Current treatment and future directions in the management of anal cancer.

Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with appropriate treatment, which has evolved significantly over the last several decades. Before the 1970s, SCCA was managed with radical surgery, resulting in a permanent colostomy. Researchers found that preoperative treatment with chemotherapy and concurrent radiation could achieve a pathologic complete response. After this observation, definitive therapy shifted from radical surgery to sphincter-preserving chemoradiation. Investigations into the necessity of chemotherapy and the optimal regimen found that chemotherapy with mitomycin-C and 5-fluorouracil is required for cure. Further studies evaluating the addition of induction or maintenance chemotherapy, monoclonal antibody therapy, or higher radiation doses have demonstrated no significant benefit to disease control. Advanced radiation delivery with intensity-modulated radiotherapy techniques is now considered the standard of care because of its prospectively determined, favorable acute toxicity profile compared with 3-dimensional conformal radiation. It is important to note that chemoradiation treatment response may be slow (up to 26 weeks) and should be assessed through serial clinical examinations. Today, surgical management of SCCA is reserved only for the lowest risk, early stage tumors or for recurrent/persistent disease. Current studies are evaluating radiation dose de-escalation in early stage disease and radiation dose escalation and the addition of immune checkpoint inhibitors in locally advanced cancers. In reviewing how and why modern-day treatment of SCCA was established, the objective of this report is to reenforce adherence to current treatment paradigms to assure the best possible outcomes for patients.

Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

Comparison of partial-breast irradiation and intraoperative radiation to whole-breast irradiation in early-stage breast cancer patients: a Kaplan-Meier-derived patient data meta-analysis.

PURPOSE: Partial breast irradiation (PBI) and intraoperative radiation (IORT) represent alternatives to whole breast irradiation (WBI) following breast conserving surgery. However, data is mixed regarding outcomes. We therefore performed a pooled analysis of Kaplan-Meier-derived patient data from randomized trials to evaluate the hypothesis that PBI and IORT have comparable long-term rates of ipsilateral breast tumor recurrence as WBI. METHODS: In February, 2023, PubMed, EMBASE and Cochrane Central were systematically searched for randomized phase 3 trials of early-stage breast cancer patients undergoing breast-conserving surgery with PBI or IORT as compared to WBI. Time-to-event outcomes of interest included ipsilateral breast tumor recurrence (IBTR), overall survival (OS) and distant disease-free survival (DDFS). Statistical analysis was performed with R Statistical Software. RESULTS: Eleven randomized trials comprising 15,460 patients were included; 7,675 (49.6%) patients were treated with standard or moderately hypofractionated WBI, 5,413 (35%) with PBI and 2,372 (15.3%) with IORT. Median follow-up was 9 years. PBI demonstrated comparable IBTR risk compared with WBI (HR 1.20; 95% CI 0.95-1.52; p = 0.12) with no differences in OS (HR 1.02; 95% CI 0.90-1.16; p = 0.70) or DDFS (HR 1.15; 95% CI 0.81-1.64; p = 0.43). In contrast, patients treated with IORT had a higher IBTR risk (HR 1.46; 95% CI 1.23-1.72; p < 0.01) compared with WBI with no difference in OS (HR 0.98; 95% CI 0.84-1.14; p = 0.81) or DDFS (HR 0.91; 95% CI 0.76-1.09; p = 0.31). CONCLUSION: For patients with early-stage breast cancer following breast-conserving surgery, PBI demonstrated no difference in IBTR as compared to WBI while IORT was inferior to WBI with respect to IBTR.

Exercise oncology clinical trials during treatments: a commentary to address the safety concerns of human subjects regulatory reviewers and committees.

Exercise oncology clinical trials contribute to the advancement of our scientific knowledge and to the safety and care of patients diagnosed with cancer. Nevertheless, regulatory reviewers and committees may not be familiar with the well-documented long-term health benefits and safety of the regular practice of physical activity. Moreover, they may not see how the benefits outweigh the risks in the context where patients diagnosed with cancer are typically seen as vulnerable. Therefore, we would like to provide a purpose-built overview of exercise oncology clinical trials for members involved in institutional review committees, including the Scientific Review Committee (SRC), the Institutional Review Board (IRB), and the Data Safety Monitoring Committee (DSMC) to facilitate a greater understanding of the safety and benefits of physical activity during cancer treatments. Communication is key to improve the success of exercise oncology clinical trials, which are vital for patients diagnosed with cancer.

