Do female and male patients derive similar benefits from approved systemic oncology therapies? A systematic review and meta-analysis.

PURPOSE: The National Institutes of Health's policy for the inclusion of females in clinical research was a pivotal step towards the consideration of sex as a biological variable, which is of particular importance in oncology, given differential incidence and outcomes of cancer between the sexes, and known pharmacodynamic, pharmacokinetic, and immunological differences. Therefore, we aim to investigate if such biological sex-based differences translate to clinically meaningful outcome differences from recently approved systemic oncology therapies. METHODS: A systematic review of randomized control trials (RCTs) cited in Food and Drug Administration, European Medicines Agency, and Health Canada approvals was conducted. Chemotherapy, targeted agents, and immunotherapy RCTs reporting sex-based sub-group analyses for overall/progression-free survival (OS/PFS) were considered. Hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized. Sensitivity analyses for survival endpoints, drug type, and cancer site were conducted. RESULTS: Ninety-nine RCTs were included, representing 62,384 patients (23,574 (38%) female). Pooled OS HRs [95% CIs] were 0.77 [0.72-0.81] and 0.76 [0.72-0.79] for females and males, respectively (P = 0.73), and 0.51 [0.47-0.56] and 0.57 [0.53-0.61] (P = 0.08) for PFS. Sensitivity analyses yielded similar results. No RCTs reported sex-based toxicity or quality-of-life (QOL) data. CONCLUSION: Female and male patients appear to derive comparable benefits from recently approved systemic oncology therapies. Future RCTs are encouraged to report sex-based toxicity and QOL data.

Economic Evaluation of a Geriatric Oncology Clinic.

Geriatric assessment (GA) is supported by recent trials and guidelines yet rarely implemented due to a lack of resources. We performed an economic evaluation of a geriatric oncology clinic. Pre-GA proposed treatments and post-GA actual treatments were obtained from a detailed chart review of patients seen at a single academic centre. GA-based costs for investigations and referrals were calculated. Unit costs were obtained for surgical, radiation, systemic therapy, laboratory, imaging, physician, nursing, and allied health care (all in 2019 Canadian dollars). A six-month time horizon and government payer perspective were used. Consecutive patients aged 65 years or older (n = 152, mean age 82 y) and referred in the pre-treatment setting between July 2016 and June 2018 were included. Treatment plans were modified for 51% of patients. Costs associated with planned treatment were CAD 3,655,015. Costs associated with GA and related interventions were CAD 95,798. Final treatment costs were CAD 2,436,379. Net savings associated with the clinic were CAD 1,122,837, or CAD 7387 per patient seen. Findings were robust in multiple sensitivity analyses. Combined with mounting trial data demonstrating the clinical benefits of GA, our data can inform a strong business case for geriatric oncology clinics in health care environments similar to ours, but additional studies in diverse health care settings are warranted.

Assessment of Food and Drug Administration- and European Medicines Agency-Approved Systemic Oncology Therapies and Clinically Meaningful Improvements in Quality of Life: A Systematic Review.

Importance: For patients with cancer treated with palliative intent, quality of life (QOL) is a critical aspect of treatment decision-making, alongside survival. However, regulatory approval can be based solely on survival measures or antitumor activities, without QOL evidence. Objective: To investigate whether recently approved oncology therapies demonstrate clinically meaningful improvements in QOL. Evidence Review: This systematic review study identified oncology drug indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) from January 2006 to December 2017 and supporting clinical trials (QOL publications identified to October 2019). Indications were evaluated for the presence of published QOL evidence; QOL benefits according to the American Society of Clinical Oncology Value Framework version 2.0 (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) QOL bonus criteria; and clinically meaningful improvements in QOL beyond minimal clinically important differences. Hematology trials were not evaluated by ESMO-MCBS. Associations between QOL evidence and approval year were examined using logistic regression models. Findings: In total, 214 FDA-approved (77 [36%] hematological) and 170 EMA-approved (52 [31%] hematological) indications were included. QOL evidence was published for 40% and 58% of FDA- and EMA-approved indications, respectively. QOL bonus criterion for ASCO-VF and ESMO-MCBS was met in 13% and 17% of FDA-approved and 21% and 24% of EMA-approved indications, respectively. Clinically meaningful improvements in QOL beyond minimal clinically important differences were noted in 6% and 11% of FDA- and EMA-approved indications, respectively. Availability of published QOL evidence at the time of approval increased over time for EMA (odds ratio [OR], 1.13; P = .03), however not for FDA (OR, 1.10; P = .12). Over time, no increase in awarded QOL bonuses or clinically meaningful improvements in QOL were found. Conclusions and Relevance: The findings of this systematic review suggest that approved systemic oncology therapies often do not have published evidence to suggest QOL improvement, despite its recognized importance. Of indications with evidence of statistical improvement, few have demonstrated clinically meaningful improvements.

