Neoadjuvant Short- Vs. Long-Course Radiation for Locally Advanced Rectal Cancer: How to Choose.

OPINION STATEMENT: Over the past decades, the treatment of locally advanced rectal cancer has evolved dramatically due to improvements in diagnostic imaging, surgical technique, and the addition of radiotherapy and/or chemotherapy. Fractionation of neoadjuvant radiotherapy with or without concurrent chemotherapy remains the subject of discussion and the question multiple recent trials have aimed to answer. In light of recent data and concern for locoregional recurrence, our institution favors long-course chemoradiation in most cases, especially in low-lying primaries, threatened circumferential resection margin, consideration of non-operative management, or if the surgeon has concerns for resectability. Exceptions would include cases of oligometastatic disease planned for metastasectomy in which curative-intent treatment was pursued or if additional factors required a reduction in treatment time.

Anal Carcinoma, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Rectal Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a "watch-and-wait" nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

Fostering Radiation Oncology Physician Scientist Trainees Within a Diverse Workforce: The Radiation Oncology Research Scholar Track.

There is a need to foster future generations of radiation oncology physician scientists, but the number of radiation oncologists with sufficient education, training, and funding to make transformative discoveries is relatively small. A large number of MD/PhD graduates have entered he field of radiation oncology over the past 2 decades, but this has not led to a significant cohort of externally funded physician scientists. Because radiation oncologists leading independent research labs have the potential to make transformative discoveries that advance our field and positively affect patients with cancer, we created the Duke Radiation Oncology Research Scholar (RORS) Program. In crafting this program, we sought to eliminate barriers preventing radiation oncology trainees from becoming independent physician scientists. The RORS program integrates the existing American Board of Radiology Holman Pathway with a 2-year post-graduate medical education instructor position with 80% research effort at the same institution. We use a separate match for RORS and traditional residency pathways, which we hope will increase the diversity of our residency program. Since the inception of the RORS program, we have matched 2 trainees into our program. We encourage other radiation oncology residency programs at peer institutions to consider this training pathway as a means to foster the development of independent physician scientists and a diverse workforce in radiation oncology.

NCCN Guidelines Insights: Rectal Cancer, Version 6.2020.

The NCCN Guidelines for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy approach for localized rectal cancer; and biomarker-targeted therapy for metastatic colorectal cancer, with a focus on new treatment options for patients with BRAF V600E- or HER2 amplification-positive disease.

Evaluating treatment protocols for rectal squamous cell carcinomas: the Duke experience and literature.

BACKGROUND: Colorectal cancer is the third most common cancer in the United States and associated with significant morbidity and mortality. Within colorectal cancer histologies, squamous cell carcinomas (SCC) are rare compared to adenocarcinomas, with only about 200 cases reported to date. Because rectal SCC is rarely encountered, there is a lack of literature and clinical consensus surrounding its optimal treatment approach. Staging and management of SCC can be partly analogous to both rectal adenocarcinoma and anal canal SCC, which leads to a dilemma in how to best approach these patients. As large randomized prospective trials are unrealistic in the setting of this rare malignancy, this study evaluates an institutional experience and reviews the existing literature to help guide future management approaches. METHODS: This retrospective study compared various treatment regimens for rectal SCC patients treated at Duke University Medical Center from January 1, 1980 through December 31, 2016. Patients ≥18 years old with histologically confirmed, nonmetastatic rectal SCC were included. Due to small sample size, all statistical analyses were descriptive. For our systematic review, a comprehensive search of PubMed from 1933 to March 2018 was performed, with selected articles referenced to ensure all relevant publications were included. A qualitative analysis was performed to examine patient diagnoses, treatments, and disease- and treatment-related outcomes. RESULTS: Eight patients were included. Three patients underwent initial, curative attempt surgery and two of these patients required colostomy. With follow-up ranging from 7.1 to 31.5 months, one patient was alive with no evidence of disease while two developed local/regional recurrences. Five patients received definitive chemoradiation. Of these, three patients developed local/regional and/or metastatic recurrence. Two patients achieved complete response on imaging and currently remain disease-free (follow-up of 31.5 and 33.6 months). CONCLUSIONS: Although the review of our institutional experience is limited by small numbers, our analysis suggests that definitive chemoradiation therapy is the preferred treatment approach to rectal SCC based on improved disease-related outcomes, sphincter preservation and morbidity profiles. This conclusion is supported by a systematic literature review.

Multi-Institutional Analysis of Synchronous Prostate and Rectosigmoid Cancers.

