy were at significantly higher risk of requiring readmission (43% vs 7%; P = .02). CONCLUSION: Transanal local excision with the use of endoscopic microsurgical approach may result in significant postoperative morbidity, wound dehiscence, and readmission rates, in particular, because of rectal pain secondary to wound dehiscence. In this setting, the benefits of this minimally invasive approach either for diagnostic or therapeutic purposes become significantly restricted to highly selected patients that can potentially avoid a major operation but will still face a significantly morbid and painful procedure.

Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization.

BACKGROUND: Complete tumor regression may develop after neoadjuvant chemoradiation therapy for distal rectal cancer. Studies have suggested that selected patients with complete clinical response may avoid radical surgery and close surveillance may provide good outcomes with no oncologic compromise. However, definition of complete clinical response is often imprecise and may vary between different studies. The aim of this study is to provide a clear definition for a complete clinical response after neoadjuvant chemoradiation therapy in patients with distal rectal cancer in addition to actual endoscopic videos from patients managed nonoperatively. METHODS: Patients with nonmetastatic distal rectal cancer treated by neoadjuvant chemoradiation therapy, including 50.4 Gy and concomitant 5-fluorouracil and leucovorin, were assessed for tumor response at least 8 weeks after chemoradiation therapy completion. Complete and incomplete clinical responses were defined based on clinical and endoscopic findings. Patients with complete clinical response were not immediately operated on and were closely followed. Early and late endoscopic findings were recorded. RESULTS: Definition of a complete clinical response should be based on very strict clinical and endoscopic criteria. The finding of any residual superficial ulceration, irregularity, or nodule should prompt surgical attention, including transanal full-thickness excision or even a radical resection with total mesorectal excision. Standard or incisional biopsies should be avoided in this setting. Complete clinical responders should harbor no more than whitening of the mucosa, teleangiectasia with mucosal integrity to be considered for a nonoperative approach. In the presence of these findings, regularly scheduled reassessments may provide a safe alternative to these patients with early detection of recurrent disease. CONCLUSION: Strict definition of the clinical and endoscopic findings of patients experiencing complete clinical response after neoadjuvant chemoradiation therapy may provide a useful tool for the understanding of outcomes of patients managed with no immediate surgery allowing standardization of classifications and comparison between the experiences of different institutions.

Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the resting period.

OBJECTIVES: Addition of chemotherapy in the resting period between radiotherapy completion and response assessment during neoadjuvant treatment for distal rectal cancer could potentially increase rates of complete tumor regression. The purpose of this study was to evaluate toxicity rates and the impact of an extended neoadjuvant chemoradiation regimen on complete response rates. METHODS: Thirty-four consecutive patients with nonmetastatic distal rectal cancer were prospectively included. Patients were managed by 5,400 Gy of radiation and 5-fluorouracil/leucovorin-based chemotherapy given for three consecutive days every 21 days for six cycles (three cycles concomitant with radiotherapy). Tumor response assessment was performed at ten weeks from radiation completion. Patients with complete clinical response were strictly monitored and were not immediately operated on. Patients with incomplete clinical response were referred to surgery. RESULTS: Twenty-nine patients had completed 12 months of follow-up and were included in this preliminary analysis. Twenty-eight (97%) successfully completed treatment. Fifteen of 16 patients had Grade III toxicities that were skin-related (93%). Median follow-up was 23 months. Fourteen patients (48%) were considered as complete clinical responders sustained for at least 12 months (median, 24 months) after chemoradiation completion by clinical assessment alone. An additional five patients (17%) were considered as complete responders with ypT0 results after full-thickness local excision. Overall, the complete response rate was 65%. CONCLUSIONS: The addition of chemotherapy during the resting period after neoadjuvant chemoradiation is associated with acceptable toxicity and high tolerability rates. The considerably high rates of complete response in this preliminary series requires further follow-up, but they may provide valuable information for future prospective, randomized trials.

The role of carcinoembriogenic antigen in predicting response and survival to neoadjuvant chemoradiotherapy for distal rectal cancer.

PURPOSE: Carcinoembriogenic antigen (CEA) is the most frequently used tumor marker in rectal cancer. A decrease in carcinoembriogenic antigen after radical surgery is associated with survival in these patients. Neoadjuvant chemoradiotherapy may lead to significant primary tumor downstaging, including complete tumor regression in selected patients. Therefore, we hypothesized that a decrease in CEA after neoadjuvant chemoradiotherapy could reflect tumor response to chemoradiotherapy, affecting final disease stage and ultimately survival. METHODS: Patients with distal rectal cancer managed by neoadjuvant chemoradiotherapy and available pretreatment and postchemoradiotherapy levels of CEA were eligible for the study. Outcomes studied included final disease stage, relapse, and survival, and these were compared according to initial CEA level, post-chemoradiotherapy CEA level, and the reduction in CEA. RESULTS: Overall 170 patients were included. Post-chemoradiotherapy CEA levels <5 ng/ml were associated with increased rates of complete clinical response and pathologic response. Additionally, postchemoradiotherapy CEA levels <5 ng/ml were associated with increased overall and disease-free survival (P = 0.01 and P = 0.03). There was no correlation between initial CEA level or reduction in CEA and complete response or survival. CONCLUSION: A postchemoradiotherapy CEA level <5 ng/ml is a favorable prognostic factor for rectal cancer and is associated with increased rates of earlier disease staging and complete tumor regression. Postchemoradiotherapy CEA levels may be useful in decision making for patients who may be candidates for alterative treatment strategies.