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BACKGROUND This study was done to determine the representation of minorities, women, and the elderly in National Cancer Institute (NCI) clinical trials. METHODS This is an analysis in the NCI Clinical Data Update System. Patients were evaluated in breast, colorectal, lung, and prostate cancer trials from 2000 to 2019. Representation in a trial was determined by race/ethnicity, sex, and age. Secondarily, the change in trial participation by multivariable analysis by comparing years 2000 through 2004 to 2015 through 2019 was evaluated. RESULTS The cohort included 242,720 participants: 197,320 Non-Hispanic White (81.3%), 21,190 Black (8.7%), 11,587 Hispanic (4.8%), and 6880 Asian/Pacific Islander (2.8%). Black and Hispanic patients were underrepresented for colorectal (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001 and OR, 0.74; 95% CI, 0.64-0.87; P < .001, respectively), lung (OR, 0.83; 95% CI, 0.76-0.91; P < .001 and 0.66; 95% CI, 0.57-0.77; P < .001, respectively), and prostate cancer trials (OR, 0.85; 95% CI, 0.79-0.92; P < .001 and OR, 0.58; 95% CI, 0.51-0.66; P < .001) between 2015 and 2019. The odds of participation in 2015 to 2019 increased among Black patients in breast (OR, 2.19; 95% CI, 2.07-%2.32; P < .001), lung (OR, 1.54; 95% CI, 1.38-1.73; P < .001), and prostate cancer trials (OR, 1.14; 95% CI, 1.04-1.26; P < .001). The odds of participation in a trial among Hispanic patients increased for breast (OR, 3.32; 95% CI, 3.09-3.56; P < .001), colorectal (OR, 2.46; 95% CI, 2.04-2.96; P < .001), lung (OR, 3.88; 95% CI, 3.20-4.69; P < .001), and prostate cancer (OR, 1.70; 95% CI, 1.42-2.04; P = .005). CONCLUSIONS This study identified that Black and Hispanic patients remain underrepresented in trials, but in recent years, participation has increased. These findings indicate that minority participation has increased over time, but further efforts are needed.

Background The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. Methods In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. Results One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. Conclusions The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Background The clinical benefit of cusatuzumab, a CD70-directed monoclonal antibody with enhanced effector functions, was investigated in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). Methods In this cohort expansion of the ARGX-110-1201 study, 27 patients with R/R CTCL received cusatuzumab at 1 (n = 11) or 5 mg/kg (n = 16) once every 3 weeks to investigate its safety, dose, and exploratory efficacy. The pharmacokinetics, immunogenicity, CD70 expression, and CD70/CD27 biology were also assessed. Results The most common adverse events included infusion-related reactions, pyrexia, and asthenia. Eighteen serious adverse events (grade 1-3) were reported in 11 patients; 1 of these (vasculitis) was considered drug-related. For 8 of the 11 patients receiving 1 mg/kg, anti-drug antibodies (ADAs) affected the minimal concentration, and this resulted in undetectable cusatuzumab concentrations at the end of treatment and, in some cases, a loss of response. This effect was greatly reduced in the patients receiving 5 mg/kg. The overall response rate was 23%; this included 1 complete response and 5 partial responses (PRs) in 26 of the 27 evaluable patients. In addition, 9 patients achieved stable disease. The mean duration on cusatuzumab was 5.2 months, and the median duration was 2.5 months. Patients with Sezary syndrome (SS) achieved a 60% PR rate with a dosage of 5 mg/kg and a 33% PR rate with a dosage of 1 mg/kg; this resulted in an overall response rate of 50% for patients with SS at both doses. Conclusions Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose-dependent effect on exposure supports the use of 5 mg/kg for future development.

The 2016 revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular features with histologic grading, revolutionizing how oncologists conceptualize primary brain and spinal cord tumors as well as providing new insights into their management and prognosis. The 2021 revised fifth edition of the WHO classification further integrates molecular alterations for CNS tumor categorization, updating current understanding of the pathophysiology of many of these disease entities. Here, the authors review changes in the new classification for the most common primary adult tumors-gliomas (including astrocytomas, oligodendrogliomas, and ependymomas) and meningiomas-highlighting the key genomic alterations for each group classification to help clinicians interpret them as they consider therapeutic options-including clinical trials and targeted therapies-and discuss the prognosis of these tumors with their patients. The revised, updated 2021 WHO classification also further integrates molecular alterations in the classification of pediatric CNS tumors, but those are not covered in the current review.

Background The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective. Methods A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs. Results Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices. Conclusions Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions. Lay summary Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.

For older patients with clinically lymph node-negative breast cancer who have estrogen receptor-positive tumors and are treated with tamoxifen, randomized trials comparing axillary lymph node dissection (ALND) versus no ALND show that the omission of ALND improves patient quality of life and has no adverse effects on mortality. These results have served to justify sentinel node biopsy (SNB) omission in selected older patients with breast cancer. More recently, clinical trials were launched to assess SNB omission in younger patients, with recurrence and survival as the primary outcomes of interest. Three important considerations serve as the basis for these ongoing trials. First, it is assumed that SNB omission will improve patient quality of life, although, to date, there is no level I evidence to support this assumption. Second, axillary surgery has never been shown to reduce breast cancer mortality, but it does reduce the risk of axillary recurrences, although adjuvant systemic therapy and radiotherapy also reduce these recurrence risks. Finally, nodal status is losing importance as a guide for adjuvant systemic therapy decision making because these decisions are now increasingly predicated on tumor biomarkers and gene profiling, but it is gaining importance for adjuvant radiotherapy decision making. Because quality-of-life considerations are the primary motivation for abandoning SNB, there is a need for randomized trials comparing SNB versus no SNB/no axillary surgery, with quality of life as the primary end point (level I evidence). Moreover, suitable alternatives to guide adjuvant radiotherapy decision making will require validation before SNB omission can be justified for patients of all ages who have clinically node-negative breast cancer. LAY SUMMARY: In this review article, the authors provide a brief historical overview of the role of axillary surgery in breast cancer management and discuss additional studies and ramifications that should be considered before abandoning the sentinel node biopsy (SNB) procedure. Specifically, there is a need for level I evidence demonstrating that omission of the SNB procedure will improve patient quality of life and a need to validate suitable alternatives to SNB as a guide for adjuvant radiotherapy decision making.