Comparing Manufacturer Submitted and Pan-Canadian Oncology Drug Review Reanalysed Incremental Cost-Effectiveness Ratios for Novel Oncology Drugs.

BACKGROUND: To determine the magnitude of difference between manufacturer-submitted and pan-Canadian Oncology Drug Review (pCODR) calculated incremental cost-effectiveness ratios (ICERs), incremental cost (ΔC), and incremental effectiveness (ΔE); to examine whether there is a significant difference in the proportion of ICERs deemed cost-effective; to evaluate trends in the ICERs over time; and to identify methodological issues in manufacturer-submitted economic models. METHODS: Economic guidance reports for all drug indications submitted from July 2011-November 2018 were extracted from the pCODR database. Cumulative distribution plots were constructed to compare the manufacturer-submitted economic values with both the pCODR lower- and upper-reanalyzed estimates. The proportion of drug reviews considered cost-effective at varying willingness-to-pay (WTP) thresholds by the manufacturer and pCODR were calculated. Manufacturer changes in ICERs over time from 2012 to 2018 were determined. Recurring methodological issues with manufacturer submissions were tallied. RESULTS: There were 73 unique indications that were included. Manufacturer-submitted ICERs were consistently lower than pCODR estimates for most indications. Manufacturer-submitted ICERs were generally more cost-effective over a range of WTP thresholds. From 2012 to 2018, manufacturer and economic guidance panel (EGP) lower limit reanalyzed ICERs did not change significantly over time. However, EGP upper limit re-analyses did show decreasing cost-effectiveness (increasing ICERs). The two most common issues identified in the manufacturer-submitted models were related to survival time horizon and utility estimates. CONCLUSIONS: Manufacturers tend to overestimate the cost-effectiveness of their therapies when submitting economic models to pCODR. Although certain methodological issues are still common in manufacturer-submitted models, revision rates are high for most issues raised by pCODR.

Application of the ASCO Value Framework and ESMO Magnitude of Clinical Benefit Scale to Assess the Value of Abiraterone and Enzalutamide in Advanced Prostate Cancer.

PURPOSE: As novel hormonal therapies, such as abiraterone and enzalutamide, move into earlier stages of treatment of advanced prostate cancer, there are significant cost implications. We used the ASCO Value Framework (AVF) and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) to quantify and compare the incremental clinical benefit and costs of these agents in the metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC) settings. METHODS: We searched PubMed for randomized phase III trials of abiraterone and enzalutamide in mCRPC and mCSPC. Incremental clinical benefit was quantified using the AVF and ESMO-MCBS by 2 independent assessors. Incremental drug costs were calculated using average wholesale prices (AWPs) from the RED BOOK Online. RESULTS: In mCRPC, 2 abiraterone trials (COU-AA-301 and COU-AA-302) and 2 enzalutamide trials (AFFIRM and PREVAIL) met search criteria. AVF scores ranged from 46.3 to 66.6, suggesting clinical benefit; ESMO-MCBS scores ranged from 3 to 5, with lower clinical benefit in the mCRPC predocetaxel setting. The overall incremental AWP ranged from $83,460.94 to $205,128.85. In mCSPC, 4 trials met criteria (LATITUDE, STAMPEDE, ENZAMET, and ARCHES; AVF scores were 79.8, 33.3, 59, and 17, respectively). All of the studies showed benefit except ARCHES. By ESMO-MCBS, both LATITUDE and STAMPEDE showed benefit (score for 4 for both studies); ENZAMET and ARCHES were not evaluable. The overall cost of treatment was significantly higher in the mCSPC setting. CONCLUSION: The AVF and ESMO-MCBS frameworks generated slightly different results but suggested that abiraterone and enzalutamide show clinical benefit in both mCRPC and mCSPC but trended to lower clinical benefit and increased costs in earlier disease stages. Further refinement of the AVF and ESMO-MCBS is needed to facilitate their use and their ability to inform clinical practice in a rapidly changing treatment landscape.

