Flutamide With or Without PROSTVAC in Non-metastatic Castration Resistant (M0) Prostate Cancer.

BACKGROUND: Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. METHODS: This was a multicenter, randomized clinical trial comparing the ARA flutamide+/-PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. RESULTS: Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. CONCLUSION: The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463).

Long-term depression incidence and associated mortality among African American and White prostate cancer survivors.

BACKGROUND: Depression is common after a diagnosis of prostate cancer and may contribute to poor outcomes, particularly among African Americans. The authors assessed the incidence and management of depression and its impact on overall mortality among African American and White veterans with localized prostate cancer. METHODS: The authors used the Veterans Health Administration Corporate Data Warehouse to identify 40,412 African American and non-Hispanic White men diagnosed with localized prostate cancer from 2001 to 2013. Patients were followed through 2019. Multivariable logistic regression was used to measure associations between race and incident depression, which were ascertained from administrative and depression screening data. Cox proportional hazards models were used to measure associations between incident depression and all-cause mortality, with race-by-depression interactions used to assess disparities. RESULTS: Overall, 10,013 veterans (24.5%) were diagnosed with depression after a diagnosis of prostate cancer. Incident depression was associated with higher all-cause mortality (adjusted hazard ratio [aHR], 1.27; 95% confidence interval [CI], 1.23-1.32). African American veterans were more likely than White veterans to be diagnosed with depression (29.3% vs 23.2%; adjusted odds ratio [aOR], 1.15; 95% CI, 1.09-1.21). Among those with depression, African Americans were less likely to be prescribed an antidepressant (30.4% vs 31.7%; aOR, 0.85; 95% CI, 0.77-0.93). The hazard of all-cause mortality associated with depression was greater for African American veterans than White veterans (aHR, 1.32 [95% CI, 1.26-1.38] vs 1.15 [95% CI, 1.07-1.24]; race-by-depression interaction P < .001). CONCLUSIONS: Incident depression is common among prostate cancer survivors and is associated with higher mortality, particularly among African American men. Patient-centered strategies to manage incident depression may be critical to reducing disparities in prostate cancer outcomes.

Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016.

Limited data are available regarding contemporary multiple myeloma (MM) treatment practices in Latin America. In this retrospective cohort study, medical records were reviewed for a multinational cohort of 1103 Latin American MM patients (median age, 61 years) diagnosed in 2008-2015 who initiated first-line therapy (LOT1). Of these patients, 33·9% underwent autologous stem cell transplantation (ASCT). During follow-up, 501 (45·4%) and 129 (11·7%) patients initiated second- (LOT2) and third-line therapy (LOT3), respectively. In the LOT1 setting, from 2008 to 2015, there was a decrease in the use of thalidomide-based therapy, from 66·7% to 42·6%, and chemotherapy from, 20·2% to 5·9%, whereas use of bortezomib-based therapy or bortezomib + thalidomide increased from 10·7% to 45·5%. Bortezomib-based therapy and bortezomib + thalidomide were more commonly used in ASCT patients and in private clinics. In non-ASCT and ASCT patients, median progression-free survival (PFS) was 15·0 and 31·1 months following LOT1 and 10·9 and 9·5 months following LOT2, respectively. PFS was generally longer in patients treated with bortezomib-based or thalidomide-based therapy versus chemotherapy. These data shed light on recent trends in the management of MM in Latin America. Slower uptake of newer therapies in public clinics and poor PFS among patients with relapsed MM point to areas of unmet therapeutic need in Latin America.

Radium-223 Safety, Efficacy, and Concurrent Use with Abiraterone or Enzalutamide: First U.S. Experience from an Expanded Access Program.

