The current multidisciplinary management of rectal cancer.

Multidisciplinary management of rectal cancer has rapidly evolved over the last several years. This review describes recent data surrounding total neoadjuvant therapy, organ preservation, and management of lateral pelvic lymph nodes. It then presents our treatment algorithm for management of rectal cancer at The University of Texas MD Anderson Cancer Center in the context of this and other existing literature. As part of this discussion, the review describes how we tailor management based upon both patient and tumor-related factors in an effort to optimize patient outcomes.

SWOG S1820: A pilot randomized trial of the Altering Intake, Managing Bowel Symptoms Intervention in Survivors of Rectal Cancer.

BACKGROUND: Survivors of rectal cancer experience persistent bowel dysfunction after treatments. Dietary interventions may be an effective approach for symptom management and posttreatment diet quality. SWOG S1820 was a pilot randomized trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention for bowel dysfunction in survivors of rectal cancer. METHODS: Ninety-three posttreatment survivors were randomized to the AIMS-RC group (N = 47) or the Healthy Living Education attention control group (N = 46) after informed consent and completion of a prerandomization run-in. Outcome measures were completed at baseline and at 18 and 26 weeks postrandomization. The primary end point was total bowel function score, and exploratory end points included low anterior resection syndrome (LARS) score, quality of life, dietary quality, motivation, self-efficacy, and positive/negative affect. RESULTS: Most participants were White and college educated, with a mean age of 55.2 years and median time since surgery of 13.1 months. There were no statistically significant differences in total bowel function score by group, with the AIMS-RC group demonstrating statistically significant improvements in the exploratory end points of LARS (p = .01) and the frequency subscale of the bowel function index (p = .03). The AIMS-RC group reported significantly higher acceptability of the study. CONCLUSIONS: SWOG S1820 did not provide evidence of benefit from the AIMS-RC intervention relative to the attention control. Select secondary end points did demonstrate improvements. The study was highly feasible and acceptable for participants in the National Cancer Institute Community Oncology Research Program. Findings provide strong support for further refinement and effectiveness testing of the AIMS-RC intervention.

The value of national accreditation program for rectal cancer: A survey of accredited programs and programs seeking accreditation.

BACKGROUND: Significant variation in rectal cancer care has been demonstrated in the United States. The National Accreditation Program for Rectal Cancer was established in 2017 to improve the quality of rectal cancer care through standardization and emphasis on a multidisciplinary approach. The aim of this study was to understand the perceived value and barriers to achieving the National Accreditation Program for Rectal Cancer accreditation. METHODS: An electronic survey was developed, piloted, and distributed to rectal cancer programs that had already achieved or were interested in pursuing the National Accreditation Program for Rectal Cancer accreditation. The survey contained 40 questions with a combination of Likert scale, multiple choice, and open-ended questions to provide comments. This was a mixed methods study; descriptive statistics were used to analyze the quantitative data, and thematic analysis was used to analyze the qualitative data. RESULTS: A total of 85 rectal cancer programs were sent the survey (22 accredited, 63 interested). Responses were received from 14 accredited programs and 41 interested programs. Most respondents were program directors (31%) and program coordinators (40%). The highest-ranked responses regarding the value of the National Accreditation Program for Rectal Cancer accreditation included "improved quality and culture of rectal cancer care," "enhanced program organization and coordination," and "challenges our program to provide optimal, high-quality care." The most frequently cited barriers to the National Accreditation Program for Rectal Cancer accreditation were cost and lack of personnel. CONCLUSION: Our survey found significant perceived value in the National Accreditation Program for Rectal Cancer accreditation. Adhering to standards and a multidisciplinary approach to rectal cancer care are critical components of a high-quality care rectal cancer program.

Salvage Treatment of Recurrent or Persistent Anal Squamous Cell Carcinoma: The Role of Multi-modality Therapy.