Adjuvant treatment for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis.

Adjuvant chemotherapy has significantly improved outcomes following surgical resection for pancreatic adenocarcinoma; however, the optimal adjuvant strategy remains unclear. This systematic review and network meta-analysis was conducted to provide indirect comparative evidence across adjuvant chemotherapies. Electronic searches of EMBASE, MEDLINE, Cochrane and ASCO databases were conducted to identify eligible randomized controlled trials (RCT). Direct pairwise meta-analysis was conducted for disease-free survival (DFS), overall-survival (OS) and adverse events (AE). Network meta-analysis of DFS and OS was conducted to evaluate indirect comparisons. Ten publications of eleven RCT met eligibility criteria. Indirect DFS comparison demonstrated superiority of mFOLFIRINOX versus gemcitabine-capecitabine, gemcitabine-erlotinib and gemcitabine-nab-paclitaxel. S-1 demonstrated a DFS benefit versus gemcitabine-capecitabine, gemcitabine-erlotinib, gemcitabine-nab-paclitaxel. OS benefits were demonstrated for mFOLFIRINOX verus gemcitabine-erlotinib and for S-1 versus gemcitabine-based combination with erlotinib, capecitabine and nab-paclitaxel. In conclusion, mFOLFIRINOX is the preferred approach for adjuvant therapy. For mFOLFIRINOX-ineligible patients no additional benefit is seen with gemcitabine-nab-paclitaxel.

Value-based pricing: Toward achieving a balance between individual and population gains in health benefits.

OBJECTIVES: Value-based pricing of oncology drugs provides a best estimate for the price of a drug, as it relates to the benefits it provides for individual patients. To date, the impact of value-based pricing to reference cost-effectiveness thresholds (λ) on individual and population-level health benefits remains uncharacterized. The current study examined the potential benefits of value-based pricing by quantifying the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at manufacturer-submitted price without value-based pricing. METHODS: Pan-Canadian Oncology Drug Review (pCODR) submissions were reviewed to identify eligible drug indications from which final economic guidance panel reports were reviewed for incremental costs (ΔC) and quality-adjusted life-years (ΔQALY) from manufacturer-submitted, pCODR lower-limit (pCODR-LL) and upper-limit (pCODR-UL) re-analyzed estimates. Annual number of cases in Ontario for each drug indication was obtained from population databases. Annual QALY gain per drug indication was determined by (ΔQALY × cases). Population QALY gain/loss in the absence of value-based pricing to reference λ was estimated by the INHB: (INHB = [ΔQALY - (ΔC/λ)] × cases). RESULTS: In total, 34 drug indications (4629 cases) were identified. Annual gain in QALYs for the funded drug indications using manufacturer, pCODR-LL, and pCODR-UL estimates was 1851, 1617, and 1301, respectively. At a λ $100 000/QALY, funding in the absence of value-based pricing resulted in loss of 2311, 2519, and 2604 QALYs. This would result in a provincial net annual loss of 460, 902, and 1303 QALYs. CONCLUSIONS: Despite an annual gain in QALY per funded drug indication, a net loss in QALY for the province, in the absence of value-based pricing, was demonstrated. Supportive evidence exists for value-based pricing toward the promotion of health benefits for the greater population.

Estimating hazard ratios from published Kaplan-Meier survival curves: A methods validation study.

OBJECTIVE: Various statistical methods have been developed to estimate hazard ratios (HRs) from published Kaplan-Meier (KM) curves for the purpose of performing meta-analyses. The objective of this study was to determine the reliability, accuracy, and precision of four commonly used methods by Guyot, Williamson, Parmar, and Hoyle and Henley. DESIGN: Pivotal randomized controlled trials (RCTs) in oncology were identified from the pan-Canadian Oncology Drug Review (pCODR) database (primary analysis) and the Food and Drug Administration's (FDA) drug approvals page (secondary analysis) between January 2012 and May 2016. Two reviewers independently reconstructed HRs using each method on KM curves extracted from each trial and compared them with reported HRs (gold standard). Bland-Altman plots and summary statistics were calculated to assess accuracy and precision of these methods. Interrater reliability was assessed using intraclass correlation coefficient (ICC). These four methods were also applied to KM curves of different structures (ie, flat versus steep curves). RESULTS: A total of 118 KM curves (55 RCTs) and 77 KM curves (46 RCTs) were extracted from pCODR and FDA, respectively. In the primary analysis, the Guyot method was the most accurate with the lowest mean error (0.0094; 95% CI, -0.0012-0.020). All four methods had excellent interrater reliability. The Guyot method showed the smallest bias and greatest precision on the Bland-Altman plots. The Guyot method was consistently superior in both the secondary and all sensitivity analyses. CONCLUSION: In the absence of reported HRs, we recommend that researchers consider the Guyot method to reconstruct HRs from KM curves when performing aggregate data meta-analyses.

