A Canadian single institution real-world experience using the CROSS trial regimen in the treatment of oesophageal and gastroesophageal junction carcinoma.

BACKGROUND: Trimodality therapy using the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial protocol is an accepted standard of care for locally advanced oesophageal and gastroesophageal junction cancers. For medically inoperable patients, chemoradiotherapy (CRT) has been a therapeutic option. AIMS: This single institution review aimed to assess the real-world application of the CROSS trial protocol. METHODS: This is a retrospective review of 83 patients who underwent CRT with carboplatin and paclitaxel with trimodality or definitive intent between June 2012 and June 2018. Sixty-five patients underwent neoadjuvant CRT (NCRT); 40 had surgery, 18 had definitive CRT (DCRT). Patients' demographics, clinical, pathological, treatment and surgical characteristics were assessed. The data were analysed in exploratory analyses and Kaplan-Meier curves. RESULTS: For 83 patients, the following median values were seen: radiotherapy dose, 50.4 Gy; chemotherapy doses, 5; and time from CRT to surgery, 62 days. Twenty-three percent NCRT and 72% DCRT patients were aged ≥75 years, and 49% and 33% of these respectively had no interruptions to CRT. Patients aged ≥75 years were more likely to have DCRT (P = 0.001). Patients who underwent surgery were younger (P = 0.04). For NCRT and surgery, NCRT only and DCRT respectively, median overall survival was 35.5, 12.1 and 17.1 months (log rank P = 0.008); progression-free survival was 32.2, 10 and 9.6 months (log rank P = 0.001). CONCLUSIONS: Despite broadening of the CROSS trial eligibility criteria in our real-world data, there appears to be a survival benefit with trimodality therapy. The use of carboplatin and paclitaxel in DCRT may be of value and requires further study.

Bevacizumab for Metastatic Colorectal Cancer: A Global Cost-Effectiveness Analysis.

BACKGROUND: In the U.S., the addition of bevacizumab to first-line chemotherapy in metastatic colorectal cancer (mCRC) has been demonstrated to provide 0.10 quality-adjusted life years (QALYs) at an incremental cost-effectiveness ratio (ICER) of $571,000/QALY. Due to variability in pricing, value for money may be different in other countries. Our objective was to establish the cost-effectiveness of bevacizumab in mCRC in the U.S., U.K., Canada, Australia, and Israel. METHODS: We performed the analysis using a previously established Markov model for mCRC. Input data for efficacy, adverse events, and quality of life were considered to be generalizable and therefore identical for all countries. We used country-specific prices for medications, administration, and other health service costs. All costs were converted from local currency to U.S. dollars at the exchange rates in March 2016. We conducted one-way and probabilistic sensitivity analyses (PSA) to assess the model robustness across parameter uncertainties. RESULTS: Base case results demonstrated that the highest ICER was in the U.S. ($571,000/QALY) and the lowest was in Australia ($277,000/QALY). In Canada, the U.K., and Israel, ICERs ranged between $351,000 and $358,000 per QALY. PSA demonstrated 0% likelihood of bevacizumab being cost-effective in any country at a willingness to pay threshold of $150,000 per QALY. CONCLUSION: The addition of bevacizumab to first-line chemotherapy for mCRC consistently fails to be cost-effective in all five countries. There are large differences in cost-effectiveness between countries. This study provides a framework for analyzing the value of a cancer drug from the perspectives of multiple international payers. IMPLICATIONS FOR PRACTICE: The cost-effectiveness of bevacizumab varies significantly between multiple countries. By conventional thresholds, bevacizumab is not cost-effective in metastatic colon cancer in the U.S., the U.K., Australia, Canada, and Israel.

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.

Profile and evaluation of a palliative medicine consultation service within a tertiary teaching hospital in Sydney, Australia.

