The Next Chapter in Immunotherapy and Radiation Combination Therapy: Cancer-Specific Perspectives.

Immunotherapeutic agents have revolutionized cancer treatment over the past decade. However, most patients fail to respond to immunotherapy alone. A growing body of preclinical studies highlights the potential for synergy between radiation therapy and immunotherapy, but the outcomes of clinical studies have been mixed. This review summarizes the current state of immunotherapy and radiation combination therapy across cancers, highlighting existing challenges and promising areas for future investigation.

Combinatorial Approaches for Chemotherapies and Targeted Therapies With Radiation: United Efforts to Innovate in Patient Care.

Combinatorial therapies consisting of radiation therapy (RT) with systemic therapies, particularly chemotherapy and targeted therapies, have moved the needle to augment disease control across nearly all disease sites for locally advanced disease. Evaluating these important combinations to incorporate more potent therapies with RT will aid our understanding of toxicity and efficacy for patients. This article discusses multiple disease sites and includes a compilation of contributions from expert Red Journal editors from each disease site. Leveraging improved systemic control with novel agents, we must continue efforts to study novel treatment combinations with RT.

Defining Minimum Treatment Parameters of Ablative Radiation Therapy in Patients With Hepatocellular Carcinoma: An Expert Consensus.

PURPOSE: External beam radiation therapy (EBRT) is a highly effective treatment in select patients with hepatocellular carcinoma (HCC). However, the Barcelona Clinic Liver Cancer system does not recommend the use of EBRT in HCC due to a lack of sufficient evidence and intends to perform an individual patient level meta-analysis of ablative EBRT in this population. However, there are many types of EBRT described in the literature with no formal definition of what constitutes "ablative." Thus, we convened a group of international experts to provide consensus on the parameters that define ablative EBRT in HCC. METHODS AND MATERIALS: Fundamental parameters related to dose, fractionation, radiobiology, target identification, and delivery technique were identified by a steering committee to generate 7 Key Criteria (KC) that would define ablative EBRT for HCC. Using a modified Delphi (mDelphi) method, experts in the use of EBRT in the treatment of HCC were surveyed. Respondents were given 30 days to respond in round 1 of the mDelphi and 14 days to respond in round 2. A threshold of ≥70% was used to define consensus for answers to each KC. RESULTS: Of 40 invitations extended, 35 (88%) returned responses. In the first round, 3 of 7 KC reached consensus. In the second round, 100% returned responses and consensus was reached in 3 of the remaining 4 KC. The distribution of answers for one KC, which queried the a/b ratio of HCC, was such that consensus was not achieved. Based on this analysis, ablative EBRT for HCC was defined as a BED10 ≥80 Gy with daily imaging and multiphasic contrast used for target delineation. Treatment breaks (eg, for adaptive EBRT) are allowed, but the total treatment time should be ≤6 weeks. Equivalent dose when treating with protons should use a conversion factor of 1.1, but there is no single conversion factor for carbon ions. CONCLUSIONS: Using a mDelphi method assessing expert opinion, we provide the first consensus definition of ablative EBRT for HCC. Empirical data are required to define the a/b of HCC.

Adaptive Lung Radiation Therapy in the Era of Immunotherapy: A Single-Center Retrospective Study.

Purpose: Treatment for locally advanced non-small cell lung cancer consists of concurrent chemoradiation followed by immunotherapy. Though this combination has been shown to have a benefit in both progression-free survival and overall survival, treatment is often limited by the development of pneumonitis. One way to mitigate toxicity is through adaptive radiation therapy, which does not currently have a standardized implementation in clinical practice. Methods and Materials: A single-center retrospective review of patients with locally advanced stage III or oligometastatic stage IV non-small cell lung cancer who were treated with chemoradiation with concurrent or subsequent immunotherapy from 2015 to 2020 was performed. Patients were stratified based on having 1 or more offline adapted plan. The aim of this study was to evaluate the association between dose-volume histogram values and common toxicities experienced during this treatment, including pneumonitis and esophagitis. Results: Twenty-five patients were included in the final analysis: 10 with adapted plans (AP), and 15 with nonadapted plans (NAP). Mean age at onset was 74 years. The most common histology was adenocarcinoma (N = 13). Five patients experienced pneumonitis: 2 in AP and 3 in NAP. Mann-Whitney U test of gross tumor volume sizes between AP (346.2 ± 269.7 cm3) and NAP (153.1 ± 99.6 cm3) was significant (P = .019). Multiple linear regression analysis with adjustment for covariates of pneumonitis versus plan adaptation (P = .106) and esophagitis versus plan adaptation (P = .59) did not demonstrate a significant difference in toxicity between the adapted and nonadaptive patients. Conclusions: Despite similar toxicities in both groups, the gross tumor volume size in the AP was more than double compared with NAP, suggesting that adaptive techniques provide a method for patients with larger target volumes to be treated without an observed difference in pneumonitis rates. These results suggest adaptive radiation therapy may have a role in mitigating toxicity experience from chemoradiation and immunotherapy and warrants further investigation.