Impact of Clinical Trial Design on Recruitment of Racial and Ethnic Minorities.

Knowledge related to how oncology treatment trial design influences enrollment of racial and ethnic minorities is limited. Rigorous identification of clinical trial design parameters that associate favorably with minority accrual provides educational opportunities for individuals interested in designing more representative treatment trials. We identified oncology trials with a minimum of 10 patients at an NCI-Designated Comprehensive Cancer Center from 2010 to 2021. We defined a study endpoint of racial and ethnic minority accrual greater than zero. Multivariable logistic regression was used to determine whether co-variables predicted our study endpoint. P-values of less than 0.05 were considered significant. A total of 352 cancer trials met eligibility criteria. These studies enrolled a total of 7981 patients with a total of 926 racial and ethnic minorities leading to a median enrollment of 10%. Trials open in community sites (yes versus no) were more likely to have a minority patient (OR, 2.21; 95% CI, 1.02-4.96) as well as pilot/phase I studies compared to phase II/III (OR, 3.19; 95% CI, 1.34-8.26). Trials incorporating immunotherapy (yes versus no) were less likely to have a minority patient (OR, 0.47; 95% CI, 0.23-0.94). Trials open in community sites as well as early phase treatment studies were more likely to accrue minority patients. However, studies including immunotherapy were less likely to accrue racial and ethnic minorities. Knowledge gained from our analysis may help individuals design oncology treatment trials that are representative of more diverse populations.

Female sexual function evaluation and intraoperative vaginal reconstruction in bladder cancer.

RC significantly negatively impacts sexual function (SF) in both men and women. While significant research resources have been allocated to examine the deleterious effects of post prostatectomy erectile dysfunction, little attention has been directed towards female sexual function and organ preservation post cystectomy. These academic shortcomings often result in poor provider awareness and inadequate preoperative assessment. As such, it is crucial for all providers involved in female RC care to understand the necessary and available tools for preoperative evaluation, in addition to the anatomic and reconstructive techniques. This review aims to summarize the current preoperative evaluation and available tools of SF assessment and describe in detail the varying operative techniques in the preservation or restoration of SF in women after RC. The review explores the intricacies of preoperative evaluation tools, and intraoperative techniques for organ- and nerve-sparing during radical cystectomy in females. Particular emphasis on vaginal reconstruction after partial or complete resection is provided, including split-thickness skin (STF) graft vaginoplasy, pedicled flaps, myocutaneous flaps and use of bowel segments. In conclusion, this narrative review highlights the importance of understanding anatomic considerations and nerve-sparing strategies in promoting postoperative SF and quality of life. Furthermore, the review describes the advantages and limitations of each organ- and nerve-sparing technique and their impact on sexual function and overall well-being.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis.

BACKGROUND: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. METHODS: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. FINDINGS: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. INTERPRETATION: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. FUNDING: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Retrospective comparative effectiveness research: Will changing the analytical methods change the results?

In medicine, retrospective cohort studies are used to compare treatments to one another. We hypothesize that the outcomes of retrospective comparative effectiveness research studies can be heavily influenced by biostatistical analytic choices, thereby leading to inconsistent conclusions. We selected a clinical scenario currently under investigation: survival in metastatic prostate, breast or lung cancer after systemic vs systemic + definitive local therapy. We ran >300 000 regression models (each representing a publishable study). Each model had various forms of analytic choices (to account for bias): propensity score matching, left truncation adjustment, landmark analysis and covariate combinations. There were 72 549 lung, 14 904 prostate and 13 857 breast cancer patients included. In the most basic analysis, which omitted propensity score matching, left truncation adjustment and landmark analysis, all of the HRs were <1 (generally, 0.60-0.95, favoring addition of local therapy), with all P-values <.001. Left truncation adjustment landmark analysis produced results with nonsignificant P-values. The combination of propensity score matching, left truncation adjustment, landmark analysis and covariate combinations generally produced P-values that were >.05 and/or HRs that were >1 (favoring systemic therapy alone). The use of more statistical methods to reduce the selection bias caused reported HR ranges to approach 1.0. By varying analytic choices in comparative effectiveness research, we generated contrary outcomes. Our results suggest that some retrospective observational studies may find a treatment improves outcomes for patients, while another similar study may find it does not, simply based on analytical choices.

Pan-cancer analysis of prognostic metastatic phenotypes.

