Comparative Effectiveness of FOLFIRINOX Versus Gemcitabine and Nab-paclitaxel in Initially Unresectable Locally Advanced Pancreatic Cancer: A Population-based Study to Assess Subsequent Surgical Resection and Overall Survival.

AIMS: First-line FOLFIRINOX (FOLinic acid, Fluorouracil, IRINotecan, and OXaliplatin) and gemcitabine plus nab-paclitaxel (GnP) have been publicly funded for patients with unresectable locally advanced pancreatic cancer (uLAPC) in Ontario, Canada. We examined the overall survival and surgical resection rate after first-line FOLFIRINOX or GnP and determined the association between resection and overall survival in patients with uLAPC. MATERIALS AND METHODS: We conducted a retrospective population-based study including patients with uLAPC who received first-line treatment FOLFIRINOX or GnP from April 2015 to March 2019. The cohort was linked to administrative databases to ascertain demographic and clinical characteristics. Propensity score methods were used to balance differences between FOLFIRINOX and GnP. The Kaplan-Meier method was used to calculate overall survival. Cox regression was used to determine the association between receipt of treatment and overall survival, adjusting for time-dependent surgical resections. RESULTS: We identified 723 patients with uLAPC (mean age = 65.8, 43.5% female) who received FOLFIRINOX (55.2%) or GnP (44.8%). The median overall survival and 1-year overall survival probability were higher for FOLFIRINOX (13.7 months, 54.6%) than for GnP (8.7 months, 34.0%). Post-chemotherapy surgical resection occurred in 89 (12.3%) patients (FOLFIRINOX: 74 [18.5%] versus GnP: 15 [4.6%]), with no difference in survival since surgery between FOLFIRINOX and GnP (P = 0.29). After adjusting time-dependent post-treatment surgical resection, FOLFIRINOX (inverse probability treatment weighting hazard ratio 0.72, 95% confidence interval 0.61, 0.84) was independently associated with improved overall survival. CONCLUSIONS: In this real-world population-based study of patients with uLAPC, FOLFIRINOX was associated with improved survival and higher resection rates. FOLFIRINOX was associated with improved survival in patients with uLAPC after accounting for the effect of post-chemotherapy surgical resection, suggesting the benefit of FOLFIRINOX was not solely due to improving resectability.

Outcomes Following Treatment with FOLFOX for Patients with Resectable or Potentially Resectable Metastatic Colorectal Cancer: A Population-based Cohort Study.

AIMS: To evaluate the safety and effectiveness of oxaliplatin-based combination chemotherapy for patients with metastatic colorectal cancer (mCRC) to extrahepatic sites. MATERIALS AND METHODS: We conducted a population-based retrospective study examining the safety and effectiveness of perioperative oxaliplatin for resectable or potentially resectable colorectal metastases in Ontario, Canada. Outcomes were also compared with patients with liver-only metastases. Patients received oxaliplatin for mCRC between 1 January 2013 and 30 June 2020. RESULTS: In total, 192 patients had extrahepatic metastases. Seventy per cent had R0 metastasectomy. The 3-year disease-free survival and overall survival were 62% and 79%, respectively; <4% of patients died within 60 days of metastasectomy and 74-90% of patients received treatment according to recommendations from a multidisciplinary setting. Compared with liver-only controls (n = 1306), patients had mCRC to the lung only (n = 115), lung and liver (n = 55) and liver with non-pulmonary site (n = 22). Extrahepatic metastases were more likely to be found for patients whose primary colorectal resection had positive margins (14% versus 7%, P = 0.005) and primary tumours located in the rectum [odds ratio 4.01 (2.31-6.97)]. After adjustment, there was no difference in overall survival between liver-only controls and patients with lung-only [hazard ratio 0.82 (0.59-1.15)] or liver and lung metastases [hazard ratio 1.26 (0.85-1.87)] (P = 0.24). In total, 79/115 (69%) of patients with lung-only metastases had a metastasectomy compared with 645/1306 (49%) and 15/55 (27%) of patients with liver-only and liver and lung metastases, respectively. Hospital visits were similar between patients with liver-only and extrahepatic metastases. CONCLUSION: Oxaliplatin-based chemotherapy for patients with resectable or potentially resectable mCRC with extrahepatic metastases was safe and resulted in similar outcomes in appropriately selected patients when compared with patients with liver-only metastases.

Real-world Safety of Bevacizumab with First-line Combination Chemotherapy in Patients with Metastatic Colorectal Cancer: Population-based Retrospective Cohort Studies in Three Canadian Provinces.

