The Impact of the Gut Microbiome, Environment, and Diet in Early-Onset Colorectal Cancer Development.

Traditionally considered a disease common in the older population, colorectal cancer is increasing in incidence among younger demographics. Evidence suggests that populational- and generational-level shifts in the composition of the human gut microbiome may be tied to the recent trends in gastrointestinal carcinogenesis. This review provides an overview of current research and putative mechanisms behind the rising incidence of colorectal cancer in the younger population, with insight into future interventions that may prevent or reverse the rate of early-onset colorectal carcinoma.

Trends and Determinants of Location of Death Due to Colorectal Cancer in the United States : A Nationwide Study.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States (US); however, there are limited data on location of death in patients who die from CRC. We examined the trends in location of death and determinants in patients dying from CRC in the US. METHODS: We utilized the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database to extract nationwide data on underlying cause of death as CRC. A multinomial logistic regression was performed to assess associations between clinico-sociodemographic characteristics and location of death. RESULTS: There were 850,750 deaths due to CRC from 2003 to 2019. There was a gradual decrease in deaths in hospital, nursing home, or outpatient facility/emergency department over time and an increase in deaths at home and in hospice. Relative to White decedents, Black, Asian, and American Indian/Alaska Native decedents were less likely to die at home and in hospice compared with hospitals. Individuals with lower educational status also had a lower risk of dying at home or in hospice compared with in hospitals. CONCLUSIONS: The gradual shift in location of death of patients who die of CRC from institutionalized settings to home and hospice is a promising trend and reflects the prioritization of patient goals for end-of-life care by healthcare providers. However, there are existing sociodemographic disparities in access to deaths at home and in hospice, which emphasizes the need for policy interventions to reduce health inequity in end-of-life care for CRC.

Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer.

The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating T cells in early-onset colorectal cancer (EOCRC). To address this, we investigated T-cell subsets and performed gene expression immune profiling in sporadic EOCRC tumors and matched average-onset colorectal cancer (AOCRC) tumors. Left-sided colon and rectal tumors from 40 cases were analyzed; 20 EOCRC (<45 years) patients were matched 1:1 to AOCRC (70-75 years) patients by gender, tumor location, and stage. Cases with germline pathogenic variants, inflammatory bowel disease or neoadjuvant-treated tumors were excluded. For T cells in tumors and stroma, a multiplex immunofluorescence assay combined with digital image analysis and machine learning algorithms was used. Immunological mediators in the tumor microenvironment were assessed by NanoString gene expression profiling of mRNA. Immunofluorescence revealed no significant difference between EOCRC and AOCRC with regard to infiltration of total T cells, conventional CD4+ and CD8+ T cells, regulatory T cells, or γδ T cells. Most T cells were located in the stroma in both EOCRC and AOCRC. Immune profiling by gene expression revealed higher expression in AOCRC of the immunoregulatory cytokine IL-10, the inhibitory NK cell receptors KIR3DL3 and KLRB1 (CD161), and IFN-a7 (IFNA7). In contrast, the interferon-induced gene IFIT2 was more highly expressed in EOCRC. However, in a global analysis of 770 tumor immunity genes, no significant differences could be detected. T-cell infiltration and expression of inflammatory mediators are similar in EOCRC and AOCRC. This may indicate that the immune response to cancer in left colon and rectum is not related to age of onset and that EOCRC is likely not driven by immune response deficiency.

Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Versus the Standard of Care Imaging in the Diagnosis of Peritoneal Carcinomatosis.

