Young-onset gastric cancer and Epstein-Barr Virus (EBV) - a major player in the pathogenesis?

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC. METHODS: Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records. RESULTS: Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002). CONCLUSION: Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.

A real-world analysis of cancer drug wastage due to oversized vials.

OBJECTIVES: A recent theoretical economic model suggested that oversized vials of cancer drugs lead to $1.8 billion of drug wastage annually in the United States. It is currently unknown how precisely this theoretical model is consistent with the real world. We performed a real-world analysis to assess the economic impact of drug wastage. METHODS: We performed a systematic examination of the usage and wastage of all intravenous cancer drugs in the cancer center of a large tertiary care hospital in Israel. During a period of 1 month, we collected usage and wastage data from the hospital's pharmacy dispensing computerized logs. We calculated the local financial impact using Israeli drug prices list (June 2016) from the ministry of health. We performed an additional analysis using discounted U.S. prices, using the October 2016 Average Sales Prices from the Centers of Medicare and Medicaid Services. RESULTS: Seventy-four injectable anticancer drugs were used during March 2016, and 68 Israeli drug prices were available. The total amount spent on wasted drugs in 1 month was then extrapolated to calculate the annual spending, which was $141,196 per month (5.11% of the total cost) or $1,694,352 per year. Using U.S. prices, the total wastage would be $2,208,876 annually. The 5 drugs that led to the highest expenditure on wastage were bortezomib, trastuzumab, azacytidine, pemetrexed and carfilzomib. There was no wastage of 24 of the 74 drugs. CONCLUSION: This real-world study demonstrates the economic impact of wastage of anticancer drugs on health systems. To decrease wastage, particular attention should be paid to drugs with high usage rates, high cost, and oversized vials.

PafR, a novel transcription regulator, is important for pathogenesis in uropathogenic Escherichia coli.

The metV genomic island in the chromosome of uropathogenic Escherichia coli (UPEC) encodes a putative transcription factor and a sugar permease of the phosphotransferase system (PTS), which are predicted to compose a Bgl-like sensory system. The presence of these two genes, hereby termed pafR and pafP, respectively, has been previously shown to correlate with isolates causing clinical syndromes. We show here that deletion of both genes impairs the ability of the resulting mutant to infect the CBA/J mouse model of ascending urinary tract infection compared to that of the parent strain, CFT073. Expressing the two genes in trans in the two-gene knockout mutant complemented full virulence. Deletion of either gene individually generated the same phenotype as the double knockout, indicating that both pafR and pafP are important to pathogenesis. We screened numerous environmental conditions but failed to detect expression from the promoter that precedes the paf genes in vitro, suggesting that they are in vivo induced (ivi). Although PafR is shown here to be capable of functioning as a transcriptional antiterminator, its targets in the UPEC genome are not known. Using microarray analysis, we have shown that expression of PafR from a heterologous promoter in CFT073 affects expression of genes related to bacterial virulence, biofilm formation, and metabolism. Expression of PafR also inhibits biofilm formation and motility. Taken together, our results suggest that the paf genes are implicated in pathogenesis and that PafR controls virulence genes, in particular biofilm formation genes.

Cancer of the colon and rectum: potential effects of sex-age interactions on incidence and outcome.

BACKGROUND: Sex differences in epidemiological, clinical and pathological characteristics of colorectal cancer have been under intensive investigation for the last three decades. Given that most of the sex-related differences reported were also age-related, this study sought to determine the potential effect of a sex-age interaction on colorectal cancer development and progression. MATERIAL AND METHODS: Statistical data on sex- and age-specific colon or rectal cancer incidence, disease stage and survival for white persons were derived from the United States Surveillance, Epidemiology and End Results (SEER) Program. Age-specific incidence rates in 2002-2006 were analyzed by 5-year age groups (45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84 years) in men and women. Sex differences were measured by calculating rate differences (RD) and rate ratios (RR). Equivalent analyses for a similar time period were performed for stage distribution and 5-year relative survival. RESULTS: Age-specific incidence rates were higher for men, for all life-time periods. However, the magnitude of the male predominance was age-dependent. The RR and RD did not remain constant over time: they increased gradually with age, peaked at 70-74 years, and declined thereafter. The distribution of stage at diagnosis was similar between men and women, but women seemed to have better survival, until the age of 64 years for colon cancer and 74 years for rectal cancer. CONCLUSIONS: There seem to be significant age-related sex differences in the incidence of colorectal cancer, and maybe also in its prognosis.