The role of a Palliative Medicine Liaison Consultation Service (LCS) in a large tertiary referral teaching hospital was examined by the prospective evaluation of 50 cases consecutively referred, together with the subsequent advice/recommendations (4 categories: pharmacological, non-pharmacological, clarification of goal of treatment, care system upon discharge) given during the consultation. The utility of a simple scoring system in quantifying the impact (4 grades: deleterious, no effect, positive, very positive) of the advice given on individual patient outcome, scored by both the referring team and the LCS, was studied. Eighty percent of cases had a cancer diagnosis. Pain was the most common symptom (50% cases) and "pain control" the most common referral reason cited. The median number of recommendations per patient was 3.0 and the majority (70%) concerned symptom control recommendations. Advice was given regarding discharge planning in nearly two-thirds of cases and such advice dealing with the care system upon discharge was judged by the referring team to have the highest positive impact of all recommendations. Nearly three-fourths of cases (74%) were graded by the referring team as having at least one recommendation with a positive impact. The simple scoring system used is demonstrably a useful outcome assessment tool. The LCS is perceived to have a positive impact on patient care in an acute hospital setting and appears to fill a gap in the multi-specialty provision of care.

Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer.

PURPOSE: Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR) 1 and VEGFR2 extracellular domains. We assessed the safety and efficacy of aflibercept in patients with metastatic colorectal cancer (MCRC) who had received at least one prior palliative regimen. EXPERIMENTAL DESIGN: Seventy-five patients were enrolled onto this two-stage phase II trial in two cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51). Aflibercept was administered at 4 mg/kg i.v. in two-week cycles. The primary endpoint was a combination of objective response rate and 16-week progression-free survival (PFS). RESULTS: In the bevacizumab-naïve cohort (n = 24), the best response was stable disease for 16 weeks or more in five of 24 patients. In the prior bevacizumab cohort (n = 50), one patient achieved a partial response and six patients had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was two months [95% confidence interval (CI): 1.7-8.6 months] and 2.4 months (95% CI: 1.9-3.7 months), respectively. Median overall survival (OS) was 10.4 months (95% CI: 7.6-15.5) and 8.5 months (95% CI: 6.2-10.6), respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten patients discontinued study treatment due to toxicity. Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF. CONCLUSION: Aflibercept showed limited single-agent activity in patients with pretreated MCRC with moderate toxicity. Further study of aflibercept with chemotherapy is ongoing.

Adjuvant chemotherapy uptake in non-small cell lung cancer.

INTRODUCTION: Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) has become a new standard of care. This study examines the uptake patterns for adjuvant chemotherapy outside of clinical trials. METHODS: A retrospective study of all patients diagnosed with NSCLC in the year 2005 who underwent curative-intent surgery in Nova Scotia, Canada was conducted. Logistic regression models and discriminant function analyses were employed to identify cofactors associated with referral to medical oncology and/or utilization of adjuvant chemotherapy. RESULTS: Of 540 patients with NSCLC, 108 underwent curative-intent surgery (67% lobectomy; 15% pneumonectomy; 19% wedge resection) for NSCLC (39% IA; 24% IB; 25% II; 14% III). Referral to medical oncology was observed in 44% (47 of 108) of all patients including 73% (30 of 41) of those with stage II-III. Adjuvant chemotherapy utilization was observed in 62% (29 of 47) of those referred including 73% (22 of 30) of those with stage II-III. Overall, 27% (29 of 108) of all patients received adjuvant chemotherapy, including 54% (22 of 41) of those with stage II-III. Higher uptake was significantly associated with age (younger versus older), stage (II/III versus I), and surgery type (pneumonectomy versus wedge). Weaker associations were observed with other cofactors including surgeon, health center, mean household income, and surgery-medical oncologist consult timeline. CONCLUSIONS: The uptake of adjuvant chemotherapy in patients with resected NSCLC outside of clinical trials is low overall, but is higher among younger patients and those with more advanced stages. These uptake patterns may allow future planning of health resource utilization and/or improvement of chemotherapy utilization rates.

Waiting times in early-stage non-small cell lung cancer (NSCLC).