Although cancer is highly heterogeneous, all metastatic cancer is considered American Joint Committee on Cancer (AJCC) Stage IV disease. The purpose of this project was to redefine staging of metastatic cancer. Internal validation of nationally representative patient data from the National Cancer Database (n = 461 357; 2010-2013), and external validation using the Surveillance, Epidemiology and End Results database (n = 106 595; 2014-2015) were assessed using the concordance index for evaluation of survival prediction. A Cox proportional hazards model was used for overall survival by considering identified phenotypes (latent classes) and other confounding variables. Latent class analysis was performed for phenotype identification, where Bayesian information criterion (BIC) and sample-size-adjusted BIC were used to select the optimal number of distinct clusters. Kappa coefficients assessed external cluster validation. Latent class analysis identified five metastatic phenotypes with differences in overall survival (P < .0001): (Stage IVA) nearly exclusive bone-only metastases (n = 59 049, 12.8%; median survival 12.7 months; common in lung, breast and prostate cancers); (IVB) predominant lung metastases (n = 62 491, 13.5%; 11.4 months; common in breast, stomach, kidney, ovary, uterus, thyroid, cervix and soft tissue cancers); (IVC) predominant liver/lung metastases (n = 130 014, 28.2%; 7.0 months; common in colorectum, pancreatic, lung, esophagus and stomach cancers); (IVD) bone/liver/lung metastases predominant over brain (n = 61 004, 13.2%; 5.9 months; common in lung and breast cancers); and (IVE) brain/lung metastases predominant over bone/liver (n = 148 799, 32.3%; 5.7 months; lung cancer and melanoma). Long-term survivors were identified, particularly in Stages IVA-B. A pan-cancer nomogram model to predict survival (STARS: site, tumor, age, race, sex) was created, validated and provides 13% better prognostication than AJCC: 1-month concordance index of 0.67 (95% confidence interval [CI]: 0.66-0.67) vs 0.61 (95% CI: 0.60-0.61). STARS is simple, uses easily accessible variables, better prognosticates survival outcomes and provides a platform to develop novel metastasis-directed clinical trials.

Impact of Left-Digit Age Bias in the Treatment of Localized Prostate Cancer.

PURPOSE: Left-digit bias is a phenomenon in which the leftmost digit of a number disproportionately influences decision making. We measured the effect of left-digit age bias on treatment recommendations for localized prostate cancer. MATERIALS AND METHODS: We included men with clinically localized prostate adenocarcinoma in Surveillance, Epidemiology, and End Results from 2004 to 2018 and the National Cancer Database from 2004 to 2016. Primary outcomes were recommendations for radiation therapy and radical prostatectomy. Regression discontinuity was used to assess whether age increase from 69 to 70 years was associated with disproportionate changes in treatment recommendations. RESULTS: In Surveillance, Epidemiology, and End Results, discontinuities were found in the proportion of patients recommended for radiation among the entire cohort (effect size 2.2%, P < .01) and among patients with Gleason 6 (1.6%, P < .01), Gleason 7 (2.5%, P < .01), and Gleason ≥8 (2.1%, P < .01) cancer, while the proportion recommended for prostatectomy decreased in the entire cohort (-1.4%, P < .01) and in patients with Gleason 7 cancer (-2.4%, P < .01). In the National Cancer Database, discontinuity from age 69 to 70 was found in recommendations for radiation in the entire cohort (effect size: 3.1%, P < .01) and in patients with Gleason 6 (2.2%, P < .01), Gleason 7 (4.0%, P < .01), and Gleason ≥8 (2.3%, P < .02) cancer, while the proportion recommended for prostatectomy decreased at this cutoff in the entire cohort (effect size: -2.7%, P < .01) and patients with Gleason 6 (-2.2%, P < .01) and Gleason 7 (-3.7%, P < .01) cancer. CONCLUSIONS: In patients with localized prostate cancer, left-digit age change from 69 to 70 was associated with disproportionately increased recommendations for radiation and decreased recommendations for prostatectomy.

Adjuvant radiotherapy may not significantly change outcomes in high-risk cutaneous squamous cell carcinomas with clear surgical margins: A systematic review and meta-analysis.