AIMS: To examine the real-world safety of adding bevacizumab to first-line irinotecan-based chemotherapy for patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: Patients diagnosed with CRC in three Canadian provinces (Ontario, Saskatchewan and British Columbia) who received publicly funded bevacizumab and/or irinotecan from 2000 to 2016 were identified from cancer registries. Propensity score 1:1 matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to contemporaneous and historical controls, adjusting for baseline demographic and clinical characteristics. Safety end points evaluated during first-line treatment plus 30 days included mortality within 30 days and all-cause-, chemotherapy- and bevacizumab-related hospitalisations. Chemotherapy- and bevacizumab-related visits were defined as hospitalisations for specific conditions commonly associated with chemotherapy (e.g. infections) or bevacizumab (e.g. arteriovenous thromboembolism) using most responsible diagnosis codes. In PSM and IPTW-weighted cohorts, we assessed event frequencies using odds ratios from logistic regressions and event rate ratios using negative binomial regression models. The results from each province and comparison were pooled using random-effects meta-analysis. RESULTS: We identified 16 250 mCRC patients who received first-line irinotecan-based treatment. In PSM cohorts, bevacizumab was associated with fewer deaths within 30 days of treatment compared with contemporaneous (pooled odds ratio = 0.62; 95% confidence interval 0.50-0.75) and historical controls (pooled odds ratio = 0.73; 95% confidence interval 0.58-0.93). Hospitalisations were more frequent among patients treated with bevacizumab compared with historical controls but similar to contemporaneous controls. As patients receiving bevacizumab were exposed to a longer average treatment duration, across their full treatment duration, patients receiving bevacizumab had significantly lower rates of hospitalisations (contemporaneous pooled rate ratio = 0.56; 95% confidence interval 0.47-0.67; historical pooled rate ratio = 0.73; 95% confidence interval 0.56-0.95). Similar trends were observed for chemotherapy- and bevacizumab-related hospitalisations and in IPTW-weighted cohorts. DISCUSSION: We did not observe any increase in rates of hospitalisation or death within 30 days of treatment among mCRC patients treated with bevacizumab plus chemotherapy versus chemotherapy alone; these findings should be interpreted with caution due to the risk of residual confounding.

Impact of a novel prioritization framework on clinician-led oncology drug submissions.

Background: In Canada, requests for public reimbursement of cancer drugs are predominately initiated by pharmaceutical manufacturers. Clinician-led submissions provide a mechanism to initiate the drug funding process when industry does not submit a request for funding consideration. Although such requests are resource-intensive to produce, Cancer Care Ontario (cco) has the capacity to facilitate clinician-led submissions. In 2014, cco began developing a cancer drug prioritization framework that allocates resources to systematically address a growing number of clinician-identified funding gaps with clinician-led submissions. Methods: Cancer site-specific drug advisory committees established by cco consist of health care practitioners whose roles include identifying and prioritizing funding gaps. The committees submit their identified gaps to a cross-cancer-site prioritization exercise in which the requests are ranked based on a set of guiding principles derived from health technology assessment. The requests are then sequentially allocated the resources needed to meet submission requirements. Whether the funding gap is of provincial or pan-Canadian relevance determines where the submission is filed for assessment. Results: Since its inception, the cco framework has identified 17 funding gaps in 9 cancer sites. In 4 prioritizations, the framework supported 6 submissions. As of June 2018, the framework had contributed to the eventual funding of more than 9 new drug-indication pairs, with more awaiting funding consideration. Conclusions: The cco prioritization framework has enabled clinicians to effectively and systematically identify, prioritize, and fill funding gaps not addressed by industry. Ultimately, the framework helps to ensure that patients can access evidence-informed and cost-effective therapies. The framework will continue to evolve as it encounters new challenges, including funding requests for rare indications.

Estimating the costs of intensity-modulated and 3-dimensional conformal radiotherapy in Ontario.

BACKGROUND: Radiotherapy is a common treatment for many cancers, but up-to-date estimates of the costs of radiotherapy are lacking. In the present study, we estimated the unit costs of intensity-modulated radiotherapy (imrt) and 3-dimensional conformal radiotherapy (3D-crt) in Ontario. METHODS: An activity-based costing model was developed to estimate the costs of imrt and 3D-crt in prostate cancer. It included the costs of equipment, staff, and supporting infrastructure. The framework was subsequently adapted to estimate the costs of radiotherapy in breast cancer and head-and-neck cancer. We also tested various scenarios by varying the program maturity and the use of volumetric modulated arc therapy (vmat) alongside imrt. RESULTS: From the perspective of the health care system, treating prostate cancer with imrt and 3D-crt respectively cost $12,834 and $12,453 per patient. The cost of radiotherapy ranged from $5,270 to $14,155 and was sensitive to analytic perspective, radiation technique, and disease site. Cases of head-and-neck cancer were the most costly, being driven by treatment complexity and fractions per treatment. Although imrt was more costly than 3D-crt, its cost will likely decline over time as programs mature and vmat is incorporated. CONCLUSIONS: Our costing model can be modified to estimate the costs of 3D-crt and imrt for various disease sites and settings. The results demonstrate the important role of capital costs in studies of radiotherapy cost from a health system perspective, which our model can accommodate. In addition, our study established the need for future analyses of imrt cost to consider how vmat affects time consumption.

Economic evaluation of hormonal therapies for postmenopausal women with estrogen receptor-positive early breast cancer in Canada.