INTRODUCTION: Wait times in cancer care continue to be an important clinical, social, and political issue. This study examines wait times along the care path from suspicious imaging study (Detection) to adjuvant chemotherapy initiation (Chemotherapy) for patients with early-stage non-small cell lung cancer (NSCLC) who undergo surgical resection. METHODS: A retrospective chart review of patients diagnosed in 2005 with NSCLC who underwent curative-intent surgery in Nova Scotia, Canada was conducted to abstract dates of care events (Detection, Surgery Consultation, Surgery, Medical Oncology [MO] Referral, MO Consultation and Chemotherapy) and patient characteristics. Multifactorial regression methods were used to identify statistically-significant cofactors associated with wait times at various resolutions of care intervals (low, intermediate, high). RESULTS: A median wait time of 141 days elapsed between Detection-Chemotherapy; and a median 107 and 52 days elapsed between Detection-Surgery and Surgery-Chemotherapy, respectively. A number of demographic, clinical, epidemiological, and system resource dependant factors influenced wait times at different resolutions, and were best detailed utilizing high resolution analysis. Wait time between MO referral-MO Consultation was inversely related to that experienced in the preceding interval of Surgery-MO Referral. CONCLUSIONS: This study provides a first detailed examination of wait times experienced by NSCLC patients undergoing curative-intent surgery according to care interval definitions; demonstrates the value of high care interval resolution analysis to detect bottlenecks in access to care; and reports on the interdependence of elapsed times between care events along the care path for cancer patients.

Requests for euthanasia made to a tertiary referral teaching hospital in Sydney, Australia in the year 2000.

A request for euthanasia (RFE) in the terminally ill raises concerns that physical and/or mental suffering remain unaddressed and thus mandates a critical appraisal of the physical and psychosocial aspects of the individual concerned. An alert datasheet (AD) is completed at the weekly Palliative Care Service (PCS) meeting as a measure of self-audit and deals with issues considered to be of importance in ensuring high-quality patient care, one of which is a RFE. The ADs for the year 2000 were examined, and where a RFE was made, the contributing factors as documented on the forms together with demographic data, the case synopsis and patient-rated main three problems/issues were appraised. Among 490 patients referred to the service, there were 6 RFE (1.6%) recorded. These were made by 1 female (age 44) and 5 male (age range 58-78 years) patients. Four of these patients had a cancer diagnosis (all had metastatic disease). Median survival from first contact with the PCS was 13 days (range 4-29). The contributing factors identified were: uncontrolled symptoms (2/6 - severe constipation in both), depression (1/6), issues of burden/dependency (6/6), lack of autonomy/control (4/6), sense of hopelessness (3/6) and social isolation (4/6). The patient-rated main three problems were: (i) physical symptoms (5/6), specifically pain (2/6), shortness of breath (2/6), fatigue (1/6) and nausea (1/6), and (ii) psychosocial issues (4/6). A RFE was seen to be a multifactorial entity (issues of burden/dependency being universal) and merits a focused appraisal in order to adequately address potentially unrecognised issues that contribute to suffering. The short median survival from the time of referral to the service suggests that (i) RFEs are made late in the trajectory of the illness and (ii) these patients are being referred late in the course of their illness - thus limiting the window in which these issues can be addressed.

A systematic review of physicians' survival predictions in terminally ill cancer patients.

OBJECTIVE: To systematically review the accuracy of physicians' clinical predictions of survival in terminally ill cancer patients. DATA SOURCES: Cochrane Library, Medline (1996-2000), Embase, Current Contents, and Cancerlit databases as well as hand searching. STUDY SELECTION: Studies were included if a physician's temporal clinical prediction of survival (CPS) and the actual survival (AS) for terminally ill cancer patients were available for statistical analysis. Study quality was assessed by using a critical appraisal tool produced by the local health authority. DATA SYNTHESIS: Raw data were pooled and analysed with regression and other multivariate techniques. RESULTS: 17 published studies were identified; 12 met the inclusion criteria, and 8 were evaluable, providing 1563 individual prediction-survival dyads. CPS was generally overoptimistic (median CPS 42 days, median AS 29 days); it was correct to within one week in 25% of cases and overestimated survival by at least four weeks in 27%. The longer the CPS the greater the variability in AS. Although agreement between CPS and AS was poor (weighted kappa 0.36), the two were highly significantly associated after log transformation (Spearman rank correlation 0.60, P < 0.001). Consideration of performance status, symptoms, and use of steroids improved the accuracy of the CPS, although the additional value was small. Heterogeneity of the studies' results precluded a comprehensive meta-analysis. CONCLUSIONS: Although clinicians consistently overestimate survival, their predictions are highly correlated with actual survival; the predictions have discriminatory ability even if they are miscalibrated. Clinicians caring for patients with terminal cancer need to be aware of their tendency to overestimate survival, as it may affect patients' prospects for achieving a good death. Accurate prognostication models incorporating clinical prediction of survival are needed.