Patient-reported outcomes (PROs) in NRG Oncology RTOG 0436: a phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for esophageal cancer treated without surgery.

PURPOSE/OBJECTIVES: NRG/RTOG 0436 evaluated cetuximab added to chemoradiation (CRT) for non-operative esophageal cancer management. PRO objectives assessed improvement in the FACT-Esophageal cancer subscale (ECS), version 4, with cetuximab, and if improved ECS correlated with clinical complete response (cCR). MATERIALS/METHODS: Patients were randomized to cisplatin/paclitaxel/radiation ± cetuximab. Overall survival (OS) was the primary endpoint, with a 420 patient target, which also provided 82% power to detect ≥ 15 increase in the proportion of cetuximab patients with ECS improvement from baseline to 6-8 weeks post-CRT; α = 0.05, using a χ2 test. Improvement in ECS and its Swallowing and Eating Indices (SI, EI) was defined as 5, 4 and 2 point increases, respectively, from baseline to 6-8 weeks post-CRT. Univariate logistic regression assessed if cCR was associated with improved ECS. RESULTS: This study was stopped early for not meeting a pre-specified OS endpoint and did not show survival benefit. Of 420 planned patients, 344 enrolled and 281 consented to PROs. ECS was completed by 261 (93%) at baseline, 173 (66%) 6-8 weeks post-CRT, and 117 (64%) at 1 year. At 6-8 weeks, patients receiving CRT + Cetuximab didn't have improved ECS; they experienced a lower proportion of improvement compared to standard CRT (37% vs. 53%; P = 0.04). The proportion of CRT patients with improvement in SI was 9% higher than with cetuximab, but not statistically significant (39% vs. 30%, P = 0.22). There was no association between treatment and EI. When examining ECS scores at 1 year by cCR vs. residual disease, a higher proportion of cCR patients improved, but not statistically significant (48% vs. 45%, P = 0.74). CONCLUSIONS: The addition of cetuximab to CRT for the nonoperative management of esophageal cancer did not improve PROs.

Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma.

BACKGROUND: Many studies show significantly improved survival after R0 resection compared with R1 resection in pancreatic adenocarcinoma (PAC); however, the effect of neoadjuvant chemoradiation (NACRT) on this association is unknown. OBJECTIVE: The aim of this study was to evaluate the prognostic significance of positive surgical margins (SMs) after NACRT compared with upfront surgery + adjuvant therapy in PAC. METHODS: All cases of surgically resected PAC at a single institution were reviewed from 1996 to 2014; patients treated with palliative intent, metastatic disease, and biliary/ampullary tumors were excluded. The primary endpoint was overall survival (OS). RESULTS: Overall, 300 patients were included; 134 patients received NACRT with concurrent 5-fluorouracil or gemcitabine followed by surgery, and 166 patients received upfront surgery (+ adjuvant chemotherapy in 72% of patients and RT in 65%); 31% of both groups had a positive SM (+SM). The median OS for patients with a +SM or negative SM (-SM) was 26.6 and 31.6 months, respectively for NACRT, and 12.0 and 24.5 months, respectively, for upfront surgery. OS was significantly improved with -SM compared with +SM in both groups (p = 0.006). When resection yielded +SM, NACRT patients had improved OS compared with upfront surgery patients (p < 0.001). On multivariable analysis, +SM in the upfront surgery group (hazard ratio [HR] 2.94, 95% confidence interval [CI] 2.04-4.24; p < 0.001) and older age (HR 1.01, 95% CI 1.00-1.03, per year; p = 0.007) predicted worse OS. +SM in the NACRT group was not associated with worse OS (HR 1.09, 95% CI 0.72-1.65; p = 0.70). CONCLUSION: Patients with a positive margin after NACRT and surgery had longer survival compared with patients with a positive margin after upfront surgery. NACRT should be strongly considered for patients at high risk of R1 resections.

Initial Clinical Experience With Novel Directional Low-Dose Rate Brachytherapy for Retroperitoneal Sarcoma.