OBJECTIVE: To compare positron emission tomography (PET)/magnetic resonance imaging (MRI) to the standard of care imaging (SCI) for the diagnosis of peritoneal carcinomatosis (PC) in primary abdominopelvic malignancies. SUMMARY BACKGROUND DATA: Identifying PC impacts prognosis and management of multiple cancer types. METHODS: Adult subjects were prospectively and consecutively enrolled from April 2019 to January 2021. Inclusion criteria were: 1) acquisition of whole-body contrast-enhanced (CE) 18F-fluorodeoxyglucose PET/MRI, 2) pathologically confirmed primary abdominopelvic malignancies. Exclusion criteria were: 1) greater than 4 weeks interval between SCI and PET/MRI, 2) unavailable follow-up. SCI consisted of whole-body CE PET/computed tomography (CT) with diagnostic quality CT, and/or CE-CT of the abdomen and pelvis, and/or CE-MRI of the abdomen±pelvis. If available, pathology or surgical findings served as the reference standard, otherwise, imaging followup was used. When SCI and PET/MRI results disagreed, medical records were checked for management changes. Follow-up data were collected until August 2021. RESULTS: One hundred sixty-four subjects were included, 85 (52%) were female, and the median age was 60 years (interquartile range 50-69). At a subject level, PET/MRI had higher sensitivity (0.97, 95% CI 0.86-1.00) than SCI (0.54, 95% CI 0.37-0.71), P < 0.001, without a difference in specificity, of 0.95 (95% CI 0.90-0.98) for PET/MRI and 0.98 (95% CI 0.93-1.00) for SCI, P » 0.250. PET/MRI and SCI results disagreed in 19 cases. In 5/19 (26%) of the discordant cases, PET/MRI findings consistent with PC missed on SCI led to management changes. CONCLUSION: PET/MRI improves detection of PC compared with SCI which frequently changes management.

Molecular Basis of Extramural Vascular Invasion (EMVI) in Colorectal Carcinoma.

BACKGROUND: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.

Patient Survival With ypT0N+ Following Neoadjuvant Therapy in Rectal Cancer.

BACKGROUND: After neoadjuvant therapy, pathologic analysis of rectal cancer resected specimens may show a complete response in the primary tissue cancer with residual tumor in the lymph nodes (ypT0N+). OBJECTIVES: The aim of this study was to describe the 5-year overall survival and factors associated with survival of ypT0N+ patients with rectal cancer who had neoadjuvant therapy followed by surgery and to compare these patients' survival with patients in other pathologic categories. DESIGN: We conducted a retrospective analysis. SETTINGS: We used the National Cancer Database. PATIENTS: We identified patients with rectal adenocarcinoma who underwent total neoadjuvant therapy or neoadjuvant chemoradiation followed by surgery between 2006 and 2016. Besides ypT0N+, 5 pathologic categories were identified: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, and ypT3-4N+. MAIN OUTCOME MEASURE: The primary outcome measure was 5-year overall survival. RESULTS: We included 30,751 patients with rectal adenocarcinoma. A total of 342 patients developed ypT0N+, of whom 181 (52.9%) received total neoadjuvant therapy. Among patients who received total neoadjuvant therapy, developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, ypT0N+ disease was associated with a higher 5-year overall survival than ypT3-4N+. There were no differences in 5-year overall survival between ypT0N+ and ypT3-4N0 or ypT1-2N+. Similar findings were noticed among patients who received neoadjuvant chemoradiation and adjuvant chemotherapy. For patients with ypT0N+, older age, male gender, and higher number of positive lymph nodes were all associated with a decrease in the overall survival. LIMITATIONS: Limitations include the retrospective nature of this study, lack of variables describing the chemotherapy and radiation regimens used, and paucity of data on disease-specific survival or recurrence. CONCLUSIONS: Developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, it was associated with a higher 5-year overall survival than ypT3-4N+. See Video Abstract at http://links.lww.com/DCR/B863 . SOBREVIDA DE LOS PACIENTES CON YPTN DESPUS DE LA TERAPIA NEOADYUVANTE EN EL CNCER DE RECTO: ANTECEDENTES:Después del tratamiento neoadyuvante en el cáncer de recto bajo, el análisis patológico de la pieza operatoria resecada, puede mostrar una respuesta patológica completa del tumor primario pero con tumor residual en los ganglios linfáticos (ypT0N+).OBJETIVOS:Describir la sobrevida general a 5 años y los factores asociados con la sobrevida de los pacientes ypT0N+ con cáncer de recto, que recibieron terapia neoadyuvante seguida de cirugía y comparar la sobrevida de estos pacientes con la de pacientes con otros estadios patológicos.DISEÑO:Realizamos un análisis retrospectivo.AJUSTES:Utilizamos la base de datos nacional del cáncer.PACIENTES:Identificamos pacientes con adenocarcinoma de recto que se sometieron a terapia neoadyuvante total, seguida de cirugía entre 2006 y 2016. Además de ypT0N +, se identificaron 5 categorías patológicas: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, e ypT3-4N+.PRINCIPAL MEDIDA DE RESULTADO:La medida de resultado principal fue la supervivencia general a 5 años.RESULTADOS:Se incluyeron 30.751 pacientes con adenocarcinoma de recto. Un total de 342 pacientes desarrollaron ypT0N+, de los cuales 181 (52,9%) recibieron terapia neoadyuvante total. Entre los pacientes que recibieron terapia neoadyuvante total, el desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, la enfermedad ypT0N+ se asoció con una supervivencia general a 5 años más alta que ypT3-4N+. No hubo diferencias en la supervivencia global a 5 años entre ypT0N+ y ypT3-4N0 o ypT1-2N+. Se observaron hallazgos similares entre los pacientes que recibieron terapia neoadyuvante y quimioterapia adyuvante. Para los pacientes con ypT0N+, la edad avanzada, el sexo masculino y un mayor número de ganglios linfáticos positivos se asociaron con una disminución en la supervivencia general.LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva del estudio, la falta de variables que describan los regímenes de quimioterapia y radiación utilizados y la escasez de datos sobre la supervivencia o la recurrencia específicas de la enfermedad.CONCLUSIONES:El desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, se asoció con una supervivencia global a 5 años más alta que ypT3-4N+. Consulte Video Resumen en http://links.lww.com/DCR/B863 . (Traducción-Dr. Rodrigo Azolas ).