Gender and the Receipt of the Association of Residents in Radiation Oncology Educator of the Year Award.

Purpose: We hypothesized that there may be a gender disparity in the receipt of the Association of Residents in Radiation Oncology (ARRO) Educator of the Year Award and sought to elucidate factors that contribute to differences in award receipt. Methods and Materials: Using a database provided by the American Society for Radiation Oncology, award recipients were identified from 2010 to 2022. Publicly available websites were accessed to obtain data regarding gender, years since residency graduation, percentage of female faculty, size of residency program, and program director designation. A 1-sample Z-test was used to assess whether the proportion of female ARRO award winners, defined as the proportion of female radiation oncology faculty members in the nominating universities that year, was significantly less than the population average. Secondary analyses used univariable binary logistic regression to identify global associations between gender, year since gradation, or program size. Results: The lowest proportion of female awardees occurred in 2013 (14.3%) and the greatest proportion in 2022 (30.6%). Compared with the proportion of female faculty members in nominating programs for the respective year, there were significantly fewer female awardees in 2010 (18% female awardees vs 32% female faculty members; P = .02) and 2013 (14% female awardees vs 31% female faculty members; P = .01). There was a statistically significant increase in female awardees during the study period (P < .01). On logistic regression analysis, large program size (≥10 residents) (odds ratio [OR], 6.86; 95% CI, 2.71-23.1; P < .001) and medium program size (5-9 residents) (OR, 4.05; 95% CI, 1.60-13.7; P < .001) were associated with a greater proportion of female awardees compared with small program size (1-4 residents). There was no association between awardee gender and years since graduation. Conclusions: A gender disparity was present in the receipt of ARRO Educator Awards. Residency chiefs, program directors, and chairs should work to ensure that a diverse slate of faculty is considered annually for the ARRO Educator Award.

Oral Carbon Monoxide Enhances Autophagy Modulation in Prostate, Pancreatic, and Lung Cancers.

Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas-entrapping material containing CO in a pre-clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

Identifying the optimal treatment strategy in patients with resectable non-cardia gastric cancer.

BACKGROUND: Multimodal treatment strategy including perioperative chemotherapy (PEC), postoperative chemoradiation therapy (POCR), and postoperative chemotherapy (POC) has been accepted as the standard of care in gastric cancer (GC). The ideal sequence and type of therapy remain undetermined. METHOD: The National Cancer Database was examined from 2006 to 2016 to identify patients with resectable non-cardia gastric cancer. Patient outcomes were compared based on the receipt of PEC, POCR, and POC. This comparison was repeated in a sub-group of patients who received optimal treatment. Optimal treatment was defined as initial chemotherapy within 45 days of diagnosis, resection within 45 days of diagnosis, negative margins, adjuvant chemotherapy within 90 days of resection and standard radiation dose (45 Gy). Kaplan-Meier test, log-rank test, and multivariable analysis (MVA) were performed. RESULTS: We identified 9589 patients. Median survival was greater in the PEC group followed by POCR and POC (60.6, 42.3, and 31.2 months, respectively). On MVA, factors associated with worse overall survival included age above median (≥ 63 years), Charlson-Deyo score of ≥ 1, non-academic/research program, poorly differentiated/undifferentiated grade, positive margins, and positive lymph nodes. Both PEC and POCR were associated with improved survival when compared to POC (HR 0.78 and 0.79; p < 0.001). When compared with PEC, no significant difference was noted with POCR (HR 1.01; p = 0.987). These results were maintained in optimally treated cohort (n = 3418). CONCLUSION: In patients with resectable non-cardia gastric cancer, both perioperative chemotherapy and postoperative chemoradiation therapy were associated with improved survival when compared to postoperative chemotherapy. No difference was noted between perioperative chemotherapy and postoperative chemoradiation therapy. These results were maintained in the optimally treated cohort.