BACKGROUND: The role of adjuvant radiotherapy for high-risk cutaneous squamous cell carcinomas after surgery with negative margins is unclear. OBJECTIVE: To conduct a systematic review and meta-analysis examining the risk of poor outcomes for patients treated with surgery alone versus surgery and adjuvant radiotherapy. METHODS: A comprehensive search of articles was executed in PubMed, Embase, and the Cochrane Database. Random-effected meta-analyses were conducted. RESULTS: Thirty-three studies comprising 3867 high-risk cutaneous squamous cell carcinomas were included. There were no statistically significant differences in poor outcomes between the surgery only group and surgery with adjuvant radiotherapy group. Estimates for local recurrence for the surgery alone group versus the surgery with adjuvant radiotherapy group were 15.2% (95% confidence interval [CI], 6.3%-27%) versus 8.8% (95% CI, 1.6%-20.9%); for regional metastases, 11.5% (95% CI, 7.2%-16.7%) versus 4.4% (95% CI, 0%-18%); for distant metastases, 2.6% (95% CI, 0.6%-6%) versus 1.7% (95% CI, 0.2%-4.5%); and for disease-specific deaths, 8.2% (95% CI, 1.2%-20.6%) versus 19.7% (95% CI, 3.8%-43.7%), respectively. LIMITATIONS: Retrospective nature of most studies with the lack of sufficient patient-specific data. CONCLUSIONS: For patients with high-risk cutaneous squamous cell carcinomas treated with margin-negative resection, there were no significant differences in poor outcomes between the surgery only group and the surgery with adjuvant radiotherapy group. Randomized controlled trials are necessary to define the benefit of adjuvant radiotherapy in this setting.

Impact of radiation therapy facility volume on survival in patients with cancer.

BACKGROUND: This study examined whether radiation therapy facility volumes correlate with survival after curative intent treatment of solid tumors. METHODS: The National Cancer Database was queried for patients with solid tumors treated with curative-intent radiation therapy from 2004-2013. Facilities were stratified into 4 volume categories: low, intermediate, high, and very high. Primary cancer sites were divided into neoadjuvant, adjuvant, or definitive radiation subgroups. Kaplan-Meier curves of 5-year postradiation survival probability, stratified by facility volume, were generated with log-rank tests for group comparisons. Cox proportional hazard models were used to evaluate the effect of facility volume on survival, adjusted for multiple covariates. RESULTS: There were 253,422 patients treated at 1289 facilities: 6231 received neoadjuvant radiation, 147,980 received adjuvant radiation, and 99,211 received definitive radiation without surgery. Among patients receiving neoadjuvant radiation, survival correlated with facility volume for patients with rectal cancer (hazard ratio [HR], 0.75; 95% CI, 0.6-0.94; P = .01). For cancers of the breast and uterus, patients receiving adjuvant radiation at very high-volume facilities (vs low volume) had improved survival (HR, 0.83; 95% CI, 0.77-0.90; P < .001 and HR, 0.77, 95% CI, 0.62-0.97; P = .03, respectively). For patients receiving definitive radiation for prostate, non-small cell lung, pancreas, and head and neck cancer, there was an improvement in survival for patients treated at very high-volume centers (P < .05). CONCLUSIONS: For select cancer patients, treatment with curative radiation at higher volume facilities is associated with improved survival. In particular, patients receiving radiation therapy in the definitive setting without surgery may benefit most from treatment at high-volume centers.

Impact of Facility Surgical Volume on Survival in Patients With Cancer.

BACKGROUND: Increased facility surgical treatment volume is sometimes associated with improved survival in patients with cancer; however, published studies evaluating volume are heterogeneous and disparate in their patient inclusion and definition of volume. The purpose of this work was to evaluate uniformly the impact of surgical facility volume on survival in patients with cancer. METHODS: The National Cancer Database was searched for patients diagnosed in 2004 through 2013 with the 12 cancers most commonly treated surgically. Facilities were stratified by 4 categories using the overall population (low, intermediate, high, and very high), each including 25% of patients, and then stratified by each individual disease site. Five-year postsurgery survival was estimated using both the Kaplan-Meier method and corresponding log-rank tests for group comparisons. Cox proportional hazard models were used to evaluate the effects of facility volume on 5-year postsurgery survival further, adjusted for multiple covariates. RESULTS: A total of 3,923,618 patients who underwent surgery were included from 1,139 facilities. Of these, 40.4% had breast cancer, 12.8% prostate cancer, and 10.0% colon cancer. Most patients were female (65.0%), White (86.4%), and privately insured (51.6%) with stage 0-III disease (64.8%). For all cancers, the risk of death for patients undergoing surgery at very high-volume facilities was 88% of that for those treated at low-volume facilities. Hazard ratios (HRs) were greatest (very high vs low volume) for cancer of the prostate (HR, 0.66; 95% CI, 0.63-0.69), pancreas (HR, 0.75; 95% CI, 0.71-0.78), and esophagus (HR, 0.78; 95% CI, 0.73-0.83), and for melanoma (HR, 0.81; 95% CI, 0.78-0.84); differences were smallest for uterine and non-small cell lung cancers. Overall survival differences were greatest for cancers of the brain, pancreas, and esophagus. CONCLUSIONS: Patients treated surgically at higher-volume facilities consistently had improved overall survival compared with those treated at low-volume centers, although the magnitude of difference was cancer-specific.