Differences in Toxicity Between Ashkenazi and Sephardic Jews With Colon Cancer Treated With Adjuvant Chemotherapy: A Prospective Study.

BACKGROUND/AIM: Ethnicity of cancer patients is increasingly being recognized as an important factor that may influence intergroup variation in toxicity and efficacy of chemotherapy. Data from our institution suggested that differences in chemotherapy-associated toxicity are not limited to distanced ethnic subgroups, such as Caucasians, Afro-Americans, or Asians, but may exist even between two closely related Caucasian ethnic subgroups, such as Ashkenazi and Sephardic Jews. This study aimed to explore differences in severity and frequency of various side effects, including neurotoxicity between patients from the two Jewish subgroups receiving oxaliplatin-containing adjuvant chemotherapy for colon cancer (CC). PATIENTS AND METHODS: We recruited 75 patients, with performance status 0-1 and no background of neuropathy between 2012 and 2016. All patients completed a neurotoxicity questionnaire (NQ) and a QoL questionnaire (QoLQ) at baseline and the NQ also at each treatment cycle; during follow up, patients filled out the NQ and the QoLQ every four months for a total of one year. RESULTS: Of the 75 participants, 66 were evaluable for the study including 34 (52%) Sephardic and 32 (48%) Ashkenazi Jews. Grade ≥2 vomiting and diarrhea occurred more often in Sephardic than in Ashkenazi patients (p=0.008 and 0.012, respectively). Of the 66 evaluable patients, 11 (17%) developed grade 3 neurotoxicity; of these, 9 were Sephardic and 2 were Ashkenazi (p=0.028). There were no significant differences in the dynamics of QoL between both subgroups. CONCLUSION: Sephardic patients receiving oxaliplatin-containing regimens are at an increased risk for neurotoxicity and other side effects as compared to their Ashkenazi counterparts.

The combination of docetaxel, cisplatin, and 5-fluorouracil in advanced gastric cancer: a single-institution experience.

The addition of docetaxel to cisplatin and 5-fluorouracil was shown to confer a survival benefit in patients with advanced gastric cancer (one; AGC), although with increased toxicity. We hereby report our experience with the use of docetaxel, cisplatin, and 5-fluorouracil (DCF). Data on all consecutive patients who received first-line treatment with DCF at our institute were analyzed retrospectively. Twenty-three patients were included. The median age was 63 years. Patients received an average of 10 cycles (range, 1-24). All experienced grade ≥3 toxicity, requiring hospitalization in 35%. There was one toxic death. The median progression-free and overall survival rates were 10.0 and 12.8 months, respectively; the 2-year and 3-year survival rates were 22 and 17%, respectively. The DCF regimen is indeed associated with substantial toxicity, although manageable. Nevertheless, the observed benefit was remarkable compared with any previous report on chemotherapy in AGC, and should therefore represent a valid treatment option in AGC and a platform for future combinations.

Early prediction of residual disease after neoadjuvant chemoradiotherapy and cetuximab for locally advanced esophageal cancer using 18F-FDG PET-CT imaging: a prospective cohort study.