BACKGROUND: The standard treatment for recurrent or persistent anal squamous cell carcinoma is surgical salvage, but disease control and survival are suboptimal. PATIENTS/METHODS: Patients treated for recurrent or persistent anal squamous cell carcinoma at our institution from 2002 to 2022 were included. Patients were classified by type of salvage treatment received: surgery alone vs. reirradiation followed by surgery and by whether they received intraoperative radiation at the time of surgery. Clinical and pathologic variables were collected and assessed for association with risk of second local recurrence and death from any cause. RESULTS: Sixty four patients were included; 55(85.9%) were treated with surgery alone and 9 (14.1%) were treated with reirradiation followed by surgery. Median (IQR) follow up from the time of salvage treatment was 40.0 (20.3-68.0) months. The 3-year cumulative incidence of second local recurrence (95% CI) after salvage surgery was 36% (24%-48%); 39% (26%-52%) for patients treated with surgery alone and 15% (0.46%-51%) for patients treated with reirradiation followed by surgery. Factors associated with increased second local recurrence after salvage surgery included a locoregional recurrence, lymphovascular space invasion and positive surgical margins. The 3-year overall survival (95% CI) after salvage surgery was 70% (59%-83%); 68% (7%-56%) after surgery alone and 89% (10.5%-70.6%) after reirradiation followed by surgery. Factors associated with worse overall survival included male sex, a larger recurrent tumor and positive surgical margins. CONCLUSIONS: Approximately 60% of patients achieved pelvic control after salvage therapy for recurrent or persistent anal squamous cell carcinoma. Although receipt of reirradiation and intraoperative radiation were not associated with improved second local recurrence or overall survival in our cohort, patients with positive surgical margins and lymphovascular space invasion on surgical pathology had higher rates of pelvic recurrence after salvage surgery and may benefit from escalated salvage therapy.

Daily Vaginal Dilator Use During Radiation for Women With Squamous Cell Carcinoma of the Anus: Vaginal Wall Dosimetry and Patient-Reported Sexual Function.

PURPOSE: At our institution, we treat patients with a daily vaginal dilator (VD) during chemoradiation (CRT) for squamous cell carcinoma of the anus (SCCA). We evaluated compliance with daily VD use, radiation dose to the vaginal wall (VW), and anterior vaginal wall (AVW), and patient-reported long-term sexual function. METHODS AND MATERIALS: We included women with SCCA who received definitive, intensity-modulated radiation therapy-based CRT. Women who were alive without evidence of disease received a patient-reported outcome survey, which included the Female Sexual Function Index (FSFI). We identified factors associated with FSFI, such as radiation dose to the VW and AVW using linear regression models and used Youden index analysis to estimate a dose cutoff to predict sexual dysfunction. RESULTS: Three hundred thirty-nine consecutively treated women were included in the analysis; 285 (84.1%) were treated with a daily VD. Of 184 women alive without disease, 90 patients (49%) completed the FSFI, and 51 (56.7%) were sexually active with valid FSFI scores. All received therapy with a daily VD. Forty-one women (80%) had sexual dysfunction. Univariate analysis showed higher dose to 50% (D50%) of the AVW correlated with worse FSFI (ß -.262; P = .043), worse desire FSFI subscore (ß -.056; P = .003), and worse pain FSFI subscore (ß -.084; P = .009). Younger age correlated with worse pain FSFI subscale (ß .067; P = .026). Age (ß .070; P = .013) and AVW D50% (ß -.087; P = .009) were significant on multivariable analysis. AVW D50% >48 Gy predicted increased risk of sexual dysfunction. CONCLUSIONS: Daily VD use is safe and well tolerated during CRT for SCCA. Using a VD during treatment to displace the AVW may reduce the risk for sexual dysfunction. Limiting the AVW D50% <48 Gy may further reduce the risk but additional data are needed to validate this constraint.

Endoscopic and imaging outcomes of PD-1 therapy in localised dMMR colorectal cancer.

BACKGROUND: Neoadjuvant immune checkpoint blockade (IO) is emerging as a therapeutic option for patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) given high pathological response rates. The aim of the study was to characterise imaging and endoscopic response to IO. METHODS: A retrospective analysis of patients with localised dMMR CRC that received at least one cycle of neoadjuvant anti-PD-1 therapy was conducted. Endoscopy, imaging, and pathological outcomes were reviewed to determine response to treatment according to standardised criteria. RESULTS: Thirty-eight patients had received IO for the treatment of localised CRC (median eight cycles). Among evaluable cases (n = 31 for endoscopy and n = 34 for imaging), the best endoscopic response was complete response (CR) in 45% of cases, and the best radiographic response was CR in 23% of cases. Imaging CR rate after ≤4 cycles of IO (n = 1) was 6% compared to 44% after >4 IO cycles (n = 7). Among 28 patients with imaging and endoscopy available, a discrepancy in best response was noted in 15 (54%) cases. At a median follow-up of 28.2 months from IO start, 18 patients underwent surgical resection of which 11 (61%) had pathological CR (pCR). Despite pCR or no evidence of progression ≥6 months after completion of IO among non-operatively managed patients, 72% and 42% of patients had non-CR on imaging and endoscopy, respectively. CONCLUSIONS: Discrepancies between imaging and endoscopy are prevalent, and irregularities identified on these modalities can be identified despite pathological remission. Improved clinical response criteria are warranted.

