Impact of definitive radiotherapy on metabolic response measured with 68Ga-PSMA-PET/CT in patients with intermediate-risk prostate cancer.

PURPOSE: To assess the early metabolic response of the primary tumor using Gallium-68 (68Ga)-labeled-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-PET/CT), as well as the relationship between PSMA change in the primary tumor and PSA response after definitive radiotherapy (RT), either alone or in combination with androgen deprivation therapy (ADT) in intermediate risk prostate cancer (IR-PCa) patients. METHODS: The clinical data of 71 IR-PCa patients treated with RT alone (36 patients, 50.7%) or RT and ADT (35 patients, 49.3%) were retrospectively analyzed. The difference between pre- and Posttreatment primary tumor PSMA expression and serum PSA values measured 4 months after completion of treatment were compared between treatment arms. Correlation between primary tumor metabolic response and serum PSA changes was analyzed. RESULTS: The median duration between pre- and Posttreatment 68Ga-PSMA-PET/CT for the entire patient population was 6.9 months (range, 5.6-8.4 months), and it was similar in both treatment arms. A decrease in primary tumor maximum standardized uptake value (SUVmax) was seen in 66 patients (93.0%), with a median value of 61.2%, which is significantly lower in patients undergoing RT alone than those undergoing RT and ADT (45.1 ± 30.6% vs. 59.1 ± 24.7%; p = 0.004). The complete metabolic response rate was significantly higher in patients undergoing RT and ADT than those treated with RT alone (40% vs. 0%; p < 0.001). Although moderate and positive correlation between pretreatment SUVmax and oosttreatment SUVmax was observed, there was no significant correlation between SUV change and PSA change. For patients treated with RT and ADT, posttreatment SUVmax was significantly lower and SUV change was significantly higher in patients with PSA nadir than in those without. CONCLUSIONS: Our preliminary results show that RT, with or without ADT, significantly reduces primary tumor SUVmax and serum PSA levels. Nonetheless, our findings indicate that early treatment response using 68Ga-PSMA-PET/CT is not feasible for those treated with RT alone, and it may only be useful in better distinguishing patients with and without PSA nadir for those who received both RT and ADT.

PIK3/Akt/mTOR pathway alterations in metastatic castration-sensitive prostate cancer.

BACKGROUND: Alterations in the PIK3/Akt/mTOR pathway are commonly seen in metastatic castration-sensitive prostate cancer (mCSPC), however their role in outcomes is unknown. We aim to evaluate the prognostic significance as well as the genetic landscape of PIK3/Akt/mTOR pathway alteration in mCSPC. METHODS: Fourhundred and seventy-two patients with mCSPC were included who underwent next generation sequencing. PIK3/Akt/mTor pathway alterations were defined as mutations in Akt1, mTOR, PIK3CA, PIK3CB, PIK3R1, PTEN, TSC1, and TSC2. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of castration resistant prostate cancer (tdCRPC), and overall survival (OS). Kaplan-Meier analysis was performed and Cox regression hazard ratios (HR) were calculated. RESULTS: One hundred and fifty-two (31.9%) patients harbored a PIK3/Akt/mTOR pathway alteration. Median rPFS and tdCRPC were 23.7 and 21.0 months in PIK3/Akt/mTOR altered compared to 32.8 (p = 0.08) and 32.1 months (p = 0.002) in wildtype tumors. On multivariable analysis PIK3/Akt/mTOR pathway alterations were associated with tdCRPC (HR 1.43, 95% CI, 1.05-1.94, p = 0.02), but not rPFS [Hazard ratio (HR) 1.20, 95% confidence interval (CI), 0.90-1.60, p = 0.21]. PIK3/Akt/mTOR pathway alterations were more likely to be associated with concurrent mutations in TP53 (40% vs. 28%, p = 0.01) and TMPRSS2-ERG (37% vs. 26%, p = 0.02) than tumors without PIK3/Akt/mTOR pathway alterations. Concurrent mutations were typically associated with shorter median times to rPFS and tdCRPC. DAVID analysis showed p53 signaling and angiogenesis pathways were enriched in PIK3/Akt/mTOR pathway altered tumors while beta-catenin binding and altered BRCA pathway were enriched in PIK3/Akt/mTOR pathway wildtype tumors. CONCLUSIONS: PIK3/Akt/mTOR pathway alterations were common in mCSPC and associated with poorer prognosis. The genetic landscape of PIK3/Akt/mTOR pathway altered tumors differed from wildtype tumors. Additional studies are needed to better understand and target the PIK3/Akt/mTOR pathway in mCSPC.