BACKGROUND: A novel Palladium-103 low-dose rate (LDR) brachytherapy device was developed to provide dose-escalation to the tumor bed after resection while shielding adjacent tissues. This multicenter report describes the initial experience with this device in patients with retroperitoneal sarcoma (RPS). MATERIALS AND METHODS: Patients with recurrent RPS, prior radiotherapy, and/or concern for positive margins were considered. An LDR brachytherapy dose of 20-60 Gy was administered, corresponding to biologically effective dose values of 15-53 Gy and equivalent dose values of 12-43 Gy. RESULTS: Six patients underwent implantation at four institutions. Of these, five had recurrent disease in the retroperitoneum or pelvic sidewall, one had untreated locally advanced leiomyosarcoma, two had prior external beam radiation therapy at the time of initial diagnosis, and four received neoadjuvant external beam radiation therapy plus brachytherapy. The device was easily implanted and conformed to the treatment area. Median follow-up was 16 mo; radiation was delivered to the at-risk margin with minimal irradiation of adjacent structures. No local recurrences at the site of implantation, device migration, or radiation-related toxicities were observed. CONCLUSIONS: The novel LDR directional brachytherapy device successfully delivered a targeted dose escalation to treat RPS high-risk margins. Lack of radiation-related toxicity demonstrates its safety.

Impact of PET/CT for Restaging Patients With Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiation.

BACKGROUND: A major challenge in identifying candidates for nonoperative management of locally advanced rectal cancer is predicting pathologic complete response (pCR) following chemoradiation. We evaluated pre- and post-CRT PET-CT imaging to predict pCR and prognosis in this set of patients undergoing resection after neoadjuvant therapy. METHODS: We retrospectively identified patients from 2002 to 2015 with locally advanced rectal cancer who underwent CRT, pre- and post-CRT PET-CT imaging, and resection. Univariate and multivariate analysis was performed and receiver operating characteristic (ROC) curves were generated to evaluate the association of PET-CT characteristics with pCR and survival. ROC curves were generated to define optimal cutoff points for predictive PET-CT characteristics. RESULTS: 125 patients were included. pCR rate was 28%, and follow-up was 48 mo. On multivariable analysis, patients who had a pCR had lower median post-CRT maximal standardized uptake value (SUVmax) (3.2 versus 5.2, P = 0.009) and higher median %SUV decrease (72 versus 58%, P = 0.009). ROC curves were generated for %SUVmax decrease (AUC = 0.70) and post-CRT SUV (AUC = 0.69). Post-CRT SUVmax <4.3 and %SUVmax decrease of >66% were equally predictive of pCR with a sensitivity of 65%, specificity of 72%, PPV of 44%, and NPV of 86%. Median 5-y overall and relapse-free survival were improved for patients with post-CRT SUV <4.3 (OS: 86 versus 66%, P = 0.01; RFS: 75 versus 52%, P = 0.01) or %SUV decrease of >66% (OS, 82 versus 66%, P = 0.05; RFS, 75 versus 54%, P = 0.01). CONCLUSIONS: PET/CT may be useful in identifying patients who did not achieve pCR, as well as overall survival in patients undergoing CRT for rectal cancer. Patients with a post-CRT SUV of >4.3 should be considered for operative management, as an estimated 86% of these patients will not have a pCR.

Predictive Value of Leukocyte- and Platelet-Derived Ratios in Rectal Adenocarcinoma.

BACKGROUND: Advances in treatment of rectal cancer have improved survival, but there is variability in response to therapy. Recent data suggest the utility of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in predicting survival. Our aim was to examine these ratios in rectal cancer patients and determine whether any association exists with overall survival (OS). METHODS: Using prospectively maintained institutional data, a query was completed for clinical stage II-III rectal adenocarcinoma patients treated from 2002 to 2016. We included patients who had a complete blood count collected before neoadjuvant chemoradiation (pre-CRT) and again before surgery (post-CRT). The LMR, NLR, and PLR were calculated for the pre-CRT and post-CRT time points. Potential cutpoints associated with OS differences were determined using maximally selected rank statistics. Survival curves were compared using log-rank tests and were adjusted for age and stage using Cox regression. RESULTS: A total of 146 patients were included. Cutpoints were significantly associated with OS for pre-CRT ratios but not for post-CRT ratios. Within the pretreatment group, a "low" (<2.86) LMR was associated with decreased OS (log-rank P = 0.004). In the same group, a "high" (>4.47) NLR and "high" PLR (>203.6) were associated with decreased OS (log-rank P < 0.001). With covariate adjustment for age, and separately for final pathologic stage, the associations between OS and LMR, NLR, and PLR each retained statistical significance. CONCLUSIONS: If obtained before the start of neoadjuvant chemoradiation, LMR, NLR, and PLR values are accurate predictors of 5-y OS in patients with locally advanced rectal adenocarcinoma.

Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma.

Cholangiocarcinomas are rare biliary tract tumors that are often challenging to diagnose and treat. Cholangiocarcinomas are generally categorized as intrahepatic or extrahepatic depending on their anatomic location. The majority of patients with cholangiocarcinoma do not have any of the known or suspected risk factors and present with advanced disease. The optimal evaluation and management of patients with cholangiocarcinoma requires thoughtful integration of clinical information, imaging studies, cytology and/or histology, as well as prompt multidisciplinary evaluation. The current review focuses on recent advances in the diagnosis and treatment of patients with cholangiocarcinoma and, in particular, on the role of endoscopy, surgery, transplantation, radiotherapy, systemic therapy, and liver-directed therapies in the curative or palliative treatment of these individuals. Cancer 2016;122:1349-1369. © 2016 American Cancer Society.

Patterns and predictors of failure following tri-modality therapy for locally advanced esophageal cancer.

BACKGROUND: Although tri-modality therapy is an acceptable standard of care in patients with locally advanced esophageal cancer, data regarding patterns of failure is lacking. We report bi-institutional patterns of failure experience treating patients using tri-modality therapy. MATERIALS AND METHODS: We retrospectively reviewed patients who underwent chemoradiation followed by esophagectomy between 2006 and 2011 at two NCI-designated cancer centers. First failure sites were categorized as local, regional nodal, or distant. Statistical analysis was performed using Fisher's exact test, non-parametric Wilcoxon rank-sum test, and multiple logistic regression. Kaplan-Meier curves were generated for relapse-free survival (RFS) and overall survival. RESULTS: A total of 132 patients met the inclusion criteria with a median age of 62 (range 36-80) and median follow-up of 28 months (range 4-128). There were a total of six (4.5%) local, 13 (10%) regional nodal, and 32 (23.5%) distant failures. Local failure was correlated with fewer lymph nodes (LN) assessed (p = 0.01) and close/positive margins (p < 0.01). Regional nodal failure was correlated with fewer LN assessed (p < 0.01) and larger pretreatment tumor size (p = 0.04). Patients with ≤13 LN evaluated had an inferior locoregional RFS versus patients with >13 LN evaluated (p = 0.003). Distant recurrence was correlated with higher pathologic nodal stage (p < 0.001), ulceration (p = 0.017), perineural invasion (p = 0.029), residual disease (p = 0.004), and higher post-treatment PET SUV max (p = 0.049). Patients with a pathologic complete response (OR 0.19, 95% CI 0.05-0.68) were less likely to experience distant recurrence. CONCLUSION: Tumor and treatment factors may predict for failure in patients undergoing tri-modality therapy for locally advanced esophageal cancer. Further data is needed to identify patterns of failure in these patients.

Association of treatment factors with surgical outcomes in tri-modality therapy for esophageal cancer.

BACKGROUND AND OBJECTIVES: To identify the impact of the interval between chemoradiation to surgery on morbidity and mortality in patients undergoing tri-modality therapy for esophageal cancer. METHODS: Eighty-five patients completed chemoradiation followed by esophagectomy between 2006 and 2011. The interval between completion of chemoradiation and surgery was calculated for each patient. We evaluated the association of quartiles and 3-week groups with morbidity and mortality using logistic regression. Other treatment and clinical factors were also assessed. RESULTS: A total of 59 patients(69%) experienced at least one complication. When examining specific complications, patients with pulmonary complications had a longer mean time interval from chemoradiation to surgery (P = 0.02). Linear regression showed an association between longer interval between chemoradiation to surgery and hospital length of stay (LOS) >14 days when analyzing by both interval quartile (P = 0.04) and 3-week intervals (P = 0.04). On multivariable analysis, increased time interval predicted for pulmonary complications (P < 0.01) and LOS >14 days (P = 0.03). When examining other treatment factors, squamous cell histology (P = 0.02) also predicted for a hospital length of stay >14 days. CONCLUSIONS: Factors such as interval between completion of chemoradiation and surgery and squamous cell histology may be associated with surgical morbidity. Further data is warranted to confirm these findings.