Assessment of Whether the American Society of Clinical Oncology's Value Framework and the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale Measure Absolute or Relative Clinical Survival Benefit: An Analysis of Randomized Clinical Trials.

IMPORTANCE: The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have independently published value frameworks. To date, whether the clinical benefit scoring algorithms from these framework were intended to measure absolute or relative survival benefit remains unclear. OBJECTIVE: To empirically examine the measurement characteristics of these frameworks by comparing their survival efficacy components (ASCO clinical benefit score [CBS] and ESMO preliminary magnitude of clinical benefit grade [PMCBG]) with established measures of absolute (median survival difference and restricted mean survival time [RMST] difference) and relative (hazard ratios [HRs]) survival benefit. DATA SOURCES: The US Food and Drug Administration (FDA)'s Hematology and Oncology Approvals and Safety Notifications database was retrospectively reviewed to identify phase 3 randomized controlled trials (RCTs) cited for clinical efficacy evidence in oncology drug approvals from January 1, 2006, through December 31, 2017. STUDY SELECTION: Two reviewers searched the database for initial trials cited for approval. Phase 3 trials with overall survival, progression-free survival, and/or time to progression as their primary or coprimary end points were included. Notifications for noncancer indications or presenting label changes and trials that did not report HRs for the required end points and/or did not publish survival curves with number-at-risk data were excluded. Of 269 notifications initially identified, 107 met the selection criteria. DATA EXTRACTION AND SYNTHESIS: Sensitivity analyses were conducted by calculating the scores using (1) the framework-defined end point, including tail-of-curve bonus points (ASCO) or long-term plateau adjustments (ESMO) (framework-defined end point plus tail-of-curve bonus), (2) overall survival data only, and (3) progression-free survival data only. For primary and sensitivity analyses, Spearman correlation coefficients were calculated to examine the relationships between (1) ASCO-CBS or ESMO-PMCBG and RMST difference, (2) ASCO-CBS or ESMO-PMCBG and median survival difference, and (3) ASCO-CBS or ESMO-PMCBG and HR. Data were analyzed from January 7 through April 30, 2018. MAIN OUTCOMES AND MEASURES: In the primary analysis, ASCO-CBSs and ESMO-PMCBGs were calculated for the included trials using the framework-defined end point. RESULTS: Compared with measures of absolute survival benefit, ESMO-PMCBGs showed low to moderate correlations with RMST difference (ρ = 0.44) and moderate to high correlations with median survival difference (ρ = 0.64). ASCO-CBSs showed low to moderate correlations with both measures of absolute benefit (ρ = 0.43 for RMST difference; ρ = 0.44 for median survival). Compared with a relative measure of survival (HRs), ESMO-PMCBGs showed a low correlation (ρ = 0.47) and ASCO-CBSs showed a higher correlation (ρ = 0.76). CONCLUSIONS AND RELEVANCE: Neither framework consistently performed as an absolute measure of survival benefit. The incorporation of a direct measure of absolute clinical benefit, such as RMST difference, into the survival efficacy components of their algorithms should be considered.

Do older and younger patients derive similar survival benefits from novel oncology drugs? A systematic review and meta-analysis.