Conventionally fractionated radiation therapy versus stereotactic body radiation therapy for locally advanced pancreatic cancer (CRiSP): An international systematic review and meta-analysis.

BACKGROUND: The goal of this study was to characterize the efficacy and safety of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy with concurrent chemotherapy (CFRT) for the definitive treatment of locally advanced pancreatic cancer. The primary outcome measure was efficacy, defined by 2-year overall survival (OS). Secondary outcomes were incidence of any grade 3/4 toxicity and 1-year OS. METHODS: A PICOS/PRISMA/MOOSE selection protocol was used to identify eligible studies. Inclusion criteria were: 1) patients diagnosed with locally advanced N0-1 M0 pancreatic cancer; 2) CFRT 1.8 to 2.0 Gy/fraction with chemotherapy per protocol or SBRT ≥5 Gy/fraction in ≤5 fractions; 3) either no control group or another definitive chemotherapy or radiation therapy arm; 4) at least 1 of the outcome measures reported; and 5) single or multi-arm phase 2/3 prospective study for CFRT and/or phase 1/2 or retrospective study for SBRT. Neoadjuvant and/or adjuvant chemotherapy was prescribed per protocol specifications. Weighted random effects meta-analyses were conducted using the DerSimonian and Laird method to characterize summary effect sizes for each outcome. RESULTS: A total of 470 studies were initially screened; of these, 9 studies assessed SBRT and 11 studies assessed CFRT. For SBRT, the median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. For CFRT, doses ranged from 45 to 54 Gy in 1.8- to 2.0-Gy fractions, with the majority of studies delivering 50.4 Gy in 28 fractions with concurrent gemcitabine. The random effects estimate for 2-year OS was 26.9% (95% CI, 20.6%-33.6%) for SBRT versus 13.7% (95% CI, 8.9%-19.3%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for 1-year OS was 53.7% (95% CI, 39.3%-67.9%) for SBRT versus 49.3% (95% CI, 39.3%-59.4%) for CFRT, and was not statistically significant. The random effects estimate for acute grade 3/4 toxicity was 5.6% (95% CI, 0.0%-20.0%) for SBRT versus 37.7% (95% CI, 24.0%-52.5%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for late grade 3/4 toxicity was 9.0% for SBRT (95% CI, 3.3%-17.1%) versus 10.1% (95% CI, 1.8%-23.8%) for CFRT, which was not statistically significant. CONCLUSION: These results suggest that SBRT for LAPC may result in a modest improvement in 2-year OS with decreased rates of acute grade 3/4 toxicity and no change in 1-year-OS or late toxicity. Further study into the use of stereotactic body radiation therapy for these patients is needed.

Long-term causes of death among pediatric patients with cancer.

BACKGROUND: The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. METHODS: This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database (1980-2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. RESULTS: There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person-years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100-50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87-76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28-181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82-620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89-102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51-57.09). CONCLUSIONS: The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

A population-based study of cardiovascular disease mortality risk in US cancer patients.