Circulating Tumor DNA Predicts Pathologic and Clinical Outcomes Following Neoadjuvant Chemoradiation and Surgery for Patients With Locally Advanced Rectal Cancer.

PURPOSE: This study was designed to assess the ability of perioperative circulating tumor DNA (ctDNA) to predict surgical outcome and recurrence following neoadjuvant chemoradiation for locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Twenty-nine patients with newly diagnosed LARC treated between January 2014 and February 2018 were enrolled. Patients received long-course neoadjuvant chemoradiation prior to surgery. Plasma ctDNA was collected at baseline, preoperatively, and postoperatively. Next-generation sequencing was used to identify mutations in the primary tumor, and mutation-specific droplet digital polymerase chain reaction was used to assess mutation fraction in ctDNA. RESULTS: The median age was 54 years. The overall margin-negative, node-negative resection rate was 73% and was significantly higher among patients with undetectable preoperative ctDNA (n = 17, 88%) versus patients with detectable preoperative ctDNA (n = 9, 44%; P = .028). Undetectable ctDNA was also associated with more favorable neoadjuvant rectal scores (univariate linear regression, P = .029). Recurrence-free survival (RFS) was calculated for the subset (n = 19) who both underwent surgery and had postoperative ctDNA available. At a median follow-up of 20 months, patients with detectable postoperative ctDNA experienced poorer RFS (hazard ratio, 11.56; P = .007). All patients (4 of 4) with detectable postoperative ctDNA recurred (positive predictive value = 100%), whereas only 2 of 15 patients with undetectable ctDNA recurred (negative predictive value = 87%). CONCLUSION: Among patients treated with neoadjuvant chemoradiation for LARC, patients with undetectable preoperative ctDNA were more likely to have a favorable surgical outcome as measured by the rate of margin-negative, node-negative resections and neoadjuvant rectal score. Furthermore, we have confirmed prior reports indicating that detectable postoperative ctDNA is associated with worse RFS. Future prospective study is needed to assess the potential for ctDNA to assist with personalizing treatment for LARC.

Clinical impact of PET/MRI in oligometastatic colorectal cancer.

BACKGROUND: Oligometastatic colorectal cancer (CRC) is potentially curable and demands individualised strategies. METHODS: This single-centre retrospective study investigated if positron emission tomography (PET)/magnetic resonance imaging (MR) had a clinical impact on oligometastatic CRC relative to the standard of care imaging (SCI). Adult patients with oligometastatic CRC on SCI who also underwent PET/MR between 3/2016 and 3/2019 were included. The exclusion criterion was lack of confirmatory standard of reference, either surgical pathology, intraoperative gross confirmation or imaging follow-up. SCI consisted of contrast-enhanced (CE) computed tomography (CT) of the chest/abdomen/pelvis, abdominal/pelvic CE-MR, and/or CE whole-body PET/CT with diagnostic quality (i.e. standard radiation dose) CT. Follow-up was evaluated until 3/2020. RESULTS: Thirty-one patients constituted the cohort, 16 (52%) male, median patient age was 53 years (interquartile range: 49-65 years). PET/MR and SCI results were divergent in 19% (95% CI 9-37%) of the cases, with PET/MR leading to management changes in all of them. The diagnostic accuracy of PET/MR was 90 ± 5%, versus 71 ± 8% for SCI. In a pairwise analysis, PET/MR outperformed SCI when compared to the reference standard (p = 0.0412). CONCLUSIONS: These findings suggest the potential usefulness of PET/MR in the management of oligometastatic CRC.

Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer.

PURPOSE: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection. EXPERIMENTAL DESIGN: A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence. RESULTS: Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (n = 39) or completion of adjuvant therapy (n = 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 (P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 (P = 0.18); PPV = 53.9%]. CONCLUSIONS: Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.See related commentary by Bent and Kopetz, p. 5449.

Refusal of surgery for colon cancer: Sociodemographic disparities and survival implications among US patients with resectable disease.

BACKGROUND: We aimed to identify factors associated with refusal of surgery among patients with colon cancer. METHODS: This 2004-2016 NCDB retrospective study identified AJCC stage I-III colon cancer patients who were recommended surgery. Multivariable logistic regression defined adjusted odds ratios of refusing treatment, with sociodemographic and clinical covariates. Treatment propensity-adjusted Cox proportional hazard ratios defined differential survival stratified by clinical stage, controlling for potential confounders. RESULTS: Of 170,594 patients recommended surgery, 1116 refused. Increased rates of surgery refusal were associated with older age, African American race, CDCC>3, and female sex. Decreased rates of surgery refusal were associated with higher income and private insurance. Stratifying by stage, refusal rates among African Americans remained disparately high. Refusal of surgery was associated with worse overall survival. CONCLUSIONS: Disparate rates of refusal of surgery for resectable colon cancer by race and other sociodemographic factors highlight potential treatment adherence reinforcement beneficiaries, necessitating further study of shared decision-making.

Ten-year survival after pathologic complete response in rectal adenocarcinoma.

BACKGROUND: Multimodal treatment is the standard of care for rectal adenocarcinoma, with a subset of patients achieving a pathologic complete response (pCR). While pCR is associated with improved overall survival (OS), long-term data on patients with pCR is limited. METHODS: This is a single institution retrospective cohort study of all patients with clinical stages II/III rectal adenocarcinoma who underwent neoadjuvant chemoradiation therapy and operative resection (January 1, 2004-December 31, 2017). PCR was defined as no tumor identified in the rectum or associated lymph nodes by final pathology. RESULTS: Of 370 patients in this cohort, 50 had a pCR (13.5%). For pCR patients, 5-year disease-free survival (DFS) was 92%, 5-year OS was 95%. Twenty-six patients had surgery > 10 years before the study end date, of which 20 had an OS > 10 years (77%) with median OS 12.1 years and 95% alive to date (19/20). Of the 50 pCR patients, there was a single recurrence in the lung at 44.3 months after proctectomy which was surgically resected. CONCLUSION: For patients with rectal adenocarcinoma that undergo neoadjuvant chemoradiation and surgical resection, pCR is associated with excellent long-term DFS and OS. Many patients live greater than 10 years with no evidence of disease recurrence.

Infiltrating Tumor Border Configuration is a Poor Prognostic Factor in Stage II and III Colon Adenocarcinoma.

INTRODUCTION: Tumor border configuration (TBC) is a prognostic factor in colorectal adenocarcinoma; however, the significance of TBC is not well-documented in colon adenocarcinoma alone. OBJECTIVE: Our aim was to study the effect of TBC on overall and disease-free survival in stage II and III colon adenocarcinoma. METHODS: We included patients with stage II and III colon adenocarcinoma who were surgically treated at a tertiary medical center between 2004 and 2015, to ensure long-term follow-up. Patients were stratified into four groups based on stage and TBC. A Cox regression was used to model the relationship of groups while accounting for relevant confounders. RESULTS: The cohort consisted of 700 patients (371 stage II and 329 stage III). Infiltrating TBC was statistically significantly associated with stage (p < 0.001) and extramural vascular invasion (p < 0.001), but not histologic grade (p = 0.7). Compared with pushing TBC, infiltrating TBC increased the hazard of death by a factor of 1.8 [95% confidence interval (CI) 1.4-2.4; p < 0.001] and 1.7 (95% CI 1.3-2.2; p < 0.001). The hazard of death in patients with stage II disease (infiltrating TBC) or stage III disease (pushing TBC) was not significantly different (adjusted hazard ratio 1.1, 95% CI 0.7-1.7; p = 0.8). CONCLUSION: Infiltrating TBC is a high-risk feature in patients with stage II and III colon adenocarcinoma. Stage II disease patients with infiltrating TBC and who are node-negative should be considered for adjuvant chemotherapy.