Fixed and random effect selections in generalized linear mixed models.

Generalized linear mixed models are commonly used to describe relationships between correlated responses and covariates in medical research. In this paper, we propose a simple and easily implementable regularized estimation approach to select both fixed and random effects in generalized linear mixed model. Specifically, we propose to construct and optimize the objective functions using the confidence distributions of model parameters, as opposed to using the observed data likelihood functions, to perform effect selections. Two estimation methods are developed. The first one is to use the joint confidence distribution of model parameters to perform simultaneous fixed and random effect selections. The second method is to use the marginal confidence distributions of model parameters to perform the selections of fixed and random effects separately. With a proper choice of regularization parameters in the adaptive LASSO framework, we show the consistency and oracle properties of the proposed regularized estimators. Simulation studies have been conducted to assess the performance of the proposed estimators and demonstrate computational efficiency. Our method has also been applied to two longitudinal cancer studies to identify demographic and clinical factors associated with patient health outcomes after cancer therapies.

Role of Stereotactic Body Radiation Therapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC)is a common type of liver cancer with a poor prognosis, especially in patients with advanced stages or underlying liver disease. While surgical resection, liver transplantation, and ablation therapies have traditionally been the mainstay of treatment for HCC, radiation therapy has become increasingly recognized as an effective alternative, particularly for those who are not surgical candidates. Stereotactic Body Radiation Therapy (SBRT) is a highly precise form of radiation therapy that delivers very high doses of radiation to the tumor while sparing surrounding healthy tissue. Several studies have reported favorable outcomes with SBRT in HCC treatment. Moreover, SBRT can be used to treat recurrent HCC after prior treatment, offering a potentially curative approach in select cases. While SBRT has demonstrated its efficacy and safety in treating HCC, future studies are needed to further investigate the potential role of SBRT in combination with other treatments for HCC.

Combination of Immunotherapy and Radiation Therapy in Gastrointestinal Cancers: An Appraisal of the Current Literature and Ongoing Research.

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers.

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline.

PURPOSE: This joint guideline by American Society for Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) was initiated to review evidence and provide recommendations regarding the use of local therapy in the management of extracranial oligometastatic non-small cell lung cancer (NSCLC). Local therapy is defined as the comprehensive treatment of all known cancer-primary tumor, regional nodal metastases, and metastases-with definitive intent. METHODS: ASTRO and ESTRO convened a task force to address 5 key questions focused on the use of local (radiation, surgery, other ablative methods) and systemic therapy in the management of oligometastatic NSCLC. The questions address clinical scenarios for using local therapy, sequencing and timing when integrating local with systemic therapies, radiation techniques critical for oligometastatic disease targeting and treatment delivery, and the role of local therapy for oligoprogression or recurrent disease. Recommendations were based on a systematic literature review and created using ASTRO guidelines methodology. RESULTS: Based on the lack of significant randomized phase 3 trials, a patient-centered, multidisciplinary approach was strongly recommended for all decision-making regarding potential treatment. Integration of definitive local therapy was only relevant if technically feasible and clinically safe to all disease sites, defined as 5 or fewer distinct sites. Conditional recommendations were given for definitive local therapies in synchronous, metachronous, oligopersistent, and oligoprogressive conditions for extracranial disease. Radiation and surgery were the only primary definitive local therapy modalities recommended for use in the management of patients with oligometastatic disease, with indications provided for choosing one over the other. Sequencing recommendations were provided for systemic and local therapy integration. Finally, multiple recommendations were provided for the optimal technical use of hypofractionated radiation or stereotactic body radiation therapy as definitive local therapy, including dose and fractionation. CONCLUSIONS: Presently, data regarding clinical benefits of local therapy on overall and other survival outcomes is still sparse for oligometastatic NSCLC. However, with rapidly evolving data being generated supporting local therapy in oligometastatic NSCLC, this guideline attempted to frame recommendations as a function of the quality of data available to make decisions in a multidisciplinary approach incorporating patient goals and tolerances.

Pneumonitis in advanced non-small cell lung cancer: no interaction between immune checkpoint inhibition and radiation therapy.

