Real-World Cost-Effectiveness of First-Line Gemcitabine Plus Nab-Paclitaxel vs FOLFIRINOX in Patients With Advanced Pancreatic Cancer.

BACKGROUND: There are no randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and fluorouracil, folinic acid, irinotecan, oxaliplatin (FOLFIRINOX) for advanced pancreatic cancer (APC). Although it is well known that RCT-based efficacy often does not translate to real-world effectiveness, there is limited literature investigating comparative cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC. We aimed to examine the real-world cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC in Ontario, Canada. METHODS: This study compared patients treated with first-line Gem-Nab or FOLFIRINOX for APC in Ontario from April 2015 to March 2019. Patients were linked to administrative databases. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring, and discounted at 1.5%. Incremental cost-effectiveness ratio and net monetary benefit were computed to estimate cost-effectiveness from the public health-care payer's perspective. Sensitivity analysis was conducted using the propensity score matching method. RESULTS: A total of 1988 patients were identified (Gem-Nab: n = 928; FOLFIRINOX: n = 1060). Mean survival was lower for patients in the Gem-Nab than the FOLFIRINOX group (0.98 vs 1.26 life-years; incremental effectiveness = -0.28 life-years [95% confidence interval = -0.47 to -0.13]). Patients in the Gem-Nab group incurred greater mean 5-year total costs (Gem-Nab: $103 884; FOLFIRINOX: $101 518). Key cost contributors include ambulatory cancer care, acute inpatient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it was less effective and more costly. Results from the sensitivity analysis were similar. CONCLUSIONS: Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore not considered cost-effective at commonly accepted willingness-to-pay thresholds.

Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a systematic review.

The purpose of the present review was to describe evidence-based indications for hyperthermic intraperitoneal chemotherapy (HIPEC), with cytoreductive surgery (CRS), in patients with a diagnosis of mesothelioma, appendiceal (including appendiceal mucinous neoplasm), colorectal, gastric, ovarian or primary peritoneal carcinoma. Relevant studies were identified from a systematic MEDLINE and EMBASE search of studies published from 1985 to 2019. Studies were included if they were RCTs. If no RCTs were identified, prospective and retrospecctive comparative studies (where confounders are controlled for studies with greater than 30 patients) were included. Overall survival, progression-free survival, recurrence-free survival, adverse events and quality of life data were extracted. For patients with newly diagnosed, primary stage III epithelial ovarian, fallopian tube or primary peritoneal carcinoma, HIPEC with CRS should be considered for those with at least stable disease following neoadjuvant chemotherapy at the time of interval CRS if complete or optimal cytoreduction is achieved. There is insufficient evidence to recommend the addition of HIPEC when primary CRS is performed for patients with newly diagnosed, primary advanced epithelial ovarian, fallopian tube or primary peritoneal carcinoma or in those with recurrent ovarian cancer outside of a clinical trial. There is insufficient evidence to recommend HIPEC with CRS for the prevention of or for the treatment of peritoneal colorectal carcinomatosis outside of a clinical trial. There is insufficient evidence to recommend HIPEC with CRS for the prevention of or for the treatment of gastric peritoneal carcinomatosis outside of a clinical trial. There is insufficient evidence to recommend HIPEC with CRS in patients with malignant peritoneal mesothelioma or in those with disseminated mucinous neoplasm in the appendix as a standard of care; however, these patients should be referred to HIPEC specialty centres for assessment for treatment as part of an ongoing research protocol.

Increased Incidence of Ventricular Arrhythmias in Patients With Advanced Cancer and Implantable Cardioverter-Defibrillators.

OBJECTIVES: This study evaluated the incidence of ventricular arrhythmia and implantable cardioverter-defibrillator (ICD) therapies in patients with a diagnosis of cancer. BACKGROUND: Cardiac disease and cancer are prevalent conditions and share common predisposing factors. No studies have assessed the impact of cancer on the burden of ventricular arrhythmia in patients with cancer and ICDs. METHODS: Retrospective study of patients with an ICD and cancer who were followed from January 2007 to June 2015. Rates of ventricular tachycardia (VT) and ventricular fibrillation (VF) before and after patients' cancers were diagnosed were evaluated by searching device data collection systems. Rates were adjusted for length of follow-up and compared using the Wilcoxon test, and times to first therapy following diagnosis (stages I to III vs. IV) were compared using Kaplan-Meier curves and log-rank test. RESULTS: Among 1,598 patients with an ICD, 209 patients (13.1%) had a pathological diagnosis of malignancy; and in 102 patients (6.4%), malignancy was diagnosed following device insertion. After the diagnosis of cancer, 32% of patients experienced VT/VF over 23.2 ± 23.6 months, and the frequency of arrhythmic events was significantly increased after the diagnosis (1.19 ± 0.32 vs. 0.12 ± 0.21 episodes per month, respectively; p = 0.03). The incidence of VT/VF was markedly higher in patients with stage IV cancer than in those with earlier stages (p = 0.03). In this group, the incidence of VT/VF was 41.2%, with an average of 7.2 ± 18.5 events per patient, all of whom received ICD shocks. The rate of ICD deactivation in stage IV patients was 35.3%. Inappropriate therapies occurred in 13.7%, and atrial fibrillation was the most frequent cause. CONCLUSIONS: One-third of patients who had received ICDs developed ventricular arrhythmia after a diagnosis of cancer. The incidence was significantly higher in those with advanced metastatic disease. Findings underscore the need to discuss ICD management as part of end-of-life care.