Background: Previous studies in locally advanced esophageal cancer (LAEC) suggested that a change in the tumor's metabolic response, i.e., decrease of its interim 18F-FDG uptake compared with baseline, may predict histopathological response. We evaluated the possible predictive correlation between various PET-CT and histopathological parameters following a neoadjuvant biological-containing chemoradiotherapy (CRT) regimen. Methods: Patients with resectable LAEC received neoadjuvant cisplatin/5-fluorouracil-based CRT and cetuximab following one cycle of induction chemotherapy and cetuximab. Changes in maximum and mean standardized uptake values (ΔSUV-max and ΔSUV-mean, respectively) and metabolic tumor volume (ΔMTV), measured by PET-CT at baseline and 2 weeks after the onset of treatment, were compared with histopathological findings at surgery. Histopathological response was defined by tumor regression grade (TRG), pathological complete response (pCR) and microscopic or macroscopic residual disease (RD). Results: Of 18 patients, 13 (72%) with adenocarcinoma (AC) and 5 (28%) with squamous cell carcinoma (SCC), were included. None of the changes in the parameters of PET was associated with pCR; only ΔSUV-mean was associated with TRG in the AC cohort. In contrast, both ΔSUV-mean% and ΔSUV-max% were significantly associated with RD, both in the whole cohort and in the AC cohort. Changes in FDG-uptake predicted RD2 at surgery: only patients with less than 13% decrease in SUV-mean% or less than 29% decrease in SUV-max% had RD2, while all patients with RD0 or RD1 had greater reductions [100% specificity and 100% positive predictive value (PPV)]. Conclusions: Changes in ΔSUV-max and ΔSUV-mean after two weeks of onset of cetuximab-based neoadjuvant chemotherapy for LAEC may predict macroscopic RD but not TRG or pCR at surgery.

Factors Associated With Off-Label Oncology Prescriptions: The Role of Cost and Financing in a Universal Healthcare System.

Purpose: Various solutions have been put forward for prescribing and reimbursing treatments outside their registered indications within universal healthcare systems. However, most off-label oncology prescriptions are not reimbursed by health funds. This study characterized the financing sources of off-label oncology use and the predictors of the decision to forego treatment. Materials and Methods: All 708 off-label oncology requests submitted for approval in a large tertiary cancer center in Israel between 2016 and 2018 were examined for disease and patient sociodemographic characteristics, costs and financing sources, and the factors predicting actual off-label drug administration using multivariate logistic regression analysis. Results: The mean monthly cost of a planned off-label treatment was ILS54,703 (SD = ILS61,487, median = ILS39,928) (approximately US$ 15,500). The main sources of funding were private health insurance (25%) and expanded access pharma company plans (30%). Approximately one third (31%) of the requests did not have a financing source at the time of approval. Of the 708 requests, 583 (or 82%) were filled and treatment was initiated. Predictors for forgoing treatment were the impossibility of out-of-pocket payments or the lack of a financing solution (OR = 0.407; p = 0.005 and OR = 0.400; p < 0.0005). Conclusion: Although off-label recommendations are widespread and institutional approval is often granted, a large proportion of these prescriptions are not filled. In a universal healthcare system, the financing sources for off-label treatments are likely to influence access.

Bevacizumab for stereotactic radiosurgery-induced radiation necrosis in patients with non-small cell lung cancer treated with immune check-point inhibitors.

BACKGROUND: Bevacizumab was shown to be effective in the treatment of brain radiation necrosis (RN) attributed to the use of stereotactic radiosurgery (SRS). Data on its efficacy and safety in non-small cell lung cancer (NSCLC) patients treated with immune check-point inhibitors (ICI) is lacking. METHODS: A multi-center retrospective analysis of all consecutive patients with NSCLC treated with ICI, who received bevacizumab for post-SRS RN between April 2017 and June 2020. Improvement in RN-associated symptoms, RN radiological improvement, and decrease in corticosteroid dose following bevacizumab initiation were assessed. RESULTS: Thirteen patients were identified. The median time from diagnosis of RN to initiation of bevacizumab was 3 months (range 1.1-7.8 months), and the median number of bevacizumab cycles before assessment was 2 (range, 1-5). Patients continued ICI during treatment with bevacizumab. Improvement in RN-associated symptoms was observed in 11 patients (85%). In ten patients (77%) the daily dose of dexamethasone was decreased. Radiological improvement of RN occurred in all 11 cases available for radiological assessment (100%). Treatment was withheld in two patients for grade 3-4 toxicity. At a median follow up of 11.9 months (range 2.0-35.4 months), one patient experienced a recurrent episode of RN; the estimated median survival since RN diagnosis was 21.9 months (95% CI 3.8-40.2 months). CONCLUSION: Treatment with bevacizumab appears to be safe and effective for the treatment of SRS-induced RN in patients with NSCLC treated with ICI. This is the first series to report on the use of bevacizumab in this clinical scenario.