HPV-related anal cancer is associated with changes in the anorectal microbiome during cancer development.

Background: Squamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are unclear and screening guidelines and approaches for anal dysplasia are less clear than for cervical dysplasia. One potential contributing factor is the anorectal microbiome. In this study, we aimed to identify differences in anal microbiome composition in the settings of HPV infection, anal dysplasia, and anal cancer in this rare disease. Methods: Patients were enrolled in two prospective studies. Patients with anal dysplasia were part of a cross-sectional cohort that enrolled women with high-grade lower genital tract dysplasia. Anorectal tumor swabs were prospectively collected from patients with biopsy-confirmed locally advanced SCCA prior to receiving standard-of-care chemoradiotherapy (CRT). Patients with high-grade lower genital tract dysplasia without anal dysplasia were considered high-risk (HR Normal). 16S V4 rRNA Microbiome sequencing was performed for anal swabs. Alpha and Beta Diversity and composition were compared for HR Normal, anal dysplasia, and anal cancer. Results: 60 patients with high-grade lower genital tract dysplasia were initially enrolled. Seven patients had concurrent anal dysplasia and 44 patients were considered HR Normal. Anorectal swabs from 21 patients with localized SCCA were included, sequenced, and analyzed in the study. Analysis of weighted and unweighted UniFrac distances demonstrated significant differences in microbial community composition between anal cancer and HR normal (p=0.018). LEfSe identified that all three groups exhibited differential enrichment of specific taxa. Peptoniphilus (p=0.028), Fusobacteria (p=0.0295), Porphyromonas (p=0.034), and Prevotella (p=0.029) were enriched in anal cancer specimens when compared to HR normal. Conclusion: Although alpha diversity was similar between HR Normal, dysplasia and cancer patients, composition differed significantly between the three groups. Increased anorectal Peptoniphilus, Fusobacteria, Porphyromonas, and Prevotella abundance were associated with anal cancer. These organisms have been reported in various gastrointestinal cancers with roles in facilitating the proinflammatory microenvironment and neoplasia progression. Future work should investigate a potential role of microbiome analysis in screening for anal dysplasia and investigation into potential mechanisms of how these microbial imbalances influence the immune system and anal carcinogenesis.

Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer.

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA.

Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors.

PURPOSE: Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS: This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS: A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION: Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Germline Cancer Risk Profiles of Patients With Young-Onset Colorectal Cancer: Findings From a Prospective Universal Germline Testing and Telegenetics Program.