BACKGROUND: In the phase III ALSYMPCA trial, metastatic castration-resistant prostate cancer (mCRPC) patients had few prior life-prolonging therapies. Following ALSYMPCA, which demonstrated radium-223 survival benefit, and before radium-223 U.S. commercial availability, an expanded access program (EAP) providing early-access radium-223 allowed life-prolonging therapies in current use. SUBJECTS, MATERIALS, AND METHODS: This phase II, open-label, single-arm, multicenter U.S. EAP (NCT01516762) enrolled patients with symptomatic mCRPC, ≥2 bone metastases, and no lung, liver, or brain metastases. Patients received radium-223 55 kBq/kg intravenously every 4 weeks × 6. Primary outcomes were acute and long-term safety. Additional analyses were done by number of radium-223 injections, and prior or concomitant abiraterone or enzalutamide use. RESULTS: Of 252 patients, 184 received radium-223: 165/184 (90%) had Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 183 (99%) had prior systemic anticancer therapy. Treatment-related adverse events occurred in 93/184 (51%) patients during treatment and 11 (6%) during follow-up. Median overall survival was 17 months, with 134/184 (73%) patients censored because of short follow-up due to radium-223 approval. In post hoc analyses, patients with ≥3 prior anticancer medications, baseline ECOG performance status ≥2, and lower baseline hemoglobin were less likely to receive 5-6 radium-223 injections and unlikely to benefit from radium-223. Radium-223 was well tolerated regardless of concurrent or prior abiraterone or enzalutamide. CONCLUSION: Radium-223 was well tolerated, with no new safety concerns; safety was maintained with abiraterone or enzalutamide. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline characteristics and therapy sequence for greatest clinical value. IMPLICATIONS FOR PRACTICE: In this phase II U.S. expanded access program, radium-223 was well tolerated, with a median overall survival of 17 months in metastatic castration-resistant prostate cancer patients. In post hoc analyses, radium-223 was safe regardless of concurrent abiraterone or enzalutamide, and median overall survival appeared longer when radium-223 was used earlier in patients with less prior treatment. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline clinical characteristics and therapy sequence to provide the greatest clinical value to patients.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND: Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS: We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS: A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.).

Clinical risk score to predict likelihood of recurrence after ductal carcinoma in situ treated with breast-conserving surgery.

PURPOSE: A majority of women with ductal carcinoma in situ (DCIS) receive breast-conserving surgery (BCS) but then face a risk of ipsilateral breast tumor recurrence (IBTR) which can be either recurrence of DCIS or invasive breast cancer. We developed a score to provide individualized information about IBTR risk to guide treatment decisions. METHODS: Data from 2762 patients treated with BCS for DCIS at centers within the National Comprehensive Cancer Network (NCCN) were used to identify statistically significant non-treatment-related predictors for 5-year IBTR. Factors most associated with IBTR were estrogen-receptor status of the DCIS, presence of comedo necrosis, and patient age at diagnosis. These three parameters were used to create a point-based risk score. Discrimination of this score was assessed in a separate DCIS population of 301 women (100 with IBTR and 200 without) from Kaiser Permanente Northern California (KPNC). RESULTS: Using NCCN data, the 5-year likelihood of IBTR without adjuvant therapy was 9% (95% CI 5-12%), 23% (95% CI 13-32%), and 51% (95% CI 26-75%) in the low, intermediate, and high-risk groups, respectively. Addition of the risk score to a model including only treatment improved the C-statistic from 0.69 to 0.74 (improvement of 0.05). Cross-validation of the score resulted in a C-statistic of 0.76. The score had a c-statistic of 0.67 using the KPNC data, revealing that it discriminated well. CONCLUSIONS: This simple, no-cost risk score may be used by patients and physicians to facilitate preference-based decision-making about DCIS management informed by a more accurate understanding of risks.

Treating Second Breast Events After Breast-Conserving Surgery for Ductal Carcinoma in Situ.