Neoadjuvant chemoradiation and duration of chemotherapy before surgical resection for pancreatic cancer: does time interval between radiotherapy and surgery matter?

BACKGROUND: Neoadjuvant chemoradiation and chemotherapy provided for borderline or locally advanced, potentially resectable pancreatic adenocarcinoma improves resectability rates. Response to therapy is also an important prognostic factor. There are no data in the literature regarding optimal time interval or duration of chemotherapy after chemoradiation before surgery, and pathologic response rates. Using our database, we evaluated these relationships and the effect on overall and progression-free survival. METHODS: We retrospectively analyzed the records of 83 patients who underwent neoadjuvant chemoradiation for locally advanced, potentially resectable, and borderline resectable pancreatic cancers before definitive resection. We divided patients into three groups according to time interval between completion of chemoradiation and resection: group A (0-10 weeks), group B (11-20 weeks), and group C (>20 weeks). After chemoradiation, patients underwent ongoing chemotherapy before resection. Pathologic response was defined as major (>95% fibrosis), partial (50-94% fibrosis), or minor (<50% fibrosis). RESULTS: There were 56 patients in group A, 17 patients in group B, and 10 patients in group C. Patients in groups B and C were significantly more likely to experience a major response than group A (p < 0.013). Patients in group C had significantly increased median progression-free and overall survival (p < 0.05). Multivariable classification and regression tree analysis demonstrated pathologic response to be the only significant factor in overall survival. CONCLUSIONS: Patients who underwent a prolonged time interval after neoadjuvant chemoradiation with ongoing chemotherapy were more likely to have an improved pathologic response at time of surgical resection, which was associated with improved median overall survival.

Impact of preoperative therapy on patterns of recurrence in pancreatic cancer.

BACKGROUND: A theoretical advantage of preoperative therapy in pancreatic adenocarcinoma is that it facilitates the early treatment of micrometastases and reduces postoperative systemic recurrence. METHODS: Medical records of 309 consecutive patients undergoing resection of adenocarcinoma in the head of the pancreas were reviewed. Survival was calculated using the Kaplan-Meier method. Associations between preoperative therapy and patterns of recurrence were determined using chi-squared analysis. RESULTS: Preoperative therapy was administered to 108 patients and upfront surgery was performed in 201 patients. Preoperative therapy was associated with a significantly longer median disease-free survival of 14 months compared with 12 months in patients submitted to upfront surgery (P = 0.035). The rate of local disease as a component of first site of recurrence was significantly lower with preoperative therapy (11.3%) than with upfront surgery (22.9%) (P = 0.016). Preoperative therapy was associated with a lower rate of hepatic metastasis (21.7%) than upfront surgery (34.3%) (P = 0.026). Preoperative therapy did not affect rates of peritoneal or pulmonary metastasis. CONCLUSIONS: Preoperative therapy for pancreatic cancer was associated with longer disease-free survival and lower rates of local and hepatic recurrences. These data support the use of preoperative therapy to reduce systemic and local failures after resection.

Survival and Toxicity in Patients With Unresectable or Inoperable Biliary Tract Cancers With Ablative Radiation Therapy Versus Nonablative Chemoradiation.