Background: Radiation pneumonitis and immune-related pneumonitis have been studied independently, but little information has emerged on the interactions between radiation therapy (RT) and immune checkpoint inhibition (ICI). We examine whether RT and ICI are synergistic in causing pneumonitis. Methods: A retrospective cohort was assembled using the Surveillance, Epidemiology, and End Results-Medicare database, including Medicare beneficiaries diagnosed with American Joint Committee on Cancer 7th ed. (AJCC) stages IIIB-IV NSCLC between 2013-2017. Exposures to RT and ICI were determined by evaluating for treatment within 12 months of diagnosis (RT group and ICI group) and for a second exposure (e.g., ICI after RT) within 3 months after the first exposure (RT + ICI group). Untreated controls were matched to treated patients who were diagnosed in the same three-month window. A validated algorithm for identifying cases of pneumonitis in claims data was used to evaluate for the outcome within 6 months after treatment. The primary outcome was the relative excess risk due to interaction (RERI), a quantitative measure of additive interaction between two treatments. Results: There were 18,780 patients included in the analysis with 9,345 (49.8%), 7,533 (40.2%), 1,332 (7.1%), and 550 (2.9%) in the control, RT, ICI, and RT + ICI groups, respectively. Relative to controls, the hazards ratios of pneumonitis were 11.5 (95% CI: 7.9 to 17.0), 6.2 (95% CI: 3.8 to 10.3), and 10.7 (95% CI: 6.0 to 19.2) in the RT, ICI, and RT-ICI groups, respectively. The RERIs were -6.1 (95% CI: -13.1 to -0.6, P=0.97) and -4.0 (95% CI: -10.7 to 1.5, P=0.91) in the unadjusted and adjusted analyses, respectively, consistent with no evidence of additive interaction (RERI ≤0) between RT and ICI. Conclusions: In this study of Medicare beneficiaries with advanced NSCLC, RT and ICI were, at most, additive rather than synergistic in causing pneumonitis. Pneumonitis risk in patients treated with RT and ICI is not more than could be expected from each therapy alone.

A Review of Advances in Radiotherapy in the Setting of Esophageal Cancers.

Esophageal cancer is the eighth most common cancer worldwide and is the sixth most common cause of cancer-related mortality. The paradigm has shifted to include a multimodality approach with surgery, chemotherapy, targeted therapy (including immunotherapy), and radiation therapy. Advances in radiotherapy through techniques such as intensity modulated radiotherapy and proton beam therapy have allowed for the more dose homogeneity and improved organ sparing. In addition, recent studies of targeted therapies and predictive approaches in patients with locally advanced disease provide clinicians with new approaches to modify multimodality treatment to improve clinical outcomes.

Does non-metastatic gastric cancer of the cardia warrant a different treatment strategy?

BACKGROUND: Multimodal treatment strategies with surgery as its centerpiece have been accepted as the standard of care in nonmetastatic cardia gastric cancer (CGC). There remains a lack of consensus regarding the optimal multimodal treatment strategy. METHOD: We queried National Cancer Database from 2004 to 2016 to identify patients with resected nonmetastatic CGC who received perioperative chemotherapy (PEC), postoperative chemoradiation therapy (POCR), or postoperative chemotherapy (POC). A subgroup analysis was performed in optimally treated patients defined as initial chemotherapy within 45 days of diagnosis, resection within 45 days of diagnosis, negative margins, adjuvant chemotherapy within 90 days of resection, and standard radiation dose (45 Gy). Kaplan-Meier, Univariate analysis (UVA), and Multivariable analysis (MVA) were performed. RESULTS: We identified 2387 patients. Median survival was 38.8 months in the PEC group, 36 months in the POCR group, and 32.3 months in the POC group (p = 0.1025). On UVA, patients treated with PEC had an association with improved survival (HR, 0.83; p = 0.037) when compared with POC. On MVA, no significant difference was noted in overall survival (OS) between PEC, POCR, and POC, similar to subgroup analysis of optimally treated cohort. CONCLUSION: OS rate in nonmetastatic CGC is not significantly different between patients receiving PEC, POCR, or POC.

Consensus Quality Measures and Dose Constraints for Lung Cancer From the Veterans Affairs Radiation Oncology Quality Surveillance Program and ASTRO Expert Panel.