Next-generation sequencing in thyroid cancers: do targetable alterations lead to a therapeutic advantage?: A multicenter experience.

ABSTRACT: Radioiodine-refractory thyroid cancers (IRTCs) are uncommon and have a poor prognosis. Treatment options for radioiodine-refractory and anaplastic tumors (ATCs) are limited. Although the genomic landscape of thyroid cancer has been studied, there is little evidence on whether next-generation sequencing (NGS) findings translate to tumor control.We analyzed all patients with IRTC and ATC who underwent commercially available NGS in 3 cancer centers.Twenty-two patients were identified, 16 patients with IRTCs and 6 patients with ATCs. Eighteen (82%) had targetable findings in NGS, nine patients were treated accordingly. Median progression-free survival for targeted treatment was 50 months [95% confidence interval (CI95%) 9.8-66.6] and2 months (CI95% 0.2-16.5) for IRTC and ATC, respectively. Of 4 patients who achieved durable responses of 7 to 50 months, 2 are ongoing. The estimated median OS of IRTC receiving targeted treatment was not reached (CI95% 89.7-111.4 months) and was 77.8 months (CI95% 52.5-114.6) for patients treated conventionally (P = .3).NGS may detect clinically significant genetic alterations and benefit patients with advanced thyroid cancers.

Fractionation scheme and treatment planning method for early glottic cancer in the United States: Economic impact of different medical decisions.

BACKGROUND: Early glottic cancers are often treated with radiotherapy (RT). We assessed the economic impact of fractionation scheme and planning method for payers in the United States. METHODS: A population-based analysis of the total cost of RT for early glottic cancers in the United States was performed annually. The target population was calculated using the Surveillance, Epidemiology, and End Results database. RT costs were based on 2019 pricing by Medicare. RESULTS: We estimate that 3794 patients with early glottic cancers are treated with RT annually. The cost of RT per patient ranges between US $13 964 and $26 599 by fractionation and planning method. Hypofractionation reduces costs by 9% to 14%, while Intensity-modulated radiotherapy (IMRT) increases costs by 65% to 72%. IMRT-based standard fractionation leads to an excess cost of $47 937 076 compared with 3D-based hypofractionation. CONCLUSIONS: 3D-based hypofractionated RT is the current standard of care. It would be reasonable for public and private payers to consider evidence-based policies for radiation reimbursement.

Next-generation sequencing in salivary gland carcinoma: Targetable alterations lead to a therapeutic advantage-Multicenter experience.

BACKGROUND: Salivary gland cancers (SGCs) are rare. The approach to metastatic patients is histology-dependent. There is little evidence on whether next-generation sequencing (NGS) findings translate to tumor control in SGCs. METHODS: We analyzed all patients with histologically confirmed SGC who underwent NGS. RESULTS: Twenty-seven patients were identified, 14 (51.8%) had targetable findings in NGS: 5 ERBB2 amplifications, 3 PIK3CA mutations, 2 RUNX1 mutations, 1 TRIM33-RET fusion, 1 FGFR3-TACC3 fusion, 1 microsatellite instability-high, and 2 high mutational burden. Ten patients were treated accordingly. Median progression-free survival for targeted treatment was 8.4 months. Of five patients who achieved durable responses of 8.4 to 31.3 months, two are ongoing. The overall median survival was not reached for patients receiving targeted treatment and was 40.4 months for patients treated conventionally (P = .18). CONCLUSIONS: In the absence of a well-established therapeutic approach, NGS may detect clinically significant genetic alterations and benefit patients with advanced SGC.

The Financial Impact of Hypofractionated Radiation for Localized Prostate Cancer in the United States.