Background Phase 1 trials are increasingly important in the molecularly driven era of oncology, but few studies have examined phase 1 participation disparities. The authors of this study investigated factors associated with phase 1 versus phase 2/3 trial enrollment. Methods They authors conducted a cross-sectional study using serial samples of patients age ≥18 years enrolling on cancer trials from October 2011 to November 2014 at an academic cancer center. They used univariable and multivariable logistic regression models to analyze sociodemographic and clinical associations with phase 1 versus phase 2/3 trial enrollment. Results Among 3103 patients enrolled in cancer trials, 2657 unique patients participated in phase 1/2/3 trials. For patients enrolled in phase 1 (n = 1401) versus phase 2/3 (n = 1256) trials, we found no significant differences by age, insurance status, marital status, and income. Overall, 1216 (93%) White, 72 (6%) Asian, and 21 (2%) Black patients enrolled on phase 1 trials, whereas 1068 (93%) White, 40 (3%) Asian, and 43 (4%) Black patients enrolled on phase 2/3 trials. Adjusting for age, sex, race, ethnicity, insurance status, marital status, income, cancer type, disease status, travel distance, and trial year, compared with White patients, Black patients had lower phase 1 enrollment (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25-0.82), as did Hispanic/Latino (OR, 0.25; 95% CI, 0.08-0.79) and male patients (OR, 0.77; 95% CI, 0.62-0.94). Asian patients had higher phase 1 enrollment (OR, 1.38; 95% CI, 0.88-2.16). Conclusions Disparities in phase 1 versus phase 2/3 cancer clinical trial enrollment underscore the urgent need for interventions addressing inequities in early-phase trial participation. Lay summary Phase 1 trials are of increasing importance in oncology. The authors of the study analyzed all patients enrolling on cancer clinical trials at a large academic cancer center from October 2011 to November 2014. Among the 2657 trial participants, when age, sex, race, ethnicity, insurance status, marital status, income, cancer type, disease status, travel distance, and trial year were taken into account, Black, Hispanic/Latino, and male patients were less likely to enroll on phase 1 trials versus phase 2/3 trials. These findings suggest a need for targeted interventions to improve access to and education about phase 1 trials for Black and Hispanic/Latino patients.

BACKGROUND Adolescent and young adult (AYA) patients with cancer have not seen the same improvements in survival as younger (pediatric) patients and older patients (adults 40 years old or older). This may be related to their lower participation in clinical trials. METHODS This study examined AYA patient accrual to SWOG Cancer Research Network phase 1 to 3 clinical treatment trials for 29 cancers over 25 years (January 1996 to December 2020). Trial enrollments for AYA patients (15-39 years old) were compared with trial enrollments for older patients (40 years old or older) in SWOG and with US AYA cancer population rates derived from US Census and National Cancer Institute/Surveillance, Epidemiology, and End Results data. RESULTS In total, 84,219 patients were enrolled in SWOG treatment trials, including 7109 AYA patients (8.4%); in contrast, AYAs constituted 3.8% of the US cancer population. By histology, the highest proportions of AYA patients were in trials for Hodgkin disease (825 of 1220; 67.6%) and acute lymphocytic leukemia (350 of 678; 51.6%), whereas breast cancer trials had the greatest number of AYA patients (3032 of 32,693; 9.3%). SWOG AYA patients were more often female (68.8% vs 58.7%; P < .001), Black (10.1% vs 8.2%; P < .001), and Hispanic (10.6% vs 5.6%; P < .001) than SWOG patients who were 40 years old or older, and they were more often female (68.8% vs 65.1%; P < .001) but less often Black (10.1% vs 11.8%; P < .001) or Hispanic (10.6% vs 12.8%; P < .001) than AYA patients in the US cancer population. CONCLUSIONS AYA patients with cancer were well represented in SWOG clinical trials in comparison with US cancer population patients with the same cancers. The SWOG AYA population was more racially/ethnically diverse than older SWOG patients, although it was less diverse than the US AYA cancer population. LAY SUMMARY Adolescent and young adult (AYA) patients with cancer (aged 15-39 years) have not seen the same improvements in survival as younger (pediatric) patients and older patients (adults 40 years old or older). This may be related to their lower participation in clinical trials. This study evaluated the extent to which AYA patients were enrolled in a large, National Cancer Institute-sponsored network group over 25 years (1996-2020). Overall, 8.4% of the enrolled patients (7109 of 84,219) were AYAs; this was twice the corresponding rate of 3.8% in the US cancer population. AYA patients were also more racially/ethnically diverse than older trial patients, although they were less racially/ethnically diverse than the US AYA cancer population.