BACKGROUND: Colorectal cancer is being increasingly diagnosed in people younger than 50 years. An inheritable cancer predisposition has been reported in 22% of the young-onset cases. Assessment of germline risk is critical for personalized cancer care. OBJECTIVE: The study aimed to implement universal germline cancer risk assessment and testing and to define the germline cancer risk profiles of patients presenting with young-onset disease. DESIGN: This is a prospective cohort study. SETTINGS: This study was conducted at a tertiary-referral academic medical center. PATIENTS: This study included newly diagnosed patients presenting to surgical clinics between September 2019 and February 2021 who were treated on a standardized care pathway including the universal germline risk assessment. INTERVENTIONS: Patients received educational material on young-onset disease, genetic testing, and insurance coverage followed by genetic counseling (either remotely by telegenetics or in person). Consenting patients were assessed on a 47-gene common hereditary cancer panel. MAIN OUTCOME MEASURES: The primary outcome was a proportion of patients with identifiable germline cancer predisposition. RESULTS: Among 500 patients with colorectal cancer, 185 (37%) were 50 years of age or younger (median: 44). A family history was absent for the majority of patients (123; 67%), and in 15 patients, tumors (8.1%) were deficient in DNA mismatch repair. Germline testing was completed in 130 patients (70%); the remainder were pending (7%), deceased (1%), or declined (22%). Pathogenic germline mutations were identified in 25 of 130 (19%) patients: 12 in mismatch repair genes and 13 in other genes. A variant of uncertain significance was found in 23 (18%) patients. Importantly, a pathogenic germline mutation was identified in 12% of the patients without a family history (versus 32% with; p = 0.015) and in 13% of those with proficient mismatch repair colorectal cancers (versus 71% if deficient; p < 0.001). LIMITATIONS: The study is limited by its implementation at a single tertiary academic institution. CONCLUSIONS: One in 5 patients with young-onset disease harbored germline cancer predisposition. This detection rate, coupled with a high level of interest and acceptance from patients and feasibility of implementation, supports universal germline cancer risk assessment in this patient population. See Video Abstract at http://links.lww.com/DCR/B925 . PERFILES DE RIESGO DE CNCER DE LNEA GERMINAL DE PACIENTES CON CNCER COLORRECTAL DE INICIO JOVEN HALLAZGOS DE UN PROGRAMA UNIVERSAL PROSPECTIVO DE PRUEBAS DE LNEA GERMINAL Y TELEGENTICA: ANTECEDENTES:El cáncer colorrectal se diagnostica cada vez más en personas menores de 50 años. Se ha informado una predisposición hereditaria al cáncer en el 22 % de los casos de aparición temprana. La evaluación del riesgo de la línea germinal es fundamental para la atención personalizada del cáncer.OBJETIVO:Implementar la evaluación y las pruebas universales de riesgo de cáncer de línea germinal, y definir los perfiles de riesgo de cáncer de línea germinal de los pacientes que presentan una enfermedad de aparición temprana.DISEÑO:Un estudio de cohorte prospectivo.AJUSTE:Un centro médico académico de referencia terciaria.PACIENTES:Los pacientes recién diagnosticados que se presentaron en clínicas quirúrgicas entre Septiembre de 2019 y Febrero de 2021 fueron tratados en una vía de atención estandarizada que incluye una evaluación de riesgo de línea germinal universal.INTERVENCIÓN:Los pacientes recibieron material educativo sobre enfermedades de aparición temprana, pruebas genéticas y cobertura de seguro, seguido de asesoramiento genético (ya sea a distancia por telegenética o en persona). Los pacientes que dieron su consentimiento fueron evaluados en un panel de cánceres hereditarios comunes de 47 genes.MEDIDA DE RESULTADO PRINCIPAL:Proporción de pacientes con predisposición identificable al cáncer de línea germinal.RESULTADOS:Entre 500 pacientes con cáncer colorrectal, 185 (37%) tenían 50 años o menos (mediana: 44). No había antecedentes familiares en la mayoría (123, 67%) y 15 tumores (8,1%) eran deficientes en la reparación del desajuste de ácido desoxirribonucleico. La prueba de línea germinal se completó en 130 pacientes (70%); el resto estaban pendientes (7%), fallecidos (1%) o declinados (22%). Se identificaron mutaciones patogénicas de la línea germinal en 25 (de 130, 19%) pacientes: 12 en genes de reparación de errores de emparejamiento y 13 en otros genes. Se encontró una variante de significado incierto en 23 (18%) pacientes. Es importante señalar que se identificó una mutación germinal patogénica en el 12% de los pacientes sin antecedentes familiares (frente al 32% con; p = 0,015) y en el 13% de aquellos con cánceres colorrectales competentes en la reparación de errores de emparejamiento (frente al 71% si eran deficientes; p < 0,001).LIMITACIÓN:Implementado en una sola institución académica terciaria.CONCLUSIÓN:Uno de cada cinco pacientes con enfermedad de inicio joven albergaba predisposición al cáncer de línea germinal. Esta tasa de detección, junto con un alto nivel de interés y aceptación por parte de los pacientes y la viabilidad de la implementación, respaldan la evaluación universal del riesgo de cáncer de línea germinal en esta población de pacientes. Consulte el Video Resumen en http://links.lww.com/DCR/B925 . (Traducción-Dr. Yesenia Rojas-Khalil ).

A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women. METHODS: This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA). RESULTS: 324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia. CONCLUSIONS: Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer. IMPACT: These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Patient-Reported Sexual Function in Long-Term Survivors of Anal Cancer Treated With Definitive Intensity Modulated Radiation Therapy and Concurrent Chemotherapy.