Background: Because of screening mammography, the number of ductal carcinoma in situ (DCIS) survivors has increased dramatically. DCIS survivors may face excess risk of second breast events (SBEs). However, little is known about SBE treatment or its relationship to initial DCIS care. Methods: Among a prospective cohort of women who underwent breast-conserving surgery (BCS) for DCIS from 1997 to 2008 at institutions participating in the NCCN Outcomes Database, we identified SBEs, described patterns of care for SBEs, and examined the association between DCIS treatment choice and SBE care. Using multivariable regression, we identified features associated with use of mastectomy, radiation therapy (RT), or antiestrogen therapy (AET) for SBEs. Results: Of 2,939 women who underwent BCS for DCIS, 83% received RT and 40% received AET. During the median follow-up of 4.2 years, 200 women (6.8%) developed an SBE (55% ipsilateral, 45% invasive). SBEs occurred in 6% of women who underwent RT for their initial DCIS versus 11% who did not. Local treatment for these events included BCS (10%), BCS/RT (30%), mastectomy (53%), or none (6%); only 28% of patients received AET. Independent predictors of RT or mastectomy for SBEs included younger age, shorter time to SBE diagnosis, and RT or AET for the initial DCIS. Conclusions: A sizable proportion of patients with SBEs were treated with mastectomy, most especially those who previously received RT for their initial DCIS and those who developed an ipsilateral SBE. Despite the occurrence of an SBE, relatively few patients received AET. Future studies should investigate optimal treatment approaches for SBEs, including the benefit of mastectomy versus lumpectomy for an ipsilateral SBE and the benefit of AET for a hormone-receptor-positive SBE contingent on AET use for the initial DCIS diagnosis.

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Validation of Molecular Pathology Codes for the Identification of Mutational Testing in Lung and Colon Cancer.

BACKGROUND: Targeted therapy for patients with lung and colon cancer based on tumor molecular profiles is an important cancer treatment strategy, but the impact of gene mutation tests on cancer treatment and outcomes in large populations is not clear. In this study, we assessed the accuracy of an algorithm to identify tumor mutation testing in administrative claims data during a period before test-specific Current Procedural Terminology codes were available. MATERIALS AND METHODS: We used Pennsylvania Cancer Registry data to select patients with lung or colon cancer diagnosed between 2007 and 2011 who were treated at the University of Pennsylvania Health System, and we obtained their administrative claims. A combination of Current Procedural Terminology laboratory codes (stacking codes) was used to identify potential tumor mutation testing in the claims data. Patients' electronic medical records were then searched to determine whether tumor mutation testing actually had been performed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: An algorithm using stacking codes had moderate sensitivity (86% for lung cancer and 81% for colon cancer) and high specificity (98% for lung cancer and 96% for colon cancer). Sensitivity and specificity did not vary significantly during 2007-2011. In patients with lung cancer, PPV was 98% and NPV was 92%. In patients with colon cancer, PPV was 96% and NPV was 83%. CONCLUSIONS: An algorithm using stacking codes can identify tumor mutation testing in administrative claims data among patients with lung and colon cancer with a high degree of accuracy.

Understanding Treatment Disconnect and Mortality Trends in Renal Cell Carcinoma Using Tumor Registry Data.

BACKGROUND AND OBJECTIVES: The paradoxical rise in overall and cancer-specific mortality despite increased detection and treatment of renal cell carcinoma (RCC) is termed "treatment disconnect." We reassess this phenomenon by evaluating impact of missing data and rising incidence on mortality trends. RESEARCH DESIGN, SUBJECTS, AND MEASURES: Using Surveillance, Epidemiology, and End Results data, we identified patients with RCC diagnosis from 1973 to 2011. We estimated mortality rates by tumor size after accounting for lags from diagnosis to death using multiple imputations for missing data from 1983. Mortality rates were estimated irrespective of tumor size after adjustment for prior cumulative incidence using ridge regression. RESULTS: A total of 78,891 patients met inclusion criteria. Of 70,212 patients diagnosed since 1983, 10.4% had missing data. Significant attenuation in cancer-specific mortality was noted from 1983 to 2011 when comparing observed with imputed rates: Δobs0.05 versus Δimp0.10 (P=0.001, <2 cm tumors); Δobs0.29 versus Δimp0.18 (P=0.005, 2-4 cm tumors); Δobs0.46 versus Δimp-0.20 (P<0.001, 4-7 cm tumors); Δobs0.93 versus Δimp-0.15 (P<0.001, >7 cm tumors). Holding incidence of RCC constant to 2011 rates, temporal increase in overall mortality for all patients was attenuated (P<0.001) when comparing observed estimates (3.9-6.8) with 2011 adjusted estimates (5.9-7.1), suggesting that rapidly rising incidence may influence reported overall mortality trends. These findings were supported by assessment of mortality to incidence ratio trends. CONCLUSIONS: Missing data and rising incidence may contribute substantially to the "treatment disconnect" phenomenon when examining mortality rates in RCC using tumor registry data. Caution is advised when basing clinical and policy decisions on these data.