Background Aggressive large B-cell lymphomas (LBCLs) are curable, but previous studies have shown inferior outcomes in minorities. Nurse navigation programs can improve patient outcomes by providing patient support. This study presents the outcomes of White and minority patients with aggressive LBCL at an institution with an active nurse navigation program. Methods The authors prospectively collected baseline characteristics, treatment regimens, and outcome data for patients with aggressive LBCL. Navigation encounters were characterized as low or high intensity. Overall survival (OS) and progression-free survival (PFS) were calculated with Kaplan-Meier methods. Baseline characteristics were compared with Fisher exact tests. Results Two hundred four consecutive patients (47 minority patients and 157 White patients) were included. Results were presented as minorities versus Whites. There were no differences in prognostic scores (Revised International Prognostic Index score of 3-5, 43% vs 47%; P = .50), frontline chemotherapy (98% vs 96%; P = .68), or the incidence of relapsed/refractory disease (40% vs 38%; P = .74). For relapsed/refractory LBCL, similar proportions of patients underwent hematopoietic stem cell transplantation (32% vs 29%; P > .99) or chimeric antigen receptor T-cell therapy (16% vs 19%; P > .99). Enrollment in clinical trials was comparable (17% vs 14%; P = .64). More than 85% received nurse navigation, but minorities had higher intensity navigation encounters (42% vs 21%; P = .01). The 2-year OS rates were 81% and 76% for minorities and Whites, respectively (P = .27); the 2-year PFS rates were 62% and 65%, respectively (P = .78). Conclusions This study shows similar survival between Whites and minorities with aggressive LBCL, which was likely due to equal access to guideline-concordant therapy. Minorities received higher intensity navigation encounters, which may have helped them to overcome socioeconomic disadvantages.

Background Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. Methods PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. Results Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). Conclusions These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

Background Patients with cancer have played a key role in advocating for legal access to cannabis, but little is known about links between cancer and cannabis use or cannabis-related beliefs. The authors used data from a national survey to study these relationships. Methods Nationally representative data collected by the National Survey on Drug Use and Health from 2015 to 2019 were acquired. Patterns of cannabis use and cancer history were examined and tested within age group subpopulations via domain analysis using survey weights. Results Data for 214,505 adults, including 4741 individuals (3.8%) with past (>1 year ago) cancer diagnosis and 1518 individuals (1.2%) with recent (≤1 year ago) cancer diagnosis, were examined. Cannabis use was less common in those with past (8.9%; 95% CI, 8.0%-9.8%) or recent (9.9%; 95% CI, 6.9%-11.1%) cancer diagnosis than in those without a history of cancer (15.9%; 95% CI, 15.7%-16.1%). However, when analyses were stratified by age group, those 18 to 34 years of age were more likely to report past cannabis use, and those 35 to 49 years of age were more likely to report past or recent cannabis use if they had a history of cancer. Younger patients felt that cannabis was more accessible and less risky if they had a history of cancer. Conclusions Patients with cancer were less likely to report cannabis use, but there were different cannabis perceptions and use patterns by age. Age should be considered in studies of cannabis and cancer, and policy initiatives may be needed to aid provision of quality information on cannabis risk to those with cancer. Lay summary Cannabis (marijuana) use is increasing in the United States, but we do not have much information on the relationship between cannabis use and cancer. We studied information from a representative group of people and found that younger patients generally reported more past and/or recent cannabis use if they had been diagnosed with cancer whereas older individuals did not. Beliefs about cannabis risk and accessibility differed by age. Clinical trials to study cannabis should account for patient age, and accurate information about cannabis should be provided to help patients with cancer make decisions about cannabis use.

Background The US Food and Drug Administration has recently approved a number of new cancer drugs. The clinical trials that serve as the basis for new cancer drug approvals may not reflect how the drugs will perform in routine practice and do not measure the impact of the drugs on spending. The authors sought to evaluate the real-world effectiveness and value of drugs recently approved for advanced prostate cancer. Methods Using Surveillance, Epidemiology, and End Results-Medicare data, the authors identified fee-for-service Medicare beneficiaries aged 65 years or older who began treatment with a drug approved for metastatic castration-resistant prostate cancer in 2007-2009, when only 1 drug was approved for metastatic castration-resistant prostate cancer, and in 2014-2016, when 5 additional drugs were approved. They calculated life expectancy and lifetime medical costs (ie, Medicare reimbursements) for each group. Results Between 2007-2009 and 2014-2016, life expectancy increased by 12.6 months. Lifetime medical costs increased by $87,000. The incremental cost per life-year gained was $83,000. Conclusion The release of 5 new drugs coincided with increases in survival rates and spending. This study's estimates indicate that the new drugs collectively were cost-effective.

During the period from 1962 to 1977, several antigens, notably carcinoembryonic antigen and prostate-specific antigen, were discovered and entered clinical use. Ultrasonography, positron emission tomography scanning, and magnetic resonance imaging were introduced, and adjuvant radiation and chemotherapy after limited surgery became routine procedures. Radioimmunoassay and immunohistochemistry techniques were standardized. The announcement in England and the United States that tobacco is a potent lung carcinogen was long delayed, important news. The US Cancer Act of 1971 made it possible to experiment with newly discovered drugs, transfer promising therapeutic agents from the laboratory to the clinic, and finance randomized clinical trials. Oncologists achieved a series of successes with combination chemotherapy in childhood cancers, adult lymphomas, and testis tumors. Clinical trials demonstrated that breast-conserving therapy is as effective as mastectomy. The discovery of retroviruses, reverse transcriptase, and vascular endothelial growth factor was coupled with learning about oncogenes. The 2-hit theory and the reciprocal translocation of chromosomes helped to solve some of the riddles of oncogenesis. The staging classification of cancers by the American Joint Committee on Cancer unified clinical and pathologic handling and prognostication of malignant tumors. The progress made in oncology between 1962 and 1977 came about through the dedicated work of many individuals. However, there were 9 pathfinders (3 medical oncologists, 2 surgeons, 1 medical nuclear physicist, 1 pediatrician geneticist, 1 hematologist geneticist, and 1 virologist) who, despite their diverse backgrounds, personalities, and interest, made extraordinary contributions to oncology.