BACKGROUND: Until recently, dose intensified radiotherapy was the standard radiation method for localized prostate cancer. Multiple studies have demonstrated similar efficacy and tolerability with moderate hypofractionation. In recent years there has been an increasing focus placed on understanding the cost and value of cancer care. In this study we aimed to assess the economic impact of moderate hypofractionation for payers in the United States. METHODS: We performed a population-based analysis of the total cost of external beam radiotherapy (EBRT) for localized prostate cancer in the US annually. The national annual target population of patients treated with definitive EBRT was calculated using the Surveillance, Epidemiology, and End Results (SEER) database. Treatment costs for various fractionation schemes were based on billing codes and 2018 pricing by the Centers for Medicare and Medicaid Services (CMS). RESULTS: We estimate that 27,146 patients with localized prostate cancer are treated with EBRT annually in the US. The cost of standard fractionation in 45 or 39 fractions is US$ 26,782 and 23,625 per patient, respectively. With moderate hypofractionation in 28 or 20 fractions, the cost is US$ 17,793 and 13,402 per patient, respectively. The use of moderate hypofractionation would lead to 25-50% annual savings US$158,315,472-US$363,213,480 in the US. CONCLUSIONS: Moderate hypofractionation may have the potential to save approximately US$0.16-0.36 billion annually, likely without impacting survival or tolerability. This may lead to lower personal financial toxicity. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement.

The Financial Impact of Fractionation Scheme and Treatment Planning Method for Rectal Cancer in the United States.

BACKGROUND: Preoperative long-course chemoradiotherapy (CRT) and short-course radiotherapy (SCR) for locally advanced rectal cancer (LARC) were found to have equivalent outcomes in 3 randomized trials. SCR has not been widely adopted in the United States (US). Three-dimensional (3D) treatment planning is standard, whereas intensity-modulated radiotherapy (IMRT) is controversial. In this study, we assessed the economic impact of fractionation scheme and planning method for payers in the US. MATERIALS AND METHODS: We performed a population-based analysis of the total cost of radiotherapy for LARC in the US annually. The national annual target population was calculated using the Surveillance, Epidemiology, and End Results database. Radiotherapy costs were based on billing codes and 2018 pricing by Medicare's Hospital Outpatient Prospective Payment System. RESULTS: We estimate that 12,945 patients with LARC are treated with radiotherapy annually in the US. The cost of CRT with 3D or IMRT is US $15,882 and $23,745 per patient, respectively. With SCR, the cost with 3D or IMRT is $5,458 and $7,323 per patient, respectively. The use of SCR would lead to 53% to 77% annual savings of $106,168,871 to $232,105,727 compared with CRT. IMRT increases the total cost of treatment by 34% to 50%, and if adopted widely, would lead to an excess cost of $24,152,134 and $101,784,723 annually with SCR and CRT, respectively. CONCLUSIONS: SCR may have the potential to save approximately US $106 to t232 million annually in the US, likely without impacting outcomes. Lack of evidence showing benefit with costly IMRT should limit its use to clinical trials. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement.

The addition of cetuximab to preoperative chemoradiotherapy for locally advanced esophageal squamous cell carcinoma is associated with high rate of long term survival: Mature results from a prospective phase Ib/II trial.