Local Excision for Early-Stage Rectal Adenocarcinomas.

ABSTRACT: Although total mesorectal excision (TME) remains the standard of care for rectal cancer, including early-stage T1/T2 rectal adenocarcinoma, local excision may be warranted for these early-stage tumors in a select group of patients who may decline surgery or may be nonoptimal surgical candidates. Operative approaches for transanal local excision include transanal endoscopic microsurgery or transanal minimally invasive surgery for tumors <4 cm, occupying <40% of the rectal circumference and <10 cm from the dentate line. The use of preoperative chemoradiation therapy may help to downstage tumors and allow for more limited resections, and chemoradiation may also be employed postoperatively. Local excision approaches appear to result in improved quality of life compared with TME, but limited resections may also compromise survival rates compared with TME. Multidisciplinary management and shared decision-making can allow for the desired patient outcomes.

Evaluation of Treatment Outcomes of Prostate Cancer Patients With Lymph Node Metastasis Treated With Definitive Radiotherapy: Comparative Analysis of PSMA PET/CT and Conventional Imaging.

PURPOSE: We investigated the impact of prostate-specific membrane antigen (PSMA) PET/CT compared with conventional imaging on treatment outcomes for node-positive prostate cancer (PCa) patients who underwent androgen deprivation therapy (ADT) and external radiotherapy (RT). PATIENTS AND METHODS: A multicentric, retrospective study recruited patients with node-positive PCa patients who underwent conventional radiological evaluation or PSMA PET/CT and received ADT and RT at 3 hospitals from 2009 to 2021 were enrolled. Patients underwent prostate and pelvis RT, accompanied by a minimum of 6 months of ADT. The primary endpoints were progression-free survival (PFS) and PCa-specific survival (PCSS). Cox regression analyzed the association of survival with potential prognostic factors, whereas logistic regression identified the predictors of bone and lymph node metastasis. RESULTS: The median follow-up time was 64.0 months. The majority of patients (64.1%) underwent PSMA PET/CT for staging. The 5-year rates of PFS and PCSS were 63.7% and 83.7%, respectively. Disease progression was observed in 90 patients (36.3%). In multivariable analysis, ADT duration of less than 24 months and post-RT prostate-specific antigen (PSA) nadir were prognostic for PFS. Early clinical T stage and PSMA PET/CT predicted better PCSS. Patients staged with PSMA PET/CT had exhibited significantly higher 5-year PCSS rates than compared with those staged with conventional imaging (95.1% vs 76.9%; P = 0.01). Shorter ADT duration and higher PSA levels after RT independently predicted bone metastasis in multivariable logistic regression. Advanced T stage, shorter ADT duration, and higher PSA levels after neoadjuvant ADT predicted nonregional lymph node recurrence. CONCLUSIONS: ADT with pelvis RT is an effective treatment option for node-positive PCa patients. The PSMA PET/CT outperformed conventional imaging in PCSS, emphasizing the importance of precise clinical staging for patients undergoing definitive RT.

Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND AND OBJECTIVE: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC. METHODS: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure. KEY FINDINGS AND CLINICAL IMPLICATIONS: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles. CONCLUSIONS AND CLINICAL IMPLICATIONS: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism. PATIENT SUMMARY: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Prognostic Significance of Immune Cell Infiltration in Muscle-invasive Bladder Cancer Treated with Definitive Chemoradiation: A Secondary Analysis of RTOG 0524 and RTOG 0712.