BACKGROUND Heterogeneity exists in the response of triple-negative breast cancer (TNBC) to standard anthracycline (AC)/taxane-based neoadjuvant systemic therapy (NAST), with 40% to 50% of patients having a pathologic complete response (pCR) to therapy. Early assessment of the imaging response during NAST may identify a subset of TNBCs that are likely to have a pCR upon completion of treatment. The authors aimed to evaluate the performance of early ultrasound (US) after 2 cycles of neoadjuvant NAST in identifying excellent responders to NAST among patients with TNBC. METHODS Two hundred fifteen patients with TNBC were enrolled in the ongoing ARTEMIS (A Robust TNBC Evaluation Framework to Improve Survival) clinical trial. The patients were divided into a discovery cohort (n = 107) and a validation cohort (n = 108). A receiver operating characteristic analysis with 95% confidence intervals (CIs) and a multivariate logistic regression analysis were performed to model the probability of a pCR on the basis of the tumor volume reduction (TVR) percentage by US from the baseline to after 2 cycles of AC. RESULTS Overall, 39.3% of the patients (42 of 107) achieved a pCR. A positive predictive value (PPV) analysis identified a cutoff point of 80% TVR after 2 cycles; the pCR rate was 77% (17 of 22) in patients with a TVR ≥ 80%, and the area under the curve (AUC) was 0.84 (95% CI, 0.77-0.92; P < .0001). In the validation cohort, the pCR rate was 44%. The PPV for pCR with a TVR ≥ 80% after 2 cycles was 76% (95% CI, 55%-91%), and the AUC was 0.79 (95% CI, 0.70-0.87; P < .0001). CONCLUSIONS The TVR percentage by US evaluation after 2 cycles of NAST may be a cost-effective early imaging biomarker for a pCR to AC/taxane-based NAST.

Background The enrollment of Black patients in cancer clinical trials continues to trend far below the true prevalence of disease in Black patients in the United States, limiting the generalizability of trial results. A potentially overlooked contributor to the underenrollment of Black patients may be the increasing enrollment of cancer trials in countries outside the United States. However, the impact of the globalization of cancer clinical trials on recruitment of racial minority patients has been understudied. Methods In this study, race and accrual location data for all cancer drugs approved by the US Food and Drug Administration (FDA) between 2015 and 2018 were analyzed. A disparity score was calculated for each approval, a metric comparing Black enrollment in clinical trials with the estimated burden of disease in Black patients. Results Of 49 global clinical trials supporting 35 FDA drug approvals with race data available, Black patients accounted for 2.5% of enrollment (range, 0%-10%), with a median disparity score of 0.19 (range, 0.01-0.98). In 21 clinical trials supporting 18 FDA drug approvals with both race and accrual location data available, 64% patients were enrolled outside the United States (range, 0%-100%). Black patients accounted for 3.2% of enrollment (range, 0.2%-10%), and the median disparity score was 0.23 (range, 0.01-0.98). There was a significant inverse correlation between the proportion of trial patients enrolled outside the United States and the disparity score (Pearson correlation, -0.61; P = .007). Conclusions The globalization of cancer clinical trials is associated with a widening racial enrollment disparity gap in the United States. The impact of global trials on domestic clinical trial generalizability warrants further consideration from a regulatory and policy standpoint. Lay summary Black patients continue to be underrepresented in cancer clinical trials; this disparity has worsened in recent years perhaps because of the globalization of cancer clinical trials. In an analysis of demographic information from 21 cancer clinical trials leading to US Food and Drug Administration approvals between 2015 and 2018, clinical trials conducted primarily outside the United States were 2-fold less likely to enroll Black participants than US clinical trials. Thus, the globalization of cancer clinical trials may have the unintended consequence of further exacerbating existing racial disparities in cancer clinical trial representation and ultimately the generalizability of trial results.

Background Recent clinical trials support adding ovarian suppression (OS) to oral endocrine therapy (ET) for premenopausal women with early breast cancer. The adoption of OS among real-world populations and the impact of OS on ET adherence have not been evaluated. Methods This study examined a retrospective, observational cohort of women under the age of 50 years with incident early breast cancer from 2001 to 2016. The IBM MarketScan Commercial insurance claims database was used to identify new users of ET with or without OS and to track discontinuation of or adherence to ET. In all, 21,948 women filled at least 1 prescription for ET within 12 months of their diagnosis after a washout period of 12 months with no prior claims. Patients who received an aromatase inhibitor without a synchronous OS drug were excluded. Results Use of OS increased over time and reached 11.3% in 2016. In an unadjusted analysis, 40.2% of ET+OS users discontinued ET early, whereas 48.8% of tamoxifen-alone users did. In adjusted analyses, ET+OS users had a similar likelihood of discontinuing ET in comparison with tamoxifen-alone users (hazard ratio, 0.92; 95% confidence interval, 0.83-1.03). Approximately 30% of women had low adherence over the first year of use. The likelihood of high adherence was similar, regardless of OS exposure. Conclusions The use of OS among young, commercially insured patients with breast cancer increased over time in agreement with recent clinical trial results but remained relatively low. Nonadherence to ET was common, but the use of OS was not associated with lower adherence to ET in this observational, nonrandomized cohort. These findings may reassure oncologists that use of OS does not endanger ET adherence, although prospective studies are needed for confirmation.