AIM: This phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative chemoradiotherapy (CRT) in locally advanced esophageal cancer (LAEC). METHODS: Patients (pts) with resectable LAEC (T2-3N0-1M0, T1-3N1M0 or T1-3N0-1M1A) received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-fluorouracil (5-FU) 1000 mg/m2/day, days 1-5, followed 4 weeks later by radiotherapy, 50.4 Gy, given with 2 cycles of cisplatin 75 mg/m2 and escalating doses of 5-FU, days 1-4 and 29-32. Pts received 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose, 400 mg/m2. Surgery was planned 6-8 weeks after CRT. RESULTS: 64 pts were treated and 60 completed CRT. Median age was 65 years and 66% were males. Adenocarcinoma/squamous ratio was 61%/39%. Tumors were advanced: 95% T3 and 67% N1. Grade ≥3 toxicities occurred in 72%, with two (3%) toxic deaths. The 5-FU maximal tolerated dose (MTD) was 1000 mg/m2/day. Clinical complete response rate was 33%. Of the 55 operated pts, R0 resection was achieved in 51 (93%) and pathological complete response (pCR) in 18 (33%), with 8 (14%) postoperative deaths. The 5-year survival rate for all pts was 38%. Pts with squamous histology had higher pCR (55% vs 20%, p = 0.015), local control (96% vs. 74%, p < 0.001) and 5-year survival (58% vs 25%, p = 0.011) rates. CONCLUSIONS: This study suggests that the addition of cetuximab to standard preoperative CRT is feasible. R0, pCR and local control rates are encouraging. Pts with squamous cell tumors benefited more from the addition of cetuximab.

Trajectories of Injectable Cancer Drug Costs After Launch in the United States.

Purpose Cancer drug prices at launch have increased in recent years. It is unclear how individual drug prices change over time after launch and what market determinants influence these changes. We measured the price trajectories of a cohort of cancer drugs after their launch into the US market and assessed the influence of market structure on price changes. Methods We studied the changes in mean monthly costs for a cohort of 24 patented, injectable anticancer drugs that were approved by the US Food and Drug Administration between 1996 and 2012. To account for discounts and rebates, we used the average sales prices published by the Centers for Medicare and Medicaid Services. Costs were adjusted to US general and health-related inflation rates. For each drug, we calculated the cumulative and annual drug cost changes. We then used a multivariable regression model to evaluate the association between market and cost changes over time. Results With a mean follow-up period of 8 years, the mean percent change in cost for all drugs was +25% (range, -14% to +96%). After adjusting for inflation, the mean cost change was +18% (range, -16% to +59%). Rituximab and trastuzumab followed a similar pattern in cost increases over time, and the inflation-adjusted monthly costs rose since approval by 49% and 44%, respectively. New supplemental US Food and Drug Administration approvals, new off-label indications, and new competitors did not influence the annual cost change rates. Conclusion Anticancer drug costs may change substantially after launch. Regardless of competition or supplemental indications, there is a steady increase in costs of patented anticancer agents over time. New regulations may be needed to prevent additional increases in drug costs after launch.

Cost Effectiveness of Nivolumab in Advanced Renal Cell Carcinoma.

BACKGROUND: In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study. However, because of the high cost of nivolumab, there is a need to define its value by considering both efficacy and cost. OBJECTIVE: To estimate the cost effectiveness of nivolumab for second-line treatment of advanced RCC from the US payer perspective. DESIGN, SETTING, AND PARTICIPANTS: A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus and placebo in second-line treatment of advanced RCC. Health outcomes were measured in life-years (LYs) and quality-adjusted LYs (QALYs). Drug costs were based on 2016 Medicare reimbursement rates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Model robustness was assessed in univariable and probabilistic sensitivity analyses. We addressed the issue of the extensive duration of immunotherapy treatment among long-term survivors, which may or may not be approved by payers. RESULTS AND LIMITATIONS: The total mean cost per patient was $101 070 for nivolumab and $50 935 for everolimus. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) compared to everolimus. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146 532/QALY versus everolimus and $226 197/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to 2 yr reduced the ICER to $121 788/QALY versus everolimus. The analysis is limited by data availability and our assumptions. CONCLUSIONS: Our analysis established that with a willingness-to-pay threshold of $100 000 to $150 000 per QALY, nivolumab is estimated to be cost-effective versus everolimus, but not cost-effective versus placebo. PATIENT SUMMARY: We assessed the cost effectiveness of nivolumab in previously treated metastatic kidney cancer. In the USA, it would cost $146 532 to gain one quality-adjusted life-year with nivolumab versus everolimus, or $226 197 versus placebo. Nivolumab is considered cost-effective versus everolimus, but not versus placebo.