AIMS: This observational study characterized cardiovascular disease (CVD) mortality risk for multiple cancer sites, with respect to the following: (i) continuous calendar year, (ii) age at diagnosis, and (iii) follow-up time after diagnosis. METHODS AND RESULTS: The Surveillance, Epidemiology, and End Results program was used to compare the US general population to 3 234 256 US cancer survivors (1973-2012). Standardized mortality ratios (SMRs) were calculated using coded cause of death from CVDs (heart disease, hypertension, cerebrovascular disease, atherosclerosis, and aortic aneurysm/dissection). Analyses were adjusted by age, race, and sex. Among 28 cancer types, 1 228 328 patients (38.0%) died from cancer and 365 689 patients (11.3%) died from CVDs. Among CVDs, 76.3% of deaths were due to heart disease. In eight cancer sites, CVD mortality risk surpassed index-cancer mortality risk in at least one calendar year. Cardiovascular disease mortality risk was highest in survivors diagnosed at <35 years of age. Further, CVD mortality risk is highest (SMR 3.93, 95% confidence interval 3.89-3.97) within the first year after cancer diagnosis, and CVD mortality risk remains elevated throughout follow-up compared to the general population. CONCLUSION: The majority of deaths from CVD occur in patients diagnosed with breast, prostate, or bladder cancer. We observed that from the point of cancer diagnosis forward into survivorship cancer patients (all sites) are at elevated risk of dying from CVDs compared to the general US population. In endometrial cancer, the first year after diagnosis poses a very high risk of dying from CVDs, supporting early involvement of cardiologists in such patients.

Risk-adapted stereotactic body radiation therapy for central and ultra-central early-stage inoperable non-small cell lung cancer.

To determine the therapeutic efficacy and safety of risk-adapted stereotactic body radiation therapy (SBRT) schedules for patients with early-stage central and ultra-central inoperable non-small cell lung cancer. From 2006 to 2015, 80 inoperable T1-2N0M0 NSCLC patients were treated with two median dose levels: 60 Gy in six fractions (range, 48-60 Gy in 4-8 fractions) prescribed to the 74% isodose line (range, 58%-79%) for central lesions (ie within 2 cm of, but not abutting, the proximal bronchial tree; n = 43), and 56 Gy in seven fractions (range, 48-60 Gy in 5-10 fractions) prescribed to the 74% isodose line (range, 60%-80%) for ultra-central lesions (ie abutting the proximal bronchial tree; n = 37) on consecutive days. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), tumor local control rate (LC), and toxicity. Median OS and PFS were 64.47 and 32.10 months (respectively) for ultra-central patients, and not reached for central patients. Median time to local failure, regional failure, and any distant failures for central versus ultra-central lesions were: 27.37 versus 26.07 months, 20.90 versus 12.53 months, and 20.85 versus 15.53 months, respectively, all P < .05. Multivariate analyses showed that tumor categorization (ultra-central) and planning target volume ≥52.76 mL were poor prognostic factors of OS, PFS, and LC, respectively (all P < .05). There was one grade 5 toxicity; all other toxicities were grade 1-2. Our results showed that ultra-central tumors have a poor OS, PFS, and LC compared with central patients because of the use of risk-adapted SBRT schedules that allow for equal and favorable toxicity profiles.

Does the addition of chemotherapy to neoadjuvant radiotherapy impact survival in high-risk extremity/trunk soft-tissue sarcoma?

BACKGROUND: The role of chemotherapy in extremity/trunk soft-tissue sarcoma (ET-STS) is controversial, even for patients at high risk for distant recurrence and death (those with high-grade tumors ≥5 cm in size). This study examines the impact of integrating chemotherapy with neoadjuvant radiotherapy (RT) on overall survival (OS) for patients with high-risk ET-STS. METHODS: The National Cancer Data Base was queried for adult patients with high-risk ET-STS who received neoadjuvant RT and limb salvage surgery between 2006 and 2014. Patients were stratified into RT and chemoradiotherapy (CRT) cohorts. OS for the RT and CRT cohorts was analyzed with the Kaplan-Meier method, log-rank tests, and Cox proportional hazards models. Propensity score matching (PSM) analysis was used to account for a potential treatment selection bias between the cohorts. RESULTS: A total of 884 patients were identified: 639 (72.3%) in the RT cohort and 245 (27.7%) in the CRT cohort. The unadjusted 5-year Kaplan-Meier OS rate was significantly higher in the CRT cohort: 72.0% versus 56.1% (P < .001). Neoadjuvant chemotherapy was associated with improved OS in univariate and multivariable analyses (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.41-0.78; P < .001). PSM identified 2 evenly matched cohorts of 212 patients each. The 5-year matched Kaplan-Meier OS rates were 69.8% and 55.4% for the CRT and RT cohorts, respectively (P = .002). The addition of neoadjuvant chemotherapy remained prognostic for OS on PSM (HR, 0.56; 95% CI, 0.39-0.83; P = .003). CONCLUSIONS: The addition of chemotherapy to neoadjuvant RT was associated with improved OS for patients with high-risk ET-STS. In the absence of randomized data evaluating CRT versus RT, these findings warrant further investigation.