Background Estimates of overall patient health are essential to inform treatment decisions for patients diagnosed with cancer. The authors applied XWAS methods, herein referred to as "laboratory-wide association study (LWAS)", to evaluate associations between routinely collected laboratory tests and survival in veterans with prostate cancer. Methods The authors identified 133,878 patients who were diagnosed with prostate cancer between 2000 and 2013 in the Veterans Health Administration using any laboratory tests collected within 6 months of diagnosis (3,345,083 results). Using the LWAS framework, the false-discovery rate was used to test the association between multiple laboratory tests and survival, and these results were validated using training, testing, and validation cohorts. Results A total of 31 laboratory tests associated with survival met stringent LWAS criteria. LWAS confirmed markers of prostate cancer biology (prostate-specific antigen: hazard ratio [HR], 1.07 [95% confidence interval (95% CI), 1.06-1.08]; and alkaline phosphatase: HR, 1.22 [95% CI, 1.20-1.24]) as well laboratory tests of general health (eg, serum albumin: HR, 0.78 [95% CI, 0.76-0.80]; and creatinine: HR, 1.05 [95% CI, 1.03-1.07]) and inflammation (leukocyte count: HR, 1.23 [95% CI, 1.98-1.26]; and erythrocyte sedimentation rate: HR, 1.33 [95% CI, 1.09-1.61]). In addition, the authors derived and validated separate models for patients with localized and advanced disease, identifying 28 laboratory markers and 15 laboratory markers, respectively, in each cohort. Conclusions The authors identified routinely collected laboratory data associated with survival for patients with prostate cancer using LWAS methodologies, including markers of prostate cancer biology, overall health, and inflammation. Broadening consideration of determinants of survival beyond those related to cancer itself could help to inform the design of clinical trials and aid in shared decision making. Lay summary This article examined routine laboratory tests associated with survival among veterans with prostate cancer. Using laboratory-wide association studies, the authors identified 31 laboratory tests associated with survival that can be used to inform the design of clinical trials and aid patients in shared decision making.

Background The objective of this analysis was to evaluate the clinical factors influencing survival outcomes in patients with localized (clinical group I-III), FOXO1 fusion-positive rhabdomyosarcoma (RMS). Methods Patients with confirmed FOXO1 fusion-positive RMS who were enrolled on 3 completed clinical trials for localized RMS were included in the analytic cohort. Outcomes were analyzed using the Kaplan-Meier method to estimate event-free survival (EFS) and overall survival (OS), and the curves were compared using the log-rank test. A Cox proportional hazards regression model was used to perform multivariate analysis of prognostic factors that were significant in the univariate analysis. Results The estimated 4-year EFS and OS of 269 patients with localized, FOXO1 fusion-positive RMS was 53% (95% CI, 47%-59%) and 69% (95% CI, 63%-74%), respectively. Univariate analysis revealed that several known favorable clinical characteristics, including age at diagnosis between 1 and 9 years, complete surgical resection, tumor size ≤5 cm, favorable tumor site, absence of lymph node involvement, confinement to the anatomic site of origin, and PAX7-FOXO1 fusion, were associated with improved outcomes. Multivariate analysis identified older age (≥10 years) and large tumor size (>5 cm) as independent, adverse prognostic factors for EFS within this population, and patients who had both adverse features experienced substantially inferior outcomes. Conclusions Patients with localized, FOXO1 fusion-positive RMS can be further risk stratified based on clinical features at diagnosis, and older patients with large primary tumors have the poorest prognosis.

Background Cabozantinib Versus Sunitinib as Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial (CABOSUN) was a randomized, open‐label, phase 2 trial evaluating first‐line cabozantinib versus sunitinib in patients with advanced renal cell carcinoma (aRCC). This post hoc analysis evaluated quality‐adjusted survival using Quality‐adjusted Time Without Symptoms of disease or Toxicity of treatment (Q‐TWiST). Methods Survival plots for cabozantinib and sunitinib (650‐day follow‐up) were partitioned into 3 health states: time spent before disease progression without toxicity (TWiST; toxicity based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] grade 3/4 adverse events), time spent before disease progression with toxicity (TOX; durations of adverse events based on published literature), and time after disease recurrence (relapse) or progression to death (REL). Q‐TWiST was the sum of the mean time spent in each state, with each state weighted to reflect patient preferences (from 0 [worst] to 1 [best]) using utility scores. TWiST was always weighted as 1. Overall survival and time to disease progression were based on all randomized patients (157 patients); TOX was based on all randomized and treated patients (150 patients). Results Across all utility combinations tested, Q‐TWiST was found to be longer with cabozantinib versus sunitinib (range of differences, +24 days to +137 days). Q‐TWiST differences that were found to be statistically significant (+92 days [95% confidence interval, 5‐178 days] to +137 days [95% confidence interval, 60‐214 days]) were of a clinically meaningful effect size (≥80 days), and were based on utility values that included those considered relevant for patients with aRCC (REL utility weight of 0.355, TOX utility weight of 0‐1, and TWiST utility weight of 1). Conclusions In patients with aRCC, first‐line cabozantinib was found to provide longer quality‐adjusted survival compared with sunitinib. These findings may help to inform clinical decision making. Lay Summary Cabozantinib and sunitinib are drugs that are used to treat patients with advanced kidney cancer. Clinical trials have shown that cabozantinib offers benefits over sunitinib, giving patients more time before their cancer progresses.It is important that this additional time before disease progression does not come at the expense of patients' quality of life, which can be affected by treatment side effects and/or ongoing cancer symptoms. Both quantity and quality of life are central to optimal treatment.In the current analysis of patients with advanced kidney cancer who were initiating treatment for the first time, cabozantinib provided more quality time before cancer progression compared with sunitinib., The current post hoc analysis of the Cabozantinib Versus Sunitinib as Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial (CABOSUN) finds that cabozantinib offers statistically and clinically significant improvements in quality‐adjusted survival compared with sunitinib in treatment‐naive patients with advanced renal cell carcinoma (aRCC). This finding may help to inform clinical decision making in the first‐line treatment of patients with aRCC.