Distress and Financial Distress in Adults With Cancer: An Age-Based Analysis.

Background: Although financial distress is commonly recognized in patients with cancer, it may be more prevalent in younger adults. This study sought to evaluate disparities in overall and financial distress in patients with cancer as a function of age. Methods: This was a single-center cross-sectional study of patients with solid malignancies requiring cancer therapy. The patient questionnaire included demographics, financial concerns, and measures of overall and financial distress. Data analyses compared patients in 3 age groups: young (<50 years), middle-aged (50-64 years), and elderly (≥65 years). Results: The cohort included 119 patients (median age, 62 years; 52% female; 84% white; 100% insured; 36% income ≥$75,000). Significant financial concerns included paying rent/mortgage (P=.003) and buying food (P=.032). Impact of Event Scale (IES) results revealed significant distress in 73% young, 64% middle-aged, and 44% elderly patients. The mean Distress Thermometer (DT) score was 6.1 (standard deviation [SD], 2.9) for young patients, 5.4 (SD, 2.6) for middle-aged, and 4.4 (SD, 3.3) for elderly patients. Young patients were more likely than elderly patients to have a higher IES distress score (P=.016) and DT score (P=.048). The mean InCharge score was lowest (indicating greatest financial distress) in the young group and progressed with age: 5.0 (SD, 1.9), 5.7 (SD, 2.7), and 7.4 (SD, 1.9), respectively (P<.001). Multivariable analyses revealed that the relationship between financial distress and overall distress was strongest in the middle-age group; as the DT increased by 1 point, the InCharge scores decreased by 0.52 (P<.001). Conclusions: Overall and financial distress are more common in young and middle-aged patients with cancer. There are several factors, including employment, insurance, access to paid sick leave, children, and education, that affect younger and middle-aged adults and are less of a potential stressor for elderly individuals.

Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.

BACKGROUND: A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. METHODS: In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. FINDINGS: Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. INTERPRETATION: A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. FUNDING: None.

Chemotherapy use and adoption of new agents is affected by age and comorbidities in patients with metastatic colorectal cancer.

BACKGROUND: The treatment of metastatic colorectal cancer (mCRC) has changed substantially in the last 2 decades, but to the authors' knowledge, the effect of age and comorbidities on chemotherapy use has not been well studied to date. METHODS: Patients with mCRC who were being treated with 5-fluorouracil (5-FU)-based chemotherapy between January 1995 to December 2009 were studied using the LifeLink Health Plan Claims Database. The cohort was divided into older (aged >70 years) and younger (aged ≤70 years) patients. The Charlson Comorbidity Index (CCI) was used to assess comorbidity burden. The Wilcoxon and chi-square tests were used in univariate and logistic regression in multivariate analyses. RESULTS: A total of 16,087 patients were identified, with 24% of the patients who were receiving chemotherapy being aged >70 years. The percentage of patients with a CCI >1 receiving chemotherapy increased over time (14% in 1996 vs 40% after 2004; P<.05). Older patients were less likely to receive treatment with >2 agents compared with younger patients (15% vs.22% and 11% vs.16%, respectively, in 2003 and 2009; P<.001). After approval by the US Food and Drug Administration in 1998, the use of irinotecan was lower in older compared with younger patients, a difference that resolved by 2002 (15% vs 38% [P<.05]; 62% in both groups [P = .9], respectively). Similarly, oxaliplatin was used more frequently in younger patients in 2003 (22% vs 15%; P<.05), with a decrease in this difference noted by 2009 (64% vs 60%; P = .95). On multivariate analysis, older age (odds ratio, 0.65; P<.001) and a CCI >1 (odds ratio, 0.84; P<.001) were found to be associated with a lower likelihood of receiving combination chemotherapy. CONCLUSIONS: In this commercially insured population, the percentage of older patients treated for mCRC was low, and the rate of chemotherapy adoption was found to lag behind that of younger patients. However, the percentage of older patients with comorbidities receiving therapy increased over time. Cancer 2016;122:3191-8. © 2016 American Cancer Society.