Background: older patients are commonly believed to derive less benefit from cancer drugs, even if they fulfil clinical trial eligibility [Talarico et al. (2004, J Clin Oncol, 22(22):4626-31)]. We aim to examine if novel oncology drugs provide differential age-based treatment outcomes for patients on clinical trials. Methods: a systematic review of randomised control trials (RCTs) cited for clinical efficacy evidence in novel oncology drug approvals by the Food and Drug Administration, European Medicines Agency and Health Canada between 2006 and 2017 was conducted. Studies reporting age-based subgroup analyses for overall or progression-free survival (OS/PFS) were included. Hazard ratios (HRs) and confidence intervals (CIs) for age-based subgroups were extracted. Meta-analyses with random effects were conducted, examining patient subgroups <65 and ≥65 years separately and pooled HRs of studies primary endpoints (OS or PFS) compared to examine if differences existed between age-based subgroups. Sensitivity analyses were conducted for cancer type, primary endpoint and systemic treatment. Results: one-hundred-two RCTs, including 65,122 patients, met the inclusion criteria. One study reported age-based toxicity and none reported age-based quality of life (QOL) results. Pooled HRs [95% CIs] for patients <65 and ≥65 years were 0.61 [0.57-0.65] and 0.65 [0.61-0.70], respectively, with no difference between them (P = 0.14). Sensitivity analyses revealed similar results. Conclusion: our results suggest that older and young patients, who fulfil clinical trial eligibility, may derive similar relative survival benefits from novel oncology drugs. There is, however, a need to report age-based toxicity and QOL results to support patient discussions regarding the balance of treatment benefit and harm, to encourage informed decision-making.

Examining Trends in Cost and Clinical Benefit of Novel Anticancer Drugs Over Time.

PURPOSE: The purpose of this study was to determine if clinical benefits of novel anticancer drugs, measured by the ASCO Value Framework and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale, have increased over time in parallel with increasing costs. METHODS: Anticancer drugs from phase III randomized controlled trials cited for clinical efficacy evidence in drug approvals between January 2006 to December 2015 were identified and scored using both frameworks. For each drug, the monthly price and incremental anticancer drug costs were calculated. Relationships between cost and year of approval were examined using generalized linear regressions models. Ordinary least square models were used to evaluate relationships between ASCO and ESMO scores and year of approval. Spearman correlation coefficients between costs and clinical benefit scores were calculated. RESULTS: In total, 42 randomized controlled trials were included. Both monthly prices and incremental anticancer drug costs were significantly associated with year of approval and showed an average annual increase of 9% and 21%, respectively. The predicted mean incremental anticancer drug cost increased from $30,447 in 2006 to $161,141 in 2015 (greater than five-fold increase). Both ASCO and ESMO scores were not statistically associated with year of approval or correlated with monthly prices or incremental anticancer drug costs. CONCLUSION: Over the past decade, costs of novel oncology drugs have increased, while clinical benefits of these medications have not experienced a proportional positive change. The incremental anticancer drug costs have increased at a much greater rate than monthly prices, indicating that the increase in anticancer drug costs may be higher than commonly reported.

Neoadjuvant treatments for locally advanced, resectable esophageal cancer: A network meta-analysis.

The relative survival benefits and postoperative mortality among the different types of neoadjuvant treatments (such as chemotherapy only, radiotherapy only or chemoradiotherapy) for esophageal cancer patients are not well established. To evaluate the relative efficacy and safety of neoadjuvant therapies in resectable esophageal cancer, a Bayesian network meta-analysis was performed. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for publications up to May 2016. ASCO and ASTRO annual meeting abstracts were also searched up to the 2015 conferences. Randomized controlled trials that compared at least two of the following treatments for resectable esophageal cancer were included: surgery alone, surgery preceded by neoadjuvant chemotherapy, neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy. The primary outcome assessed from the trials was overall survival. Thirty-one randomized controlled trials involving 5496 patients were included in the quantitative analysis. The network meta-analysis showed that neoadjuvant chemoradiotherapy improved overall survival when compared to all other treatments including surgery alone (HR 0.75, 95% CR 0.67-0.85), neoadjuvant chemotherapy (HR 0.83. 95% CR 0.70-0.96) and neoadjuvant radiotherapy (HR 0.82, 95% CR 0.67-0.99). However, the risk of postoperative mortality increased when comparing neoadjuvant chemoradiotherapy to either surgery alone (RR 1.46, 95% CR 1.00-2.14) or to neoadjuvant chemotherapy (RR 1.58, 95% CR 1.00-2.49). In conclusion, neoadjuvant chemoradiotherapy improves overall survival but may also increase the risk of postoperative mortality in patients locally advanced resectable esophageal carcinoma.

A network meta-analysis of the sequencing and types of systemic therapies with definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LASCCHN)☆.