Clinical trials are fundamental for advances in cancer treatment. The traditional framework of phase 1 to 3 trials is designed for incremental advances between regimens. However, our ability to understand and treat cancer has evolved with the increase in drugs targeting an expanding array of therapeutic targets, the development of progressively comprehensive data sets, and emerging computational analytics, all of which are reshaping our treatment strategies. A more robust linkage between drugs and underlying cancer biology is blurring historical lines that define trials on the basis of cancer type. The complexity of the molecular basis of cancer, coupled with manifold variations in clinical status, is driving the individually tailored use of combinations of precision targeted drugs. This approach is spawning a new era of clinical trial types. Although most care is delivered in a community setting, large centers support real‐time multi‐omic analytics and their integrated interpretation by using machine learning in the context of real‐world data sets. Coupling the analytic capabilities of large centers to the tailored delivery of therapy in the community is forging a paradigm that is optimizing service for patients. Understanding the importance of these evolving trends across the health care spectrum will affect our treatment of cancer in the future and is the focus of this review., With advances in cancer biology, precision therapeutics, and big data, clinical trial designs are evolving. They are transforming cancer care and research across the biomedical enterprise.

Background To the authors' knowledge, the empiric identification of agents and interventions to mitigate chemotherapy-induced peripheral neuropathy (CIPN) has resulted in only 1 agent that modestly mitigates it and no agents or interventions that prevent its development. This speaks to the need for a mechanistic understanding of CIPN to develop effective interventions. Methods To understand the extent to which mechanistic understanding of CIPN is being translated into the development of interventions, the National Cancer Institute conducted a review of the National Institutes of Health (NIH)'s portfolio of investigator-initiated grants, the literature regarding CIPN mechanisms, and the clinical trials listed in the ClinicalTrials.gov database from January 1, 2011, to May 22, 2019. Results A total of 69 NIH-supported grants and 95 published articles were identified that evaluated mechanistic pathways of 7 different chemotherapy agents that cause CIPN. The review also identified 35 clinical trials that investigated agents or devices with which to treat CIPN. Only 3 trials incorporated a mechanistic rationale to support the choice of the intervention. Conclusions To the authors' knowledge, very little of the mechanistic understanding of the development of CIPN is being translated into intervention rationale in clinical trials that evaluate interventions to mitigate CIPN. Efforts to incentivize this translation are needed.

Recent years have seen tremendous advances in treating acute myeloid leukemia (AML), largely because of progress in understanding the genetic basis of the disease. The US Food and Drug Administration approved 7 agents for AML in the last 2 years: the first new drugs in decades. In this review, the authors discuss these new approvals in the backdrop of an overall strategy for treating AML today. Treating AML in the modern era requires: 1) access to and use of upfront genetic and cytogenetic testing, not only to describe prognosis but also to help identify the best available therapy; 2) effectively working new therapies into a conventional backbone of treatment, including transplantation; and 3) continued commitment to clinical trials designed to capitalize on advances in genetics and immunology to foster the next wave of drug approvals.

LAY SUMMARY Despite longer survival with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), metastatic urothelial carcinoma remains lethal. There is an unmet need to further improve the efficacy of these agents. In their phase 2 trial, Zhang et al. evaluated the combination of pembrolizumab (a PD-1 inhibitor) plus acalabrutinib (a novel agent inhibiting an enzyme considered relevant to immunotherapy resistance) based on strong rationale but did not demonstrate clinical benefit compared with pembrolizumab alone. Future trials that examine such promising rational combinations may be able to evaluate selected patients based on validated biomarkers to optimize benefit in an endless pursuit of personalizing therapies.

With rapid advancement in clinical research, clinical trials on breast cancer in China have made great progress and are increasingly receiving worldwide recognition. Oncologists have been provided with an unprecedented opportunity to conduct clinical trials that offer both advantages and challenges. Investigator-initiated trials (IITs) and trials on domestic innovative drugs are still in the initial stages, with plenty of room to grow. The goal of this study was to systematically review time trends of the changing landscape of clinical drug development in China over the course of the last decade (from 2009 to 2018). The number of clinical trials specific to breast cancer has increased in a span of 10 years, from 36 trials in 2009 to 113 in 2018, and this trend is accompanied by an increase in publications, from 13 in 2009 to 52 in 2015. A total of 593 trials were conducted in breast cancer between 2009 and 2018. The distribution pattern of trial phases shows that phase 2 trials accounted for 34% of the total, followed by phase 3 trials at 21% and phase 1 trials at 20%. Academic trials or IITs were found to be the major sponsors, with 52% of trials being sponsored by them followed by pharmaceutical companies as a secondary sponsor (38%). Additionally, trials on chemotherapeutic agents constituted 50% of the trials followed by trials on targeted therapy (31%). The review provides insight on the effectiveness of the pharmaceutical industry and identify unmet clinical needs of stakeholders. With accumulated experience of Chinese oncologists and increasing support from the Chinese government, greater success could be anticipated in the near future.

BACKGROUND Preclinical studies have implicated excess release of catecholamines and prostaglandins in the mediation of prometastatic processes during surgical treatment of cancer. In this study, we tested the combined perioperative blockade of these pathways in patients with colorectal cancer (CRC). METHODS In a randomized, double-blind, placebo-controlled biomarker trial involving 34 patients, the β-blocker propranolol and the COX2-inhibitor etodolac were administered for 20 perioperative days, starting 5 days before surgery. Excised tumors were subjected to whole genome messenger RNA profiling and transcriptional control pathway analyses. RESULTS Drugs were well-tolerated, with minor complications in both the treatment group and the placebo group. Treatment resulted in a significant improvement (P