PURPOSE: Pelvic chemoradiation can have a profound effect on sexual function. Few data exist describing long-term sexual function patient-reported outcomes (PROs) for patients treated with intensity modulated radiation and concurrent chemotherapy (CRT) for squamous cell carcinoma of the anus (SCCA). METHODS AND MATERIALS: We identified 248 patients with SCCA treated with CRT from 2010 to 2018 who were alive and without recurrence. We sent a PRO survey to 148 patients who agreed to participate. The survey was comprised of the PROMIS sexual function and satisfaction questionnaire, the international index of erectile function 5-item questionnaire for men, and the female sexual function index questionnaire for women. Clinical and dosimetric data were collected for each patient. We used multiple regression models to identify factors associated with sexual function PROs. RESULTS: One-hundred twelve patients (45.2% of all eligible patients, 75.7% of administered surveys) completed the survey; 90 (80.4%) were women, 107 (95.5%) were white. The median (interquartile range [IQR]) age was 61.5 (53.8-66.0) years. The median (IQR) interval since CRT was 51 (37-85) months. Twelve men (54.5%) and 52 women (57.1%) were sexually active. The median (IQR) age of sexually active patients was 58.2 (50.1-64) years compared with 64.8 (59.1-68.8) years for sexually inactive patients (P < .001). The median (IQR) female sexual function index score for sexually active women was 20.2 (13.6-25.1). The median (IQR) international index of erectile function 5-item questionnaire score was 14 (6.5-19). CONCLUSIONS: Patients treated with modern CRT for SCCA experience significant long-term sexual dysfunction as reported using validated PROs. Interventions to reduce sexual toxicities and improve patient support are needed.

Patient-Reported Bowel and Urinary Function in Long-Term Survivors of Squamous Cell Carcinoma of the Anus Treated With Definitive Intensity Modulated Radiation Therapy And Concurrent Chemotherapy.

PURPOSE: Definitive radiation therapy with concurrent chemotherapy is curative for nonmetastatic squamous cell carcinoma of the anus (SCCA). However, the true effect of chemoradiation on long-term functional outcomes is poorly understood owing to limited follow-up and patient-reported outcomes (PROs). METHODS AND MATERIALS: We conducted a cross-sectional survey of 248 patients with SCCA treated with definitive intensity modulated radiation and concurrent chemotherapy from 2010 to 2018 who were alive and without recurrence. PRO measures were collected, including Functional Assessment of Cancer Therapy-General (FACT-G7), Fecal Incontinence Quality of Life (FIQoL), Low Anterior Resection Syndrome (LARS), and International Consultation on Incontinence Questionnaires (ICIQ). Models were used to determine the association between demographic, tumor, treatment, and dosimetric data with PROs. RESULTS: One hundred twelve (45%) patients completed PROs. Median [interquartile range (IQR)] time from radiation completion to survey was 51 [37-85] months. The median scores [IQR] for FACT-G7, FIQoL, and LARS were 21 [15-24], 14 [11-16], and 32 [25-37], respectively. For men, median subscores [IQR] for ICIQ voiding and incontinence subscores were 5 [2-6] and 1 [1-3], respectively. For women, median subscores [IQR] for ICIQ voiding, incontinence, and filling were 1 [1-3], 5 [3-8], and 4 [2-5], respectively. Higher (better) FIQoL scores were associated with higher (better) FACT-G7 scores (ß = 0.83; 95% confidence interval, 0.58-1.09; P < .001), and higher (worse) LARS scores were associated with lower (worse) FACT-G7 scores (ß = -0.22; 95% confidence interval, -0.31 to -0.13; P < .001). A separate multivariable analysis revealed higher bowel bag D1% was associated with lower (worse) FIQoL (P = .001) and higher (worse) LARS (P = .003) scores. Higher bladder V40 Gy was associated with increased (worse) ICIQ voiding subscore (P = .001). CONCLUSIONS: Patients treated with modern chemoradiation for SCCA experience significant long-term bowel toxic effects with considerable effect on quality of life. Minimizing bowel hotspots and bladder V40 Gy may improve bowel and urinary function. Other interventions to reduce long-term toxic effects and improve quality of life are needed.

Definitive Intensity-Modulated Chemoradiation for Anal Squamous Cell Carcinoma: Outcomes and Toxicity of 428 Patients Treated at a Single Institution.