The Parity Paradigm: Can Legislation Help Reduce the Cost Burden of Oral Anticancer Medications?

Over the last decade, there has been increased development and use of oral anticancer medications, which sometimes leads to high cost sharing for patients. Drug parity laws require insurance plans to cover oral anticancer medications with the same cost sharing as intravenous/injected chemotherapy or have a capped limit on out-of-pocket costs. There are currently 36 enacted state laws (plus the District of Columbia) addressing drug parity, but no federal laws. In this policy perspective piece, we discuss the history, opportunities, and limitations of drug parity laws in oncology. We also discuss the implications of provisions of the Affordable Care Act and other proposed policy reforms on financing oral chemotherapy.

Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer.

BACKGROUND: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC. RESULTS: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48). CONCLUSIONS: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice.

Temporal trends and factors associated with systemic therapy after cytoreductive nephrectomy: an analysis of the National Cancer Database.

PURPOSE: We evaluated temporal trends in systemic therapy use in patients undergoing cytoreductive nephrectomy for metastatic renal cell carcinoma. We used data from a large national cancer registry and assessed characteristics associated with the receipt of systemic treatment. MATERIALS AND METHODS: We reviewed the NCDB to identify patients with stage IV renal cell carcinoma who underwent cytoreductive nephrectomy between 1998 and 2010. Systemic therapy was defined as immunotherapy and/or chemotherapy, including targeted agents. We evaluated associations between clinicopathological features and receipt of systemic therapy using multivariable logistic regression with generalized estimating equations. RESULTS: Of 22,409 patients with metastatic renal cell carcinoma treated with cytoreductive nephrectomy 8,830 (39%) received systemic therapy. Use of systemic therapy increased from 32% of cases in 1998 to 49% in 2010 (p < 0.001). After adjustment older patient age (71 years or greater OR 0.36, CI 0.31-0.43), increasing comorbidity count (Charlson comorbidity index 2 or greater OR 0.79, 95% CI 0.68-0.92), papillary histology (OR 0.81, 95% CI 0.71-0.93), sarcomatoid histology (OR 0.88, 95% CI 0.80-0.98), Medicaid (OR 0.61, 95% CI 0.5-0.74), Medicare (OR 0.70, 95% CI 0.62-0.79) and no insurance (OR 0.75, 95% CI 0.63-0.91) were associated with significantly decreased systemic therapy use. Male gender (OR 1.05, 95% CI 1.02-1.08) predicted an increased likelihood of systemic therapy. CONCLUSIONS: Systemic therapy in patients undergoing cytoreductive nephrectomy has increased with time, coinciding with the introduction of targeted therapies. Nevertheless, still less than half of such patients receive systemic treatment. While the etiology of the lack of treatment is likely multifactorial, the potential health policy implications of disparities in care warrant further investigation.

Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors.

INTRODUCTION: Drugs inhibiting the mammalian target of rapamycin (mTOR) are approved in the treatment of renal cell carcinoma (RCC), but resistance inevitably emerges. Proposed escape pathways include increased phosphorylation of Akt, which can be down regulated by histone deacetylase (HDAC) inhibitors. We hypothesized that co-treatment with the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat may abrogate resistance in RCC. METHODS: This phase 1 study evaluated the co-administration of ridaforolimus and vorinostat in patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD) in RCC patients. Although all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. Using a modified 3 + 3 dose escalation design, various dose combinations were tested concurrently in separate cohorts. Efficacy was a secondary endpoint. RESULTS: Fifteen patients were treated at one of three dose levels, thirteen with RCC (10 clear cell, 3 papillary). Dosing was limited by thrombocytopenia. The MTD was determined to be ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg BID days 1-3 weekly, however late onset thrombocytopenia led to a lower recommended phase II dose: ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg daily days 1-3 weekly. Two patients, both with papillary RCC, maintained disease control for 54 and 80 weeks, respectively. CONCLUSIONS: The combination of ridaforolimus and vorinostat was tolerable at the recommended phase II dose. Two patients with papillary RCC experienced prolonged disease stabilization, thus further study of combined HDAC and mTOR inhibition in this population is warranted.