Background Antiangiogenic-targeting agents have low response rates in patients with nonpancreatic neuroendocrine tumors (NETs). Nintedanib is an oral antiangiogenic agent that has inhibitory effects on the fibroblast growth factor receptor, which is highly expressed in NETs. The authors hypothesized that nintedanib would be active in patients with nonpancreatic NETs. Methods Patients with advanced, grade 1 or 2, nonpancreatic NETs who were receiving a stable dose of somatostatin analogue were enrolled. Nintedanib was administered at a dose of 200 mg twice daily in 28-day cycles. The primary endpoint was progression-free survival (PFS) at 16 weeks. Results Thirty-two patients were enrolled, and 30 were evaluable for the primary outcome. Most had radiographic disease progression within 12 months before enrollment. The 16-week PFS rate was 83%, and the median PFS and overall survival were 11.0 months and 32.7 months, respectively. Nintedanib was well tolerated and delayed deterioration in quality of life. The baseline serotonin level had a strong, positive correlation with activated but exhausted T cells. Conclusions Nintedanib is active in nonpancreatic NETs. The immunosuppressive effect of serotonin should be targeted in future clinical trials.

Background Although increasing evidence has suggested that an efficacy-effectiveness gap exists between clinical trial (CT) and real-world evidence (RWE), to the authors' knowledge, the magnitude of this difference remains undercharacterized. The objective of the current study was to quantify the magnitude of survival and toxicity differences between CT and RWE for contemporary cancer systemic therapies. Methods Patients receiving cancer therapies funded under Cancer Care Ontario's New Drug Funding Program (NDFP) were identified. Landmark CTs with data regarding survival and adverse events (AEs) for each drug indication were identified. RWE for survival and hospitalization rates during treatment were ascertained through Canadian population-based databases. The efficacy-effectiveness gap for each drug indication was calculated as the difference between RWE and CT data for median overall survival (OS), 1-year OS, and generated hazard ratios (HRs) with 95% CIs from Kaplan-Meier OS curves. Toxicity differences were calculated as the difference between RWE of hospitalization rates and CT serious AE rates. Results Twenty-nine indications from 20 systemic therapies were included. Twenty-eight of 29 indications (97%) demonstrated worse survival in RWE, with a median OS difference of 5.2 months (interquartile range, 3.0-12.1 months). Lower effectiveness in RWE also was demonstrated through a meta-analysis of an OS hazard ratio of 1.58 (95% CI, 1.39-1.80). The median difference between RWE for hospitalization rates and CT serious AEs was 14% (95% CI, 9%-22%). Conclusions An efficacy-effectiveness gap exists for contemporary cancer systemic therapies, with a 5.2-month lower median OS observed in RWE compared with CT data. These data supports the use of RWE to better inform real-world decision making regarding the use of cancer systemic therapies.

Background Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide-based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide-based regimens in patients with myeloma. Methods The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: "lenalidomide," "venous thromboembolism," and "multiple myeloma." Phase 1, 2, and 3 clinical trials evaluating lenalidomide-based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random-effects model. Results The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low-molecular-weight heparin or warfarin, administered either per risk-stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%-7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient-cycles (95% CI, 0.9-1.7 VTE events per 100 patient-cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events/100 patient-cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was higher with combined lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles). Conclusions Despite adequate thromboprophylaxis, lenalidomide-based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.

Background The importance of capturing and reporting health-related quality of life (HRQOL) in clinical trials has been increasingly recognized in the oncology field. As a result, the National Cancer Institute (NCI) began to provide support for correlative HRQOL studies in cancer treatment trials. The current study was conducted to assess the publication rate of HRQOL correlative studies in NCI-supported treatment trials and to identify potential factors positively or negatively associated with publication rates. Methods The NCI conducted a retrospective review of existing NCI databases to identify cancer treatment trials that had obtained additional NCI funding for the assessment of HRQOL and to determine the extent to which funded HRQOL studies have been completed and published in a peer-reviewed journal. Results Of the 108 included trials, 58 (54%) had a parent trial (PT) publication; of these, 36 trials (62%) had a published HRQOL result: 20 as an independent publication and 16 that were included and/or reported in the PT publication. The length of time between trial activation and closure, as well as the specific cancer, appeared to be associated with the publication rates. Conclusions The results of the current study demonstrated that approximately 45% of the PT publications were followed by a HRQOL publication within 1 year, to allow the knowledge to be used in patient treatment decision making. The authors believe the current analysis is an important first step toward a better understand of the challenges that researchers face when reporting HRQOL endpoints.

Lessons from extinction can be used in trials designed to pursue a cure for cancer. When cancer cannot be cured, similar strategies may be unwise, and strategies that leverage the adaptations of cancer to therapy should be considered.

Background In recent years, extensive attention has been paid to the possibility that bias among health care professionals contributes to health disparities. In its 2003 report, the Institute of Medicine concluded that bias against racial minorities may affect communication or care offered. However, to the authors' knowledge, the role of bias within the context of recruitment of racial and ethnic minorities to cancer clinical trials has not been explored to date. Therefore, the authors assessed the experiences of clinical and research personnel related to factors influencing the recruitment of racial and ethnic minorities for cancer clinical trials. Methods A total of 91 qualitative interviews were conducted at 5 US cancer centers among 4 stakeholder groups: 1) cancer center leaders; 2) principal investigators; 3) referring clinicians; and 4) research staff. Data analysis was conducted using a content analysis approach to generate themes from the transcribed interviews. Results Five prominent themes emerged: 1) recruitment interactions with potential minority participants were perceived to be challenging; 2) potential minority participants were not perceived to be ideal study candidates; 3) a combination of clinic-level barriers and negative perceptions of minority study participants led to providers withholding clinical trial opportunities from potential minority participants; 4) when clinical trial recruitment practices were tailored to minority patients, addressing research misconceptions to build trust was a common strategy; 5) for some respondents, race was perceived as irrelevant when screening and recruiting potential minority participants for clinical trials. Conclusions Not only did some respondents view racial and ethnic minorities as less promising participants, some respondents reported withholding trial opportunities from minorities based on these perceptions. Some providers endorsed using tailored recruitment strategies whereas others eschewed race as a factor in trial recruitment. The presence of bias and stereotyping among clinical and research professionals recruiting for cancer clinical trials should be considered when designing interventions to increase minority enrollment.