Purpose: To perform a multi-institutional analysis of patients with synchronous prostate and rectosigmoid cancers. Materials and Methods: A retrospective review of Duke University and Durham Veterans Affairs Medical Center records was performed for men with both prostate and rectosigmoid adenocarcinomas from 1988 to 2017. Synchronous presentation was defined as symptoms, diagnosis, or treatment of both cancers within 12 months of each other. The primary study endpoint was overall survival. Univariate and multivariable Cox regression was performed. Results: Among 31,883 men with prostate cancer, 330 (1%) also had rectosigmoid cancer and 54 (16%) of these were synchronous. Prostate cancer was more commonly the initial diagnosis (59%). Fifteen (28%) underwent prostatectomy or radiotherapy before an established diagnosis of rectosigmoid cancer. Stage I, II-III, or IV rectosigmoid cancer was present in 26, 57, and 17% of men, respectively. At a median follow-up of 43 months, there were 18 deaths due rectosigmoid cancer and two deaths due to prostate cancer. Crude late grade ≥3 toxicities include nine (17%) gastrointestinal and six (11%) genitourinary. Two anastomotic leaks following low anterior resection occurred in men who received a neoadjuvant radiotherapy prostate dose of 70.6-76.4 Gy. Rectosigmoid cancer stages II-III (HR 4.3, p = 0.02) and IV (HR 16, p < 0.01) as well as stage IV prostate cancer (HR 31, p < 0.01) were associated with overall survival on multivariable analysis. Conclusions: Synchronous rectosigmoid cancer is a greater contributor to mortality than prostate cancer. Men aged ≥45 with localized prostate cancer should undergo colorectal cancer screening prior to treatment to evaluate for synchronous rectosigmoid cancer.

Long-term Consequences of Pelvic Irradiation: Toxicities, Challenges, and Therapeutic Opportunities with Pharmacologic Mitigators.

A percentage of long-term cancer survivors who receive pelvic irradiation will develop treatment-related late effects, collectively termed pelvic radiation disease. Thus, there is a need to prevent or ameliorate treatment-related late effects in these patients. Modern radiotherapy methods can preferentially protect normal tissues from radiation toxicities to permit higher doses to targets. However, concerns about chronic small bowel toxicity, for example, still constrain the prescription dose. This provides strong rationale for considering adding pharmacologic mitigators. Implementation of modern targeted radiotherapy methods enables delivery of focused radiation to target volumes, while minimizing dose to normal tissues. In prostate cancer, these technical advances enabled safe radiation dose escalation and better local tumor control without increasing normal tissue complications. In other pelvic diseases, these new radiotherapy methods have not resulted in the low probability of normal tissue damage achieved with prostate radiotherapy. The persistence of toxicity provides rationale for pharmacologic mitigators. Several new agents could be readily tested in clinical trials because they are being or have been studied in human patients already. Although there are promising preclinical data supporting mitigators, no clinically proven options to treat or prevent pelvic radiation disease currently exist. This review highlights therapeutic options for prevention and/or treatment of pelvic radiation disease, using pharmacologic mitigators. Successful development of mitigators would reduce the number of survivors who suffer from these devastating consequences of pelvic radiotherapy. It is important to note that pharmacologic mitigators to ameliorate pelvic radiation disease may be applicable to other irradiated sites in which chronic toxicity impairs quality of life.

Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial.

PURPOSE: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. METHODS: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. RESULTS: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, (P=0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P=0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). CONCLUSIONS: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

John Foster Dulles, his medical history and its impact on Cold War politics.

John Foster Dulles was the United States Secretary of State during the administration of President Dwight D Eisenhower. At the height of the Cold War, Dulles was Eisenhower's emissary, traveling over 450,000 international miles, leading United States foreign policy. In November of 1956, during an international crisis involving the Suez Canal, Dulles became ill and underwent an operation for a perforated colon cancer. During much of his impactful term as Secretary of State, Dulles was being treated for this cancer that ultimately resulted in his death in May of 1959. This paper highlights the medical care of John Foster Dulles and the global events during his illness.

Fluence Map Prediction Using Deep Learning Models - Direct Plan Generation for Pancreas Stereotactic Body Radiation Therapy.

Purpose: Treatment planning for pancreas stereotactic body radiation therapy (SBRT) is a difficult and time-consuming task. In this study, we aim to develop a novel deep learning framework to generate clinical-quality plans by direct prediction of fluence maps from patient anatomy using convolutional neural networks (CNNs). Materials and Methods: Our proposed framework utilizes two CNNs to predict intensity-modulated radiation therapy fluence maps and generate deliverable plans: (1) Field-dose CNN predicts field-dose distributions in the region of interest using planning images and structure contours; (2) a fluence map CNN predicts the final fluence map per beam using the predicted field dose projected onto the beam's eye view. The predicted fluence maps were subsequently imported into the treatment planning system for leaf sequencing and final dose calculation (model-predicted plans). One hundred patients previously treated with pancreas SBRT were included in this retrospective study, and they were split into 85 training cases and 15 test cases. For each network, 10% of training data were randomly selected for model validation. Nine-beam benchmark plans with standardized target prescription and organ-at-risk constraints were planned by experienced clinical physicists and used as the gold standard to train the model. Model-predicted plans were compared with benchmark plans in terms of dosimetric endpoints, fluence map deliverability, and total monitor units. Results: The average time for fluence-map prediction per patient was 7.1 s. Comparing model-predicted plans with benchmark plans, target mean dose, maximum dose (0.1 cc), and D95% absolute differences in percentages of prescription were 0.1, 3.9, and 2.1%, respectively; organ-at-risk mean dose and maximum dose (0.1 cc) absolute differences were 0.2 and 4.4%, respectively. The predicted plans had fluence map gamma indices (97.69 ± 0.96% vs. 98.14 ± 0.74%) and total monitor units (2,122 ± 281 vs. 2,265 ± 373) that were comparable to the benchmark plans. Conclusions: We develop a novel deep learning framework for pancreas SBRT planning, which predicts a fluence map for each beam and can, therefore, bypass the lengthy inverse optimization process. The proposed framework could potentially change the paradigm of treatment planning by harnessing the power of deep learning to generate clinically deliverable plans in seconds.