A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: A study of the Princess Margaret, Chicago and California phase II consortia.

PURPOSE: A phase II study was performed to evaluate the efficacy and safety of single-agent RO4929097 (a gamma-secretase inhibitor) in patients with recurrent platinum-resistant ovarian cancer. EXPERIMENTAL DESIGN: Women with progressive platinum-resistant ovarian cancer treated with ≤2 chemotherapy regimens for recurrent disease were enrolled in this trial. Patients received oral RO4929097 at 20 mg once daily, 3 days on/4 days off each week in a three week cycle. The primary endpoint was progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives included assessment of the safety of RO4929097 and exploration of molecular correlates of outcome in archival tumor tissue and serum. RESULTS: Of 45 patients enrolled, 40 were evaluable for response. Thirty-seven (82%) patients had high-grade ovarian cancer. No objective responses were observed. Fifteen patients (33%) had stable disease as their best response, with a median duration of 3.1 months. The median PFS for the whole group was 1.3 months (1.2-2.5). Treatment was generally well tolerated with 10% of patients discontinuing treatment due to an adverse event. In high grade serous ovarian cancer patients, the median PFS trended higher when the expression of intracellular Notch (NICD) protein by immunohistochemistry was high versus low (3.3 versus 1.3 months, p=0.09). No clear relationship between circulating angiogenic factors and PFS was found despite a suggestion of an improved outcome with higher baseline VEGFA levels. CONCLUSIONS: RO4929097 has insufficient activity as a single-agent in platinum-resistant ovarian cancer to warrant further study as monotherapy. Future studies are needed to explore the potential for cohort enrichment using NICD expression.

An organizational guideline for gynecologic oncology services.

OBJECTIVES: Documented variations in practice compelled the need to establish a network that would facilitate the flow of patients through the care continuum of a provincial health care system in accordance with best practices. Therefore, a guideline was developed to provide recommendations for the optimal organization of gynecologic oncology services in this higher resource location to improve access to multidisciplinary care and appropriate treatment. METHODS: A systematic review was conducted of Web sites of international guideline developers, relevant cancer agencies, and Medline and EMBASE from 1996 to 2011 using search terms related to gynecologic malignancies, combined with organization of services, patterns of care, and various facility and physician characteristics. The results of the review were combined with expert consensus and stakeholder consultation to develop a gynecologic oncology services organizational guideline. RESULTS: The evidence review yielded a lower quality evidence base; therefore, recommendations were determined through consensus, including guidance for physician and hospital specialization, and other domains including human and physical resources. Definitive surgical treatment of most invasive cancers by subspecialist gynecologic oncologists is recommended. In addition, it is recommended that these subspecialists provide care within designated gynecologic oncology centers. The recommendations also outline which services, such as radiation therapy, may be provided in other affiliated centers. Multidisciplinary team management is also endorsed. CONCLUSIONS: These recommendations are intended to allow a collaborative community of practice, supported by formal interorganizational processes, to evolve to facilitate adherence to guidelines and best practices at a system-wide level.

Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group.

PURPOSE: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. PATIENTS AND METHODS: Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. RESULTS: In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. CONCLUSION: mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.

Phase II study of erlotinib in recurrent or metastatic endometrial cancer: NCIC IND-148.

PURPOSE: Epidermal growth factor receptor (EGFR) overexpression is common in endometrial cancers and may have a major role in tumor growth and progression. Erlotinib is an orally active, selective inhibitor of EGFR tyrosine kinase activity. PATIENTS AND METHODS: A multinomial design two-stage phase II study was performed to evaluate single-agent activity of erlotinib in women with advanced endometrial cancer with recurrent or metastatic disease who were chemotherapy naïve and had received up to one line of prior hormonal therapy. Erlotinib was administered at daily dose of 150 mg. Archival tumor tissue was analyzed for EGFR expression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH). Mutational status of EGFR was determined in responders. RESULTS: Thirty-two of 34 entered patients are assessable for response. Treatment was well tolerated and severe toxicity infrequent, with the only grade 4 toxicity being an elevation of transaminases (AST). There were four confirmed partial responses (PRs; 12.5%; 95% CI, 3.5% to 29%) lasting 2 to 36 months. Fifteen patients had stable disease (SD), with median duration of 3.7 months (range, 2 to 12 months). EGFR expression was analyzed in thirty patients; 19 were positive, nine were negative, and two were not assessable. Of the 19 patients who were EGFR positive, three had PR (16%), seven SD, and eight progressive disease, and one was not assessable. No mutations were identified in responders. FISH showed no correlation of response with gene amplification. CONCLUSION: Erlotinib is well tolerated with an overall objective response rate of 12.5%. Molecular analysis did not identify EGFR mutations in responders or correlation of response with gene amplification.