BACKGROUND After surgery for head and neck squamous cell carcinoma (HNSCC), decisions regarding adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) are based on staging and the presence of high-risk pathology. Because higher mutant allele tumor heterogeneity (MATH; a measure of intratumor genetic heterogeneity) is associated with shorter overall survival (OS) in patients with HNSCC, the authors sought to determine whether MATH analysis might further inform these decisions. METHODS Adjuvant therapy-associated relationships between MATH and OS were analyzed for 389 patients with HNSCC who were treated surgically. Data were obtained from The Cancer Genome Atlas and analyzed with Cox proportional hazards multiple regression accounting for 7 other patient characteristics. RESULTS The relationship between MATH and OS differed with adjuvant therapy in a way that could inform therapy decisions. Adjuvant RT alone was found to provide substantial benefit for patients having high-MATH tumors (RT vs no adjuvant therapy: hazard ratio, 0.29 [95% CI, 0.17-0.51]) but no benefit for those having low-MATH tumors. In contrast, adjuvant CRT provided no benefit beyond that of adjuvant RT for patients with high-MATH tumors but substantially improved OS among patients with low-MATH tumors (CRT vs no adjuvant therapy: hazard ratio, 0.34 [95% CI, 0.15-0.78]). CONCLUSIONS The results of the current analysis suggested that patients with HNSCC with high-MATH tumors who underwent surgical treatment could benefit from adjuvant RT, even when current clinical guidelines indicate otherwise. The addition of adjuvant chemotherapy for patients with high-MATH tumors would not be indicated. Adding chemotherapy might be necessary to radiosensitize low-MATH tumors to adjuvant RT. This potential predictive role of tumor MATH analysis should be evaluated in prospective clinical trials.

Background Selective neck dissection (SND) is a mainstay of head and neck cancer treatment. A common sequela is shoulder syndrome from spinal accessory nerve (SAN) trauma. Extensive dissection in neck levels 2 and 5 leads to SAN dysfunction. However, it is not known whether limited level 2 dissection reduces SAN injury. The purpose of this double-blind randomized controlled trial was to determine whether omitting level 2b dissection would improve shoulder-related quality of life and function. Methods Patients with head and neck cancers undergoing surgery were randomized 1:1 to SND without level 2b dissection (group 1) or with it (group 2) on their dominant-hand side. Patients, caregivers, and assessors were blinded. The primary outcome was the change in the Neck Dissection Impairment Index (NDII) score after 6 months. An a priori calculation of the minimally important clinical difference in the NDII score was determined to establish a sample size of 15 patients per group (power = 0.8). Secondary outcomes included shoulder strength and range of motion (ROM) and SAN nerve conduction. The trial was registered at ClinicalTrials.gov (NCT00765791). Results Forty patients were enrolled, and 30 were included (15 per group). Six months after the surgery, group 2 demonstrated a significant median decrease in the NDII from the baseline (30 points) and in comparison with group 1, whose NDII dropped 17.5 points (P = .02). Shoulder ROM and SAN conduction demonstrated significant declines in group 2 (P ≤ .05). No adverse events occurred. Conclusions Level 2b should be omitted in SND when this is oncologically safe and feasible. This allows for an optimal balance between function and cancer cure.

Insights from basic science dissecting carcinogenesis in the fallopian tube and ovary have led to a deeper understanding of the origin, molecular characteristics, and types of ovarian cancers. This logically then has led to the development of novel approaches to treat ovarian cancer. Increasingly, novel agents are being developed to target the different growth pathways. The identification of molecular markers associated with different histopathologies has resulted in newer clinical trial designs to capture both clinical and translational endpoints. Unique molecular characteristics in DNA damage and repair pathways and unique cell surface markers have driven new drug development, yielding promise for both patients with platinum-sensitive and platinum-resistant ovarian cancers. Specific examples described include the histology-selective mutations, such as ARID1A in clear cell and endometrioid ovarian cancers; the rationale for using cell cycle checkpoint inhibitors when there already is a p53-mediated loss of cell cycle checkpoint regulation or combinations of agents that will both induce neoantigen formation and unleash immune modulators; and techniques to enhance the therapeutic delivery of known agents. A systematic and thoughtful approach to combining agents in clinical trials is needed so that irrespective of the trial outcomes, the results inform both clinical and translational endpoints.

Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti–CTLA‐4 and anti‐PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients with BRAF V600 mutations has significantly extended survival and allowed some patients to remain in durable disease remission off therapy. It has now been confirmed that these classes of agents have a benefit for patients with stage III melanoma after surgical resection, and anti‐PD1 and BRAF/MEK inhibitors are standards of care in this setting. Some patients with stage II disease (lymph node‐negative; American Joint Committee on Cancer stage IIB and IIC) have worse melanoma‐specific survival relative to some patients with stage III disease. Given these results, expanding the population of patients who are considered for adjuvant therapy to include those with stage II melanoma has become a priority, and randomized phase 3 clinical trials are underway. Moving into the future, the validation of patient risk‐stratification and treatment‐benefit prediction models will be important to improve the number needed to treat and limit exposure to toxicity in the large population of patients with early stage melanoma., Adjuvant therapy has improved outcomes in patients with stage III melanoma and is being explored in those with stage II melanoma. Stage III data as well as risk‐stratification tools and clinical considerations for the lymph node‐negative population are reviewed.