OBJECTIVES: The current standard therapy for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) is platinum-based chemotherapy plus concurrent radiotherapy (CRT), but several systemic therapies have been evaluated. We performed a Bayesian network meta-analysis (NMA) with random effects to enable direct and indirect comparisons of all existing treatment modalities for LASCCHN simultaneously. MATERIAL AND METHODS: A systematic review was conducted using MEDLINE, EMBASE, ASCO abstracts, ASTRO abstracts and the Cochrane Central of Registered Trials using Cochrane methodology to identify randomized controlled trials (RCTs) up to June 2016. Only abstracts that involved the same definitive radiotherapy in the arms for the RCT were included. RESULTS: Sixty-five RCTs involving 13,574 patients and 16 different treatment strategies were identified. Chemotherapy plus concurrent radiation (CRT) was superior to RT with a HR of 0.74 (95%CR 0.69-0.79) for OS in the NMA. Only 3 trials compared RT alone to concurrent therapy with an EGFR antibody (ERT), demonstrating a superior OS (HR 0.75, 95% CR 0.60-0.94), but this difference was not statistically significant when interpreted in a NMA (HR 0.84, 95%CR 0.65-1.08). ERT was not superior to CRT (HR 1.19, 95%CR 0.93-1.54), and the addition of neo-adjuvant taxane-based chemotherapy to CRT was not beneficial (HR 0.86, 95% CR 0.70-1.07). CONCLUSION: The addition of either adjuvant or neoadjuvant chemotherapy to the CRT backbone does not confer an OS benefit in the treatment of LASCCHN. Similarly, ERT does not confer an OS benefit for patients who are eligible for CRT.

Cost-Effectiveness Analysis of Systemic Therapies in Advanced Pancreatic Cancer in the Canadian Health Care System.

OBJECTIVES: To assess the cost-effectiveness of gemcitabine (G), G + 5-fluorouracil, G + capecitabine, G + cisplatin, G + oxaliplatin, G + erlotinib, G + nab-paclitaxel (GnP), and FOLFIRINOX in the treatment of advanced pancreatic cancer from a Canadian public health payer's perspective, using data from a recently published Bayesian network meta-analysis. METHODS: Analysis was conducted through a three-state Markov model and used data on the progression of disease with treatment from the gemcitabine arms of randomized controlled trials combined with estimates from the network meta-analysis for the newer regimens. Estimates of health care costs were obtained from local providers, and utilities were derived from the literature. The model estimates the effect of treatment regimens on costs and quality-adjusted life-years (QALYs) discounted at 5% per annum. RESULTS: At a willingness-to-pay (WTP) threshold of greater than $30,666 per QALY, FOLFIRINOX would be the most optimal regimen. For a WTP threshold of $50,000 per QALY, the probability that FOLFIRINOX would be optimal was 57.8%. There was no price reduction for nab-paclitaxel when GnP was optimal. CONCLUSIONS: From a Canadian public health payer's perspective at the present time and drug prices, FOLFIRINOX is the optimal regimen on the basis of the cost-effectiveness criterion. GnP is not cost-effective regardless of the WTP threshold.

Resistance to metronomic chemotherapy and ways to overcome it.

Therapeutic resistance is amongst the major determinants of cancer mortality. Contrary to initial expectations, antivascular therapies are equally prone to inherent or acquired resistance as other cancer treatment modalities. However, studies into resistance to vascular endothelial growth factor pathway inhibitors revealed distinct mechanisms of resistance compared to conventional cytotoxic therapy. While some of these novel mechanisms of resistance also appear to be functional regarding metronomic chemotherapy, herein we summarize available evidence for mechanisms of resistance specifically described in the context of metronomic chemotherapy. Numerous preclinically identified molecular targets and pathways represent promising avenues to overcome resistance and enhance the benefits achieved with metronomic chemotherapy eventually. However, there are considerable challenges to clinically translate the preclinical findings.

Antiangiogenic Therapy in Advanced Non-small-cell Lung Cancer: A Meta-analysis of Phase III Randomized Trials.