Using Smartphones to Capture Novel Recovery Metrics After Cancer Surgery.

Importance: Patient-generated health data captured from smartphone sensors have the potential to better quantify the physical outcomes of surgery. The ability of these data to discriminate between postoperative trends in physical activity remains unknown. Objective: To assess whether physical activity captured from smartphone accelerometer data can be used to describe postoperative recovery among patients undergoing cancer operations. Design, Setting, and Participants: This prospective observational cohort study was conducted from July 2017 to April 2019 in a single academic tertiary care hospital in the United States. Preoperatively, adults (age ≥18 years) who spoke English and were undergoing elective operations for skin, soft tissue, head, neck, and abdominal cancers were approached. Patients were excluded if they did not own a smartphone. Exposures: Study participants downloaded an application that collected smartphone accelerometer data continuously for 1 week preoperatively and 6 months postoperatively. Main Outcomes and Measures: The primary end points were trends in daily exertional activity and the ability to achieve at least 60 minutes of daily exertional activity after surgery among patients with vs without a clinically significant postoperative event. Postoperative events were defined as complications, emergency department presentations, readmissions, reoperations, and mortality. Results: A total of 139 individuals were approached. In the 62 enrolled patients, who were followed up for a median (interquartile range [IQR]) of 147 (77-179) days, there were no preprocedural differences between patients with vs without a postoperative event. Seventeen patients (27%) experienced a postoperative event. These patients had longer operations than those without a postoperative event (median [IQR], 225 [152-402] minutes vs 107 [68-174] minutes; P < .001), as well as greater blood loss (median [IQR], 200 [35-515] mL vs 25 [5-100] mL; P = .006) and more follow-up visits (median [IQR], 2 [2-4] visits vs 1 [1-2] visits; P = .002). Compared with mean baseline daily exertional activity, patients with a postoperative event had lower activity at week 1 (difference, -41.6 [95% CI, -75.1 to -8.0] minutes; P = .02), week 3 (difference, -40.0 [95% CI, -72.3 to -3.6] minutes; P = .03), week 5 (difference, -39.6 [95% CI, -69.1 to -10.1] minutes; P = .01), and week 6 (difference, -36.2 [95% CI, -64.5 to -7.8] minutes; P = .01) postoperatively. Fewer of these patients were able to achieve 60 minutes of daily exertional activity in the 6 weeks postoperatively (proportions: week 1, 0.40 [95% CI, 0.31-0.49]; P < .001; week 2, 0.49 [95% CI, 0.40-0.58]; P = .003; week 3, 0.39 [95% CI, 0.30-0.48]; P < .001; week 4, 0.47 [95% CI, 0.38-0.57]; P < .001; week 5, 0.51 [95% CI, 0.42-0.60]; P < .001; week 6, 0.73 [95% CI, 0.68-0.79] vs 0.43 [95% CI, 0.33-0.52]; P < .001). Conclusions and Relevance: Smartphone accelerometer data can describe differences in postoperative physical activity among patients with vs without a postoperative event. These data help objectively quantify patient-centered surgical recovery, which have the potential to improve and promote shared decision-making, recovery monitoring, and patient engagement.

Cost-effectiveness of Short-Course Radiation Therapy vs Long-Course Chemoradiation for Locally Advanced Rectal Cancer.