BACKGROUND: Although intensity-modulated radiation therapy (IMRT) is considered the standard of care for the treatment of squamous cell carcinoma of the anus (SCCA), few large series have reported oncologic outcomes and toxicities. In this retrospective report, we aim to describe outcomes and toxicities after IMRT-based chemoradiation (CRT) for the treatment of SCCA, evaluate the impact of dose escalation (>54 Gy), and compare concurrent fluoropyrimidine in combination with either mitomycin or with cisplatin as chemosensitizers. METHODS: Patients treated at The University of Texas MD Anderson Cancer Center between January 1, 2003 and December 31, 2018 with IMRT-based CRT were included. Median time to locoregional recurrence, time to colostomy, and overall survival were estimated using the Kaplan-Meier method. RESULTS: A total of 428 patients were included; median follow-up was 4.4 years. Three hundred and thirty-four patients (78.0%) were treated with concurrent cisplatin and fluoropyrimidine, and 160 (37.4%) with >54 Gy. Two- and 5-year freedom from locoregional failure, freedom from colostomy failure, and overall survival were 86.5% and 81.2%, respectively, 90.0% and 88.3%, respectively, and 93.6% and 85.8%, respectively. Neither dose escalation nor mitomycin-based concurrent chemotherapy resulted in improved outcomes. Mitomycin-based concurrent chemotherapy was associated with in approximately 2.5 times increased grade 3 or greater acute toxicity. Radiation dose >54 Gy was associated with approximately 2.6 times increased Grade 3 or greater chronic toxicity. CONCLUSIONS: Our results suggest IMRT-based CRT with concurrent fluoropyrimidine and cisplatin is a safe and feasible option for patient with SCCA and may cause less acute toxicity. The role for radiation dose escalation is unclear and requires further study.

Quality and Location of the Surgical Episode Mediate a Large Proportion of Socioeconomic-Based Survival Disparities in Patients with Resected Stage I-III Colon Cancer.

INTRODUCTION: Lower socioeconomic status (SES) is associated with shorter overall survival (OS) in patients with locoregional colon cancer. We aimed to estimate: (1) the proportion of SES-based OS disparities mediated by disparities in the quality and location of surgical treatment in patients with resected stage I-III colon cancer and (2) the relative importance of components of surgical quality. PATIENTS AND METHODS: We examined patients ages 18-80 years with resected stage I-III colon adenocarcinoma using the 2010-2016 National Cancer Database. SES was defined at the zip code level. Inverse odds weighting mediation analysis was used to estimate the proportion mediated (PM) for nine treatment quality-related and facility-related factors and composite PMs in models including all nine mediators. Models compared high SES patients with each lower SES stratum. RESULTS: Among 171,009 patients, 5-year OS increased from 70.4% in low SES patients to 78.1% in high SES. When high SES patients were compared with low, lower-middle, and upper-middle SES patients, PM ranges among lower SES strata were: minimally invasive surgery 16.0-16.6%, lymph nodes examined 7.7-9.6%, positive margins 3.8-6.5%, length of stay 16.7-28.1%, readmissions insignificant to 3.7%, treatment at > 1 CoC facility 2.7-3.1%, facility type insignificant to 7.3%, facility volume 2.9-8.2%, and adjusted facility 90-day mortality rates 33.2-42.8%. Composite PMs were 76.9% (95% CI 61.3%, 92.4%) for low SES, 68.7% (95% CI 56.4%, 81.1%) for lower-middle SES, and 60.9% (95% CI 43.1%, 78.6%) for upper-middle SES. CONCLUSIONS: These data suggest that improving the quality of the surgical episode for disadvantaged patients undergoing resection for locoregional colon cancer could decrease SES-based survival disparities by over half.

High Rate of Positive Circumferential Resection Margin in Colon Cancer: A National Appraisal and Call for Action.