Why Summary Comorbidity Measures Such As the Charlson Comorbidity Index and Elixhauser Score Work.

BACKGROUND: Comorbidity adjustment is an important component of health services research and clinical prognosis. When adjusting for comorbidities in statistical models, researchers can include comorbidities individually or through the use of summary measures such as the Charlson Comorbidity Index or Elixhauser score. We examined the conditions under which individual versus summary measures are most appropriate. METHODS: We provide an analytic proof of the utility of comorbidity summary measures when used in place of individual comorbidities. We compared the use of the Charlson and Elixhauser scores versus individual comorbidities in prognostic models using a SEER-Medicare data example. We examined the ability of summary comorbidity measures to adjust for confounding using simulations. RESULTS: We devised a mathematical proof that found that the comorbidity summary measures are appropriate prognostic or adjustment mechanisms in survival analyses. Once one knows the comorbidity score, no other information about the comorbidity variables used to create the score is generally needed. Our data example and simulations largely confirmed this finding. CONCLUSIONS: Summary comorbidity measures, such as the Charlson Comorbidity Index and Elixhauser scores, are commonly used for clinical prognosis and comorbidity adjustment. We have provided a theoretical justification that validates the use of such scores under many conditions. Our simulations generally confirm the utility of the summary comorbidity measures as substitutes for use of the individual comorbidity variables in health services research. One caveat is that a summary measure may only be as good as the variables used to create it.

Characteristics of clinical trials that require participants to be fluent in English.

BACKGROUND/AIMS: Diverse samples in clinical trials can make findings more generalizable. We sought to characterize the prevalence of clinical trials in the United States that required English fluency for participants to enroll in the trial. METHODS: We randomly chose over 10,000 clinical trial protocols registered with ClinicalTrials.gov and examined the inclusion and exclusion criteria of the trials. We compared the relationship of clinical trial characteristics with English fluency inclusion requirements. We merged the ClinicalTrials.gov data with US Census and American Community Survey data to investigate the association of English-language restrictions with ZIP-code-level demographic characteristics of participating institutions. We used Chi-squared tests, t-tests, and logistic regression models for analyses. RESULTS: English fluency requirements have been increasing over time, from 1.7% of trials having such requirements before 2000 to 9.0% after 2010 (p < 0.001 from Chi-squared test). Industry-sponsored trials had low rates of English fluency requirements (1.8%), while behavioral trials had high rates (28.4%). Trials opening in the Northeast of the United States had the highest regional English requirement rates (10.7%), while trials opening in more than one region had the lowest (3.3%, p<0.001). Since 1995, trials opening in ZIP codes with larger Hispanic populations were less likely to have English fluency requirements (odds ratio=0.92 for each 10% increase in proportion of Hispanics, 95% confidence interval=0.86-0.98, p=0.013). Trials opening in ZIP codes with more residents self-identifying as Black/African American (odds ratio=1.87, 95% confidence interval=1.36-2.58, p<0.001 for restricted cubic spline term) or Asian (odds ratio=1.16 for linear term, 95% confidence interval=1.07-1.25, p<0.001) were more likely to have English fluency requirements. ZIP codes with higher poverty rates had trials with more English-language restrictions (odds ratio=1.06 for a 10% poverty rate increase, 95% confidence interval=1.001-1.11, p=0.045). There was a statistically significant interaction between year and intervention type, such that the increase in English fluency requirements was more common for some interventions than for others. CONCLUSION: The proportion of clinical trials registered with ClinicalTrials.gov that have English fluency requirements for study inclusion has been increasing over time. English-language restrictions are associated with a number of characteristics, including the demographic characteristics of communities in which the sponsoring institutions are located.

A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma.

BACKGROUND: Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 µg/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles. RESULTS: Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 µg/m² every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥ 80 months, respectively. Partial responses were seen in both clear cell and papillary histology. CONCLUSION: This combination of 37.5 mg of temsirolimus with 20 µg/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.