PURPOSE: For patients with lung cancer, it is critical to provide evidence-based radiation therapy to ensure high-quality care. The US Department of Veterans Affairs (VA) National Radiation Oncology Program partnered with the American Society for Radiation Oncology (ASTRO) as part of the VA Radiation Oncology Quality Surveillance to develop lung cancer quality metrics and assess quality of care as a pilot program in 2016. This article presents recently updated consensus quality measures and dose-volume histogram (DVH) constraints. METHODS AND MATERIALS: A series of measures and performance standards were reviewed and developed by a Blue-Ribbon Panel of lung cancer experts in conjunction with ASTRO in 2022. As part of this initiative, quality, surveillance, and aspirational metrics were developed for (1) initial consultation and workup; (2) simulation, treatment planning, and treatment delivery; and (3) follow-up. The DVH metrics for target and organ-at-risk treatment planning dose constraints were also reviewed and defined. RESULTS: Altogether, a total of 19 lung cancer quality metrics were developed. There were 121 DVH constraints developed for various fractionation regimens, including ultrahypofractionated (1, 3, 4, or 5 fractions), hypofractionated (10 and 15 fractionations), and conventional fractionation (30-35 fractions). CONCLUSIONS: The devised measures will be implemented for quality surveillance for veterans both inside and outside of the VA system and will provide a resource for lung cancer-specific quality metrics. The recommended DVH constraints serve as a unique, comprehensive resource for evidence- and expert consensus-based constraints across multiple fractionation schemas.

Locally Advanced Lung Cancer.

Consolidation immunotherapy after concurrent chemoradiation has improved five-year survival rates in unresectable, locally advanced lung cancer, but disease progression and treatment personalization remain challenges. New treatment approaches with concurrent immunotherapy and consolidative novel agents are being investigated and show promising efficacy data, but at the risk of additive toxicity. Patients with PD-L1 negative tumors, oncogenic driver mutations, intolerable toxicity, or limited performance status continue to require innovative therapies. This review summarizes historical data that galvanized new research efforts, as well as ongoing clinical trials that address the challenges of current therapeutic approaches for unresectable, locally advanced lung cancer.

A narrative review of genetic biomarkers in non-small cell lung cancer: an update and future perspectives.

Background and Objective: Lung cancer has long been the leading cause of cancer deaths in the United States. Lung cancer has a poor prognosis, and our understanding of who will maximally benefit from different therapies is incomplete. This article discusses genetic biomarkers that may help in this regard. Methods: From origin until February 25, 2022, PubMed database was searched for terms "non-small cell lung cancer", "genomics" and "biomarker", with special attention paid to literature published within the past 10 years. Search was language restricted to English. Additional literature was identified through hand searches of the references of retrieved literature. Key Content and Findings: The most robustly described biomarkers for non-small cell lung cancer (NSCLC) are assessment of specific gene mutations. These are currently used in clinical practice for both prediction and prognostication. Abnormal mutation status of STK11/LKB1 and KEAP1-NFE2L2 are associated with poor response to radiotherapy (RT), and STK11/LKB1 is further associated with resistance to PD-L1 immunotherapy. Abnormal TP53 is associated with decreased benefit from cisplatin in squamous cell carcinoma (SCC). In terms of prognostication, RB1 mutations are associated with decreased overall survival (OS) in NSCLC and KEAP1-NFE2L2 mutations are associated with increased local recurrence (LR).Additional work has focused on gene expression levels, as well as analysis of genetic factors and signaling molecules affecting the tumor microenvironment (TME). High levels of Rad51c and NFE2L2 are associated with resistance to chemotherapy, and high Rad51c levels are further associated with resistance to RT. High nuclear expression of ß-catenin has additionally been associated with poor RT response. Further, there is increasing evidence that some long non-coding RNAs (lncRNAs) may play a crucial role in regulation of tumor radiosensitivity. Much of this work has had promising early results but will require further validation before routine clinical use. Finally, there is evidence that quantification of some signaling molecules and microRNAs (miRNAs) may have clinical utility in predicting adverse outcomes in RT. Conclusions: An improved understanding of tumor genetics in NSCLC has led to the development of targeted therapies and improved prognostication. As more work is done in this field, more and more genetic biomarkers will become candidates for clinical use. Much work will be required to validate these findings in the clinical setting.