Chemoradiation therapy (CRT) is a treatment for muscle-invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers to CRT using 70 pretreatment tumor samples from prospective trials of MIBC (NRG/RTOG 0524 and 0712). Disease-free survival (DFS) and overall survival (OS) were estimated via the Kaplan-Meier method and stratified by genes correlated with immune cell activation. Cox proportional-hazards models were used to assess group differences. Clustering of gene expression profiles revealed that the cluster with high immune cell content was associated with longer DFS (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.26-1.10; p = 0.071) and OS (HR 0.48, 95% CI 0.24-0.97; p = 0.040) than the cluster with low immune cell content. Higher expression of T-cell infiltration genes (CD8A and ICOS) was associated with longer DFS (HR 0.40, 95% CI 0.21-0.75; p = 0.005) and OS (HR 0.49, 95% CI 0.25-0.94; p = 0.033). Higher IDO1 expression (IFNγ signature) was also associated with longer DFS (HR 0.44, 95% CI 0.24-0.88; p = 0.021) and OS (HR 0.49, 95% CI 0.24-0.99; p = 0.048). These findings should be validated in prospective CRT trials that include biomarkers, particularly for trials incorporating immunotherapy for MIBC. PATIENT SUMMARY: We analyzed patient samples from two clinical trials (NRG/RTOG 0524 and 0712) of chemoradiation for muscle-invasive bladder cancer using a novel method to assess immune cells in the tumor microenvironment. Higher expression of genes associated with immune activation and high overall immune-cell content were associated with better disease-free survival and overall survival for patients treated with chemoradiation.

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.

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.

TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.

PURPOSE: Despite well-informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure-function and clinical impact of TP53 mutations in mCSPC. PATIENTS AND METHODS: We performed an international retrospective review of men with mCSPC who underwent next-generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression-free survival (rPFS) and overall survival (OS) evaluated with Kaplan-Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR-246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t-tests and ANOVA. RESULTS: Dominant-negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI]: 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI: 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner. CONCLUSIONS: DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.

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.

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.

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.

Metastasis-Directed Therapy for Oligometastatic Castration-Sensitive Prostate Cancer: An Alternative to ADT?

PURPOSE OF REVIEW: The standard treatment of patients with metastatic prostate cancer is systemic treatment with androgen-deprivation therapy (ADT). The spectrum-based model of metastatic disease includes the presence of an oligometastatic state, an intermediary between localized and widespread metastatic disease, in which radical local treatment might improve systemic control. Our purpose is to review the literature on metastasis-directed therapy in the treatment of oligometastatic prostate cancer. RECENT FINDINGS: Several prospective clinical trials have reported improvements in ADT-free survival and progression-free survival with metastasis-directed therapy of oligometastatic prostate cancer. Retrospective studies have found improvements in oncologic outcomes for patients with oligometastatic prostate cancer undergoing metastasis-directed therapy, and several recent prospective clinical trials have confirmed these results. Advancements in imaging as well as an understanding of the genomics of oligometastatic prostate cancer may allow for better patient selection for metastasis-directed therapy and the potential for cure in selected patients.

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.

Waiting for Big Changes in Limited-Stage Small-Cell Lung Cancer: For Now, More of the Same.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Concurrent chemoradiotherapy remains central to the treatment of limited-stage small-cell lung cancer (SCLC). SCLC is one of the few tumors treated with twice-daily radiotherapy (RT) in the primary definitive setting, a regimen that was established when Intergroup 0096 demonstrated its superiority over once-daily RT. However, questions remained about the optimal chemoradiotherapy regimen given the low RT dose used in the once-daily RT arm of Intergroup 0096. CALGB 30610/RTOG 0538 and CONVERT attempted to establish whether dose-escalated once-daily RT was superior to twice-daily RT in limited-stage SCLC. Although both studies showed similar survival between treatment regimens, once-daily RT was not found to be superior to twice-daily RT, and trial design limited the ability to conclude dose-escalated once-daily RT as noninferior to twice-daily RT. Thus, twice-daily RT with concurrent chemotherapy remains a standard of care in limited-stage SCLC.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Conclusion: Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.