Purpose: Conventional chemoradiation (CCRT) is inadequately effective for the treatment of unresectable or inoperable biliary tract cancers (UIBC). Ablative radiation therapy (AR), typically defined as a biologically effective dose (BED) ≥80.5 Gy, has shown some promise in terms of local control and survival in these patients. We compare the efficacy and toxicity of AR to non-AR in UIBC patients. Methods and Materials: Patients with UIBC treated with stereotactic body radiation therapy (SBRT; n = 18) or CCRT (n = 28) between 2006 and 2021 were retrospectively analyzed. The associations of treatment, BED groups, selected characteristics with overall survival (OS), progression-free survival (PFS), and local control were estimated separately using Cox proportional hazards regression. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: Median dose fractionation was 60 Gy in 5 fractions (median BED, 127 Gy) for SBRT and 50 Gy in 25 fractions (median BED, 64 Gy) for CCRT. The median follow-up of the entire cohort was 11.5 months. The 1-year OS rate was 62% for BED <80.5 versus 66% for BED ≥80.5 (P = .069). The 1-year PFS rate was 24% for BED <80.5 and 29% for BED ≥80.5 (P = .050). The 1-year local control rate was 20% for BED <80.5 and 41% for BED ≥80.5 (P = .097). BED as a continuous variable (P = .013), BED ≥100 Gy (P = .044), and race (white versus nonwhite) (P = .037) were associated with improved overall mortality. BED ≥80.5 Gy (P = .046), smaller tumor size (<5 cm; P = .038) and N0 disease (P <.0001) were associated with improved disease progression rates. Local control was improved in patients with N0 disease compared with N1 disease (P <.0001). Both treatments were well tolerated; there was no difference in acute and late toxicity between AR and non-AR. Conclusions: In this review, there was improved PFS with BED ≥80.5 Gy with a trend toward OS benefit. BED ≥80.5 Gy was achieved mostly through SBRT and was well tolerated. AR could be considered a more effective treatment modality than CCRT in patients with UIBC.

Factors Associated With Racial and Ethnic Disparities in Locally Advanced Rectal Cancer Outcomes.

Importance: Hispanic and non-Hispanic Black patients receiving neoadjuvant therapy and surgery for locally advanced rectal cancer (LARC) achieve less favorable clinical outcomes than non-Hispanic White patients, but the source of this disparity is incompletely understood. Objective: To assess whether racial and ethnic disparities in treatment outcomes among patients with LARC could be accounted for by social determinants of health and demographic, clinical, and pathologic factors known to be associated with treatment response. Design, Setting, and Participants: The National Cancer Database was interrogated to identify patients with T3 to T4 or N1 to N2 LARC treated with neoadjuvant therapy and surgery. Patients were diagnosed between January 1, 2004, and December 31, 2017. Data were culled from the National Cancer Database from July 1, 2022, through December 31, 2023. Exposure: Neoadjuvant therapy for rectal cancer followed by surgical resection. Main Outcomes and Measures: The primary outcome was the rate of pathologic complete response (pCR) following neoadjuvant therapy. Secondary outcomes were rate of tumor downstaging and achievement of pN0 status. Results: A total of 34 500 patient records were reviewed; 21 679 of the patients (62.8%) were men and 12 821 (37.2%) were women. The mean (SD) age at diagnosis was 59.7 (12.0) years. In terms of race and ethnicity, 2217 patients (6.4%) were Hispanic, 2843 (8.2%) were non-Hispanic Black, and 29 440 (85.3%) were non-Hispanic White. Hispanic patients achieved tumor downstaging (48.9% vs 51.8%; P = .01) and pN0 status (66.8% vs 68.8%; P = .02) less often than non-Hispanic White patients. Non-Hispanic Black race, but not Hispanic ethnicity, was associated with less tumor downstaging (odds ratio [OR], 0.86 [95% CI, 0.78-0.94]), less frequent pN0 status (OR, 0.91 [95% CI, 0.83-0.99]), and less frequent pCR (OR, 0.81 [95% CI, 0.72-0.92]). Other factors associated with reduced rate of pCR included rural location (OR, 0.80 [95% CI, 0.69-0.93]), lack of or inadequate insurance (OR for Medicaid, 0.86 [95% CI, 0.76-0.98]; OR for no insurance, 0.65 [95% CI, 0.54-0.78]), and treatment in a low-volume center (OR for first quartile, 0.73 [95% CI, 0.62-0.87]; OR for second quartile, 0.79 [95% CI, 0.70-0.90]; OR for third quartile, 0.86 [95% CI, 0.78-0.94]). Clinical and pathologic variables associated with a decreased pCR included higher tumor grade (OR, 0.58 [95% CI, 0.49-0.70]), advanced tumor stage (OR for T3, 0.56 [95% CI, 0.42-0.76]; OR for T4, 0.30 [95% CI, 0.22-0.42]), and lymph node-positive disease (OR for N1, 0.83 [95% CI, 0.77-0.89]; OR for N2, 0.73 [95% CI, 0.65-0.82]). Conclusions and Relevance: The findings of this cohort study suggest that disparate treatment outcomes for Hispanic and non-Hispanic Black patients are likely multifactorial in origin. Future investigation into additional social determinants of health and biological variables is warranted.