Surgical excision, Mohs micrographic surgery, external-beam radiotherapy, or brachytherapy for indolent skin cancer: An international meta-analysis of 58 studies with 21,000 patients.

BACKGROUND: The objective of this study was to compare the cosmesis and recurrence rates of conventional excision (CE), Mohs micrographic surgery (MMS), external-beam radiation therapy (EBRT), or brachytherapy (BT), for basal cell carcinoma and squamous cell carcinoma of the skin. METHODS: Population, Intervention, Control, Outcome, Study Design (PICOS), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) methods were used to identify studies on PubMed (from 1985 to 2018), including patients with American Joint Committee on Cancer (AJCC) T1-T2N0 basal cell carcinomas and squamous cell carcinomas and ≥10 months follow-up who received CE, MMS, EBRT, or BT. The primary endpoint was cosmesis, classified as "good," "fair," or "poor." The secondary endpoint was 1-year recurrence. Fixed-effects and random-effects meta-analyses were performed to evaluate primary and secondary outcomes with respect to treatment modality. RESULTS: In total, 18,095 studies met initial search criteria. There were 24 CE, 13 MMS, 19 EBRT, and 7 BT studies included with a total of 21,371 patients. The summary effect size for "good" cosmesis was 81% (95% CI, 70.6%-89.6%), 74.6% (95% CI, 63%-84.6%), and 97.6% (95% CI, 91.3%-100%) for CE, EBRT, and BT, respectively. Good cosmesis was 96.0% in the only MMS study that reported cosmesis. BT had improved "good" cosmesis over EBRT (P = .0025) and was similar to CE and MMS. No significant differences were seen for "fair" or "poor" cosmesis. One-year recurrence rates were low throughout at 0.8% (95% CI, 0.3%-1.6%), 0.2% (95% CI, 0%-0.6%), 2% (95% CI, 1.3%-2.7%), and 0% (95% CI, 0%-0.5%) for CE, MMS, EBRT, and BT, respectively. CONCLUSIONS: For T1-T2N0 skin cancers, BT and MMS have improved cosmesis over EBRT and CE. It is unclear whether this is because of treatment superiority or selection and reporting bias. Local control is similar among all modalities at 1 year.

Clinical Trial Accrual at Initial Course of Therapy for Cancer and Its Impact on Survival.

BACKGROUND: This retrospective cohort study sought to characterize the accrual of patients with cancer into clinical trials at the time of diagnosis and analyze the impact of accrual on survival. METHODS: The National Cancer Database (NCDB) was queried for patients enrolled in clinical trials at their initial course of treatment for 46 cancers from 2004 through 2015. Descriptive statistics were used to characterize the accrual of patients with cancer in clinical trials at diagnosis, and Kaplan-Meier graphical displays, log-rank tests, odds ratios, and stratified Cox proportional hazards models were used to analyze the impact of accrual on overall survival (OS). Strata were defined using 10 variables. Model-based adjusted survival curves of 2 groups were reverse-generated based on a Weibull distribution. RESULTS: Of 12,097,681 patients in the NCDB, 11,576 (0.1%) were enrolled in trials. Patients in clinical trials typically had metastatic disease (30.9% vs 16.4%; P<.0001), were white (88.0% vs 84.8%; P<.0001), had private/managed care insurance (56.4% vs 41.8%; P<.0001), had fewer comorbidities (Charlson-Deyo score 0: 81.9% vs 75.7%; P<.0001, and Charlson-Deyo scores 1-3: 18.1% vs 24.3%; P<.0001) compared with those not in trials. At a median follow-up of 64 months, enrollment in a clinical trial was associated with improved OS in univariate and stratified analyses, with a median survival of 60.0 versus 52.5 months (hazard ratio, 0.876; 95% CI, 0.845-0.907; P<.0001). Stratified analysis with matched baseline characteristics between patients enrolled and not enrolled in a clinical trial showed superior OS at 5 years (95.0% vs 90.2%; P<.0001). CONCLUSIONS: Enrollment in clinical trials at first line of therapy in the United States is exceedingly low and favors young, healthy, white patients with metastatic disease and private insurance who are treated at academic medical centers. Patients with cancer treated in clinical trials live longer than those not treated in trials.