Importance: Although both short-course radiotherapy and long-course chemoradiotherapy have been practiced in parallel for more than 15 years, no cost-effectiveness analysis comparing these 2 approaches in patients with locally advanced rectal cancer has been published. Objective: To analyze the cost-effectiveness of short-course radiotherapy vs long-course chemoradiotherapy for the treatment of patients with locally advanced rectal cancer. Design, Setting, and Participants: This economic evaluation used a cost-effectiveness model simulating 10-year outcomes for 1 million hypothetical patients aged 65 years with locally advanced rectal cancer treated with either short-course radiotherapy or long-course chemoradiotherapy, followed by surgery and chemotherapy. Utilities and probabilities from the literature and costs from the Healthcare Bluebook and Medicare fee schedules were used to determine incremental cost-effectiveness ratios. It was assumed that long-course chemoradiotherapy would result in higher rates of low anterior resection (LAR). To model preference-sensitive care, a 2-way sensitivity analysis was conducted in which the utilities of the no-evidence-of-disease (NED) states with LAR and abdominoperineal resection (APR) were simultaneously varied. The analysis was repeated for patients with distal rectal tumors. Analysis was conducted from January to October 2018. Exposures: Short-course radiotherapy and long-course chemoradiotherapy. Main Outcomes and Measures: Incremental cost-effectiveness ratios. Results: Short-course radiotherapy was the cost-effective strategy compared with long-course chemoradiotherapy (incremental cost-effectiveness ratio, $133 495 per quality-adjusted life-year). Two-way sensitivity analysis revealed that the cost-effective approach for a given patient depended on the utilities for the NED-LAR and NED-APR states. Assuming that a greater proportion of patients with locally advanced distal tumors undergoing long-course chemoradiotherapy (39%) would proceed to LAR compared with those treated with short-course radiotherapy (19%), long-course chemoradiotherapy was the cost-effective approach (incremental cost-effectiveness ratio, $61 123 per quality-adjusted life-year). Conclusions and Relevance: Short-course radiotherapy was the cost-effective strategy compared with long-course chemoradiotherapy for patients with locally advanced rectal cancer. The cost-effectiveness of short-course radiotherapy vs long-course chemoradiotherapy was sensitive to the utilities of the NED-LAR and NED-APR health states, highlighting the importance of care that is sensitive to patient preference. Long-course chemoradiotherapy was the cost-effective approach for patients with distal tumors.

Histologic and Outcome Study Supports Reclassifying Appendiceal Goblet Cell Carcinoids as Goblet Cell Adenocarcinomas, and Grading and Staging Similarly to Colonic Adenocarcinomas.

Goblet cell carcinoid tumors are amphicrine tumors whose biological behavior ranges from indolent to highly aggressive, depending on tumor grade. Current grading systems for these tumors are based on identifying an adenocarcinoma arising in the setting of a goblet cell carcinoid tumor, which distinguishes this tumor from other gastrointestinal tract adenocarcinomas. Because goblet cell tumors are predominantly tumors of mucin secreting cells, we propose that they be classified as goblet cell adenocarcinomas, and graded using a methodology that has parallels in colorectal adenocarcinoma grading. We graded a large series of goblet cell adenocarcinomas by assessing the proportion of the tumor that demonstrates tubular or clustered growth. Histologic grade correlated with overall survival independent of stage, with median overall survival of 204, 86, and 29 months for low-grade, intermediate-grade, and high-grade goblet cell adenocarcinomas, respectively. Tumor stage also correlated with overall survival. We also graded the tumors according to previously proposed grading systems, and found that these systems are valid, in that they segregate patients according to prognosis.

Long-term outcomes and toxicities of a large cohort of anal cancer patients treated with dose-painted IMRT per RTOG 0529.

PURPOSE: To describe the outcomes and toxicities of the largest cohort to date of patients with anal squamous cell carcinoma uniformly treated with concurrent chemoradiation using dose-painted intensity modulated radiation therapy (DP-IMRT) according to RTOG 0529. METHODS AND MATERIALS: We identified 99 eligible patients with anal cancer who were treated at our institution with definitive chemoradiation using DP-IMRT between 2005 and 2015 per RTOG 0529 dosing guidelines. Primary study endpoints included event-free survival (defined as recurrence, colostomy, or death) and overall survival. Secondary endpoints were treatment duration and acute and late toxicity. RESULTS: At a median follow-up of 49 months (range, 2-114 months), 92% of patients had a clinical complete response. Fifteen percent underwent colostomy, including 4 pretreatment colostomies, 6 planned abdominoperineal resections (APRs), 4 salvage APRs, and 1 APR for treatment-related complications. Thirteen patients developed local recurrence, of whom 6 developed synchronous metastatic disease. The 4-year overall survival was 85.8%, and 4-year event-free survival was 75.5%. Median treatment duration was 43 days (range, 10-68 days). The overall rate of non-hematologic grade 3+ acute and grade 2+ late toxicities was 20% and 15%, respectively. CONCLUSIONS: Long-term outcomes and tolerability were excellent In the largest cohort to date of patients with anal cancer who received DP-IMRT prescribed per RTOG 0529.