OBJECTIVE: To identify rates of positive circumferential resection margin (CRM) for colon cancer surgery in the US. SUMMARY BACKGROUND DATA: CRM is one of the most important determinants of local control in colorectal cancers. The extent to which CRM involvement exists after colon cancer surgery is unknown. METHODS: Colon cancer cases with resection 2010 to 2015 were identified from the National Cancer Data Base. Adjusting for patient and tumor characteristics, comparisons were made between cases with CRM > 1 mm (negative margin) and those with margin involved with tumor or ≤ 1 mm (positive margin, CRM+). Hospital-level analysis was performed, examining observed-to-expected CRM+ rates. RESULTS: In total, 170,022 cases were identified: 150,291 CRM- and 19,731 CRM+ (11.6%). Pathologic T-category was the greatest predictor of CRM+, with higher rates in pT4(25.8%), pT4A(24.7%), and pT4B(31.5%) versus pT1(4.5%), pT2(6.3%) and pT3 (10.9%, P < 0.001). Within pT4 patients, predictors of CRM+ included signet-ring histology (38.1% vs 26.7% nonmucinous, and 26.9% mucinous adenocarcinoma, P < 0.001), removing < 12 lymph nodes (36.5% vs 26.1% >12, P < 0.001), community facilities (32.7%) versus academic/research (23.6%, P < 0.001), year (30.1% 2010 vs 22.6% 2015, P < 0.001), and hospital volume (24.5% highest quartile vs 32.7% lowest, P < 0.001). Across 1288 hospitals, observed-to-expected ratios for CRM+ ranged from 0 to 7.899; 429 facilities had higher than expected rates. CONCLUSIONS: Overall rate of CRM+ in US colon cancer cases is high. Variation exists across hospitals, with higher than expected rates in many facilities. Although biology is a major influencing factor, CRM+ rates represent an area for multidisciplinary improvement in quality of colon cancer care.

Current treatment and future directions in the management of anal cancer.

Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with appropriate treatment, which has evolved significantly over the last several decades. Before the 1970s, SCCA was managed with radical surgery, resulting in a permanent colostomy. Researchers found that preoperative treatment with chemotherapy and concurrent radiation could achieve a pathologic complete response. After this observation, definitive therapy shifted from radical surgery to sphincter-preserving chemoradiation. Investigations into the necessity of chemotherapy and the optimal regimen found that chemotherapy with mitomycin-C and 5-fluorouracil is required for cure. Further studies evaluating the addition of induction or maintenance chemotherapy, monoclonal antibody therapy, or higher radiation doses have demonstrated no significant benefit to disease control. Advanced radiation delivery with intensity-modulated radiotherapy techniques is now considered the standard of care because of its prospectively determined, favorable acute toxicity profile compared with 3-dimensional conformal radiation. It is important to note that chemoradiation treatment response may be slow (up to 26 weeks) and should be assessed through serial clinical examinations. Today, surgical management of SCCA is reserved only for the lowest risk, early stage tumors or for recurrent/persistent disease. Current studies are evaluating radiation dose de-escalation in early stage disease and radiation dose escalation and the addition of immune checkpoint inhibitors in locally advanced cancers. In reviewing how and why modern-day treatment of SCCA was established, the objective of this report is to reenforce adherence to current treatment paradigms to assure the best possible outcomes for patients.

Benchmarking Outcomes for Definitive Treatment of Young-Onset, Locally Advanced Rectal Cancer.

PURPOSE: There has been an increase in the incidence of rectal cancer diagnosed in young adults (age < 50 years). We evaluated outcomes among young adults treated with pre-operative long course chemoradiation (CRT) and total mesorectal excision (TME). METHODS: The medical records of 219 patients, age 18-49, with non-metastatic, cT3-4, or cN1-2 rectal adenocarcinoma treated from 2000 to 2017 were reviewed for demographic and treatment characteristics, as well as pathologic and oncologic outcomes. The Kaplan-Meier test, log-rank test, and Cox regression analysis were used to evaluate survival outcomes. RESULTS: The median age at diagnosis was 44 years. CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n = 196), with FOLFOX (n = 115) as the predominant adjuvant chemotherapy. There was no difference in sex, stage, MSS/pMMR, or pCR by age (< 45 years [n = 111] vs. ≥ 45 years [n = 108]). The 5-year rates of DFS were 77.2% for all patients, 69.8% for age < 45 years and 84.7% for age ≥ 45 years (P = .01). The 5-year rates of OS were 89.6% for all patients, 85.1% for patients with age < 45 years and 94.3% for patients with age ≥ 45 years (P = .03). Age ≥ 45 years was associated with a lower risk of disease recurrence or death on multivariable Cox regression analysis (HR = 0.55, 95% CI 0.31-0.97, P = .04). CONCLUSION: Among young adults, patients with age < 45 years had lower rates of DFS and OS, compared to those with age ≥ 45 years. These outcomes could serve as a benchmark by which to evaluate newer treatment approaches.