We conducted a meta-analysis to evaluate the efficacy of adding any antiangiogenic therapy (AT) to the standard of care in advanced non-small-cell lung cancer (NSCLC). The electronic databases Ovid PubMed, Cochrane Central Register of Controlled Trials, and Embase were searched to identify eligible trials. We included all phase III randomized trials with any line and type of treatment, histology. and AT dose. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for overall response rates (RR) were calculated. We divided the population into 2 subgroups based on the bevacizumab dose. Data of 19,098 patients from 25 phase III trials were analyzed. Compared with the standard of care, the addition of AT did not prolong OS (HR 0.98; 95% confidence interval [CI], 0.96-1.00; P = .1 and HR 0.97; 95% CI, 0.94-1.00; P = .06 for groups 1 and 2, respectively). However, there was a significant improvement in PFS with the addition of AT (HR 0.85; 95% CI, 0.79-0.91; P < .00001 and HR 0.81; 95% CI, 0.75-0.88; P < .00001 for groups 1 and 2, respectively) and overall RR (OR 1.61; 95% CI, 1.30-2.01; P < .0001 and OR 1.72; 95% CI, 1.39-2.14; P < .00001 for groups 1 and 2, respectively). This is the first meta-analysis including only all phase III trials with AT in NSCLC showing no significant effect on OS and an improvement in PFS and RR only. The role of AT in advanced NSCLC is still questionable; strong validated biomarkers are eagerly needed to predict which subgroup might benefit the most from such therapy.

High prevalence of potential drug-drug interactions in patients with castration-resistant prostate cancer treated with abiraterone acetate.

PURPOSE: Abiraterone acetate (AA), used to treat metastatic castration-resistant prostate cancer (mCRPC), inhibits androgen biosynthesis by blocking cytochrome P450 (CYP) 17A1. It also inhibits other cytochromes involved in the metabolism of various widely used medications. As such, there is presumably a high potential for drug-drug interactions (DDIs) that can diminish the efficacy of AA or concurrent medications, or increase the risk of DDI-related adverse events (AEs). However, the scale of AA-associated DDIs is currently unknown. METHODS: We conducted a retrospective review of pharmacy records and electronic patient charts to retrieve individual drug histories and on-treatment AEs of mCRPC patients beginning AA therapy in a tertiary care setting. Potential DDIs were analyzed using two commercial databases, Lexicomp and Micromedex. RESULTS: Eighty-four informative patients were identified. Sixty-five patients (77 %) and 44 patients (52 %) were flagged for one or more potential DDIs by the Lexicomp and Micromedex databases, respectively. One hundred eighty-four potential DDIs were identified overall, with a median of 1 DDI per patient in both databases. Possibly due to rigorous DDI screening before AA treatment initiation, we did not identify a definite instance of DDI-related AEs. CONCLUSIONS: The use of commercial DDI databases suggests a substantial risk of potentially consequential DDIs in mCRPC patients undergoing AA therapy. However, prospective investigations with larger patient populations are required to better establish the clinical relevance of these DDIs.

Avascular Necrosis of the Femoral Head After Palliative Radiotherapy in Metastatic Prostate Cancer: Absence of a Dose Threshold?

Avascular necrosis (AVN) is the final common pathway resulting from insufficient blood supply to bone, commonly the femoral head. There are many postulated etiologies of non-traumatic AVN, including corticosteroids, bisphosphonates, and radiotherapy (RT). However, it is unclear whether there is a dose threshold for the development of RT-induced AVN. In this case report, we describe a patient with prostate cancer metastatic to bone diagnosed with AVN after receiving single-fraction palliative RT to the left femoral head. Potential contributing factors are discussed, along with a review of other reported cases. At present, the RT dose threshold below which there is no risk for AVN is unknown, and therefore detrimental impact from the RT cannot be excluded. Given the possibility that RT-induced AVN is a stochastic effect, it is important to be aware of the possibility of this diagnosis in any patient with a painful hip who has received RT to the femoral head.

Disease volume and distribution as drivers of treatment decisions in metastatic prostate cancer: From chemohormonal therapy to stereotactic ablative radiotherapy of oligometastases.

The prognosis of men with metastatic, castration-sensitive prostate cancer (CSPC) depends on both the distribution and extent of metastases, among other things. Patients with low-volume or oligometastatic disease have improved survival compared with those with high-volume metastases. While chemohormonal therapy is the new standard of care for men with high-volume metastatic CSPC, stereotactic ablative radiotherapy (SABR) is emerging as a promising treatment option with low toxicity for the management of oligometastatic CSPC. Our review summarizes the current evidence on the role of SABR in oligometastatic prostate cancer. SABR shows control rates of metastases ranging from 88% to 100% at 6 months to 3 years, and progression-free survival commonly reported as >50% for the first 12 months. In addition, SABR may allow androgen-deprivation therapy to be delayed by more than 2 years in selected patients, minimizing the chronic side effects associated with such therapy. However, much still needs to be learned before SABR can be implemented as standard treatment for oligometastatic prostate cancer.