Cost-effectiveness of Pembrolizumab in Second-line Advanced Bladder Cancer.

BACKGROUND: Immune-modulating drugs have recently been introduced to the second-line setting of advanced bladder cancer. Pembrolizumab increases overall survival and is associated with less toxicity compared with chemotherapy in this setting based on the Keynote 045 study. The high cost of immunotherapy necessitates an assessment of its value by considering both efficacy and cost. OBJECTIVE: To estimate the cost-effectiveness of pembrolizumab for the second-line treatment of advanced bladder cancer from the perspective of payers in multiple countries. DESIGN, SETTING, AND PARTICIPANTS: We developed a Markov model to compare the cost and effectiveness of pembrolizumab with those of chemotherapy in the second-line treatment of advanced bladder cancer based on the Keynote 045 study. Drug costs were acquired for the United States (US), United Kingdom (UK), Canada, and Australia. All costs were converted from local currency to US dollars at the exchange rates in September 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Health outcomes were measured in quality-adjusted life-years (QALYs). RESULTS AND LIMITATIONS: Pembrolizumab generated a gain of 0.36-0.37 QALYs compared with chemotherapy. Our analysis established the following incremental cost-effectiveness ratios (ICERs) for pembrolizumab versus chemotherapy in second-line advanced bladder cancer treatment: US $122 557/QALY; UK $91 995/QALY; Canada $90 099/QALY; and Australia $99 966/QALY. The willingness-to-pay (WTP) thresholds per QALY are considered to be around 100 000-150 000 US dollars for the US, 20 000-50 000 pounds for the UK (US$25 000-65 000), 20 000-100 000 CAD for Canada (US$16 000-80 000), and 40 000-75 000 AUD for Australia (US$32 000-60 000). CONCLUSIONS: Cost-effectiveness and WTP thresholds vary between countries. Compared with the other countries examined, US drug prices were found to be the highest, leading to the highest ICER. With standard WTP thresholds, pembrolizumab may be considered cost-effective in the US but not in the other countries examined. PATIENT SUMMARY: This article assessed the cost-effectiveness of pembrolizumab for the treatment of patients with metastatic bladder cancer who had previously failed one treatment regimen. It would cost $122 557 in the United States, $91 995 in the United Kingdom, $90 099 in Canada, and $99 966 in Australia to gain one quality-adjusted life-year with pembrolizumab versus chemotherapy in these patients, which may be considered cost-effective only in the United States because of the differences in willingness-to-pay thresholds.

Early PET-CT in patients with pathological stage III colon cancer may improve their outcome: Results from a large retrospective study.

BACKGROUND: Current staging of pathological stage III colon cancer (CC) is suboptimal; many patients recur despite unremarkable preoperative staging. We previously reported that early postoperative PET-CT can alter the stage and management of up to 15% of patients with high-risk stage III CC. This study aimed to determine the role of the test in the general stage III CC population. METHODS: A retrospective study of all consecutive patients with stage III CC who underwent early postoperative PET-CT between 2005 and 2017. RESULTS: A total of 342 patients, 166 (48.5%) males, median age 66 years (range, 29-90), were included. Pathological stage was IIIA, IIIB, and IIIC in 18 (5.3%), 257 (75.1%), and 67 (19.6%) patients, respectively. Median number of positive lymph nodes was 2 (range, 0-32). PET-CT results modified the management of 46 patients (13.4%): 37 (10.8%) with overt metastatic disease and 9 (2.6%) with a second primary. The 5-year disease-free survival for true stage III patients was 81%. The median overall survival for the entire cohort and for true stage III patients was not reached and was 57.2 months for true stage IV. Of the 37 patients found to be metastatic, 14 (37.8%) underwent curative treatments and 9/14 (64.3%) remain disease-free, with a median follow-up of 83.8 months. Predictive factors for upstaging following PET-CT were identified. CONCLUSION: Early postoperative PET-CT changed the staging and treatment of 13.4% of stage III CC patients and has the potential for early detection of curable metastatic disease. Outcome results are encouraging. Prospective validation is ongoing.