Small Bowel Adenocarcinoma, Version 1.2020, NCCN Clinical Practice Guidelines in Oncology.

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Role of pelvic chemoradiation therapy in patients with initially metastatic anal canal cancer: A National Cancer Database review.

BACKGROUND: Although the management of localized anal canal squamous cell carcinomas is well established, the role of pelvic chemoradiation (CRT) in the treatment of patients presenting with synchronous metastatic (stage IV) disease is poorly defined. This study used a national cancer database to compare the overall survival (OS) rates of patients with synchronous metastatic disease receiving CRT to the pelvis and patients treated with chemotherapy (CT) alone. METHODS: This study included adult patients with anal canal squamous cell carcinomas presenting with synchronous metastases diagnosed from 2004 to 2012. Multiple imputation and 2:1 propensity score matching were used to create a matched data set for testing. The proportional hazards model was used to estimate the hazard ratio (HR) for the effect of the treatment group on OS. With only patients in the matched data set, the OS of the treatment groups was estimated with the Kaplan-Meier method by treatment group. RESULTS: This study started with an unmatched data set of 978 patients, and 582 patients were selected for the matched data set: 388 in the CRT group and 194 in the CT-alone group. The HR for the group effect was 0.75 (95% confidence interval [CI], 0.61-0.92; P = .006). The median OS was 21.1 months in the CRT group (95% CI, 17.4-24.0 months) and 14.6 months in the CT group (95% CI, 12.2-18.4 months). The corresponding 5-year OS rates were 23% (95% CI, 18%-28%) and 14% (95% CI, 7%-21%), respectively. CONCLUSIONS: In this large series analyzing OS in patients with stage IV anal cancer, CRT was associated with improved OS in comparison with CT alone. Because of the lack of prospective data in this setting, this evidence will help to guide treatment approaches in this group of patients.

NRG Oncology/RTOG 0438: A Phase 1 Trial of Highly Conformal Radiation Therapy for Liver Metastases.

PURPOSE: This study aimed to determine the feasibility and maximally tolerated dose of hypofractionated, conformal radiation therapy (RT) in patients with liver metastases. METHODS AND MATERIALS: Nonsurgical patients with ≤5 liver metastases (sum of maximal diameter of all lesions ≤8 cm) were included in the study. There were 4 dose levels: 35 Gy, 40 Gy (starting level), 45 Gy, and 50 Gy, in 10 fractions. The clinical target volume included metastases identified on contrast computed tomography or magnetic resonance imaging with a 5-mm margin within the liver. The planning target volume margin ranged from 4 to 30 mm, depending on breathing motion. Dose-limiting toxicities were defined as RT-related grade ≥4 hepatic or gastrointestinal toxicities or thrombocytopenia occurring within 90 days of the start of RT. RESULTS: A total of 26 patients with metastases from colorectal (8 patients), breast (7 patients) and other malignancies (11 patients) were enrolled between November 2005 and December 2010. Twenty-three patients were evaluable (8, 7, and 8 on the 40, 45, and 50 Gy dose levels, respectively). Two patients assigned to 50 Gy received 35 Gy owing to normal tissue limits, so 2 additional patients were treated to 50 Gy. There were no dose-limiting toxicities on any of the dose levels. On the 45 Gy dose level, 1 patient developed reversible grade 3 enteritis (37 days from RT start) and diarrhea (22 days); another patient developed grade 3 lymphopenia (23 days). At the 50 Gy dose level, 1 patient had grade 3 hyperglycemia (74 days), and another patient developed grade 3 lymphopenia (13 days), colonic hemorrhage (325 days), and colonic gastrointestinal obstruction (325 days). With a potential median follow-up of 66.1 months (range, 34.6-89.0 months), no other late toxicities were observed. CONCLUSIONS: Treatment of liver metastases with 50 Gy in 10 fractions was feasible and safe in a multi-institutional setting.

Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Anal Carcinoma provide recommendations for the management of patients with squamous cell carcinoma of the anal canal or perianal region. Primary treatment of anal cancer usually includes chemoradiation, although certain lesions can be treated with margin-negative local excision alone. Disease surveillance is recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is essential for optimal patient care.

Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer. This portion of the guidelines focuses on the management of localized disease, which involves careful patient selection for curative-intent treatment options that sequence multimodality therapy usually comprised of chemotherapy, radiation, and surgical resection.