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts.

Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment. Our ex vivo research demonstrates that PLDR, in combination with chemotherapy, promotes a shift from tumor-promoting to tumor-suppressing properties in a key component of the pancreatic cancer microenvironment we called CAFu (cancer-associated fibroblasts and selfgenerated extracellular matrix functional units). This beneficial effect translates to reduced desmoplasia (fibrous tumor expansion) and suggests PLDR's potential to improve total neoadjuvant therapy effectiveness. To comprehensively assess this functional shift, we developed the HOST-Factor, a single score integrating multiple biomarkers. This tool provides a more accurate picture of CAFu function compared to individual biomarkers and could be valuable for guiding and monitoring future therapeutic strategies. Our findings support the ongoing NCT04452357 clinical trial testing PLDR safety and TME normalization potential in pancreatic cancer patients. The HOST-Factor will be used in samples collected from this trial to validate its potential as a key tool for personalized medicine in this aggressive disease.

Comparing Lifestyle Modifications and the Magnitude of Their Associated Benefit on Cancer Mortality.

Many cancers are associated with poor diet, lack of physical activity, and excess weight. Improving any of these three lifestyle factors would likely reduce cancer deaths. However, modifications to each of these-better nutrition, enhanced activity and fitness, and loss of extra body fat-have different effect sizes on cancer mortality. This review will highlight the relative benefit that each lifestyle change, enacted prior to a diagnosis of cancer, might impart on cancer-related deaths, as well as attempt to quantify the changes required to derive such a benefit. The review relies primarily on epidemiological data, with meta-analyses serving as the backbone for comparisons across interventions and individual studies within the larger meta-analyses providing the data necessary to form more quantitative conclusions. The reader can then use this information to better understand, recommend, and implement behaviors that might ultimately reduce cancer mortality. Of all the interventions, it seems clear that exercise, specifically improving cardiorespiratory fitness, is the best way to decrease the risk of dying from cancer.

Understanding the Challenges Faced by Esophageal and Gastroesophageal Junction Cancer Survivors.

The primary aim of this study is to characterize long-term quality of life (QOL) in patients with esophageal and gastroesophageal junction (EGEJ) cancers who underwent curative intent treatment. EGEJ survivors were recruited to participate in a one-time cross-sectional survey study using validated questionnaires assessing QOL. Chart review was conducted for patient demographics and clinical characteristics. Spearman correlation coefficients, Wilcoxon signed-rank test, and Fisher's exact test were used to assess relationships between patient characteristics and long-term outcomes. QOL was relatively high in this sample, as evidenced by high median scores on the functional scales and low median scores in the symptom domains of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, with an overall median global health score of 75.0 (range 66.7-83.3). Patients using opiates at the time of survey reported lower role functioning (P = .004), social functioning (P = .052), and overall global health (P = .041). Younger patients had significantly higher rates of reflux (P = .019), odynophagia (P = .045), choking (P = .005), and cough (P = .007). Patients using opiates or of younger age had lower QOL and higher symptoms in this cohort of long-term EGEJ survivors.

Source, co-occurrence, and prognostic value of PTEN mutations or loss in colorectal cancer.

Somatic PTEN mutations are common and have driver function in some cancer types. However, in colorectal cancers (CRCs), somatic PTEN-inactivating mutations occur at a low frequency (~8-9%), and whether these mutations are actively selected and promote tumor aggressiveness has been controversial. Analysis of genomic data from ~53,000 CRCs indicates that hotspot mutation patterns in PTEN partially reflect DNA-dependent selection pressures, but also suggests a strong selection pressure based on protein function. In microsatellite stable (MSS) tumors, PTEN alterations co-occur with mutations activating BRAF or PI3K, or with TP53 deletions, but not in CRC with microsatellite instability (MSI). Unexpectedly, PTEN deletions are associated with poor survival in MSS CRC, whereas PTEN mutations are associated with improved survival in MSI CRC. These and other data suggest use of PTEN as a prognostic marker is valid in CRC, but such use must consider driver mutation landscape, tumor subtype, and category of PTEN alteration.

NCI Rectal-Anal Task Force consensus recommendations for design of clinical trials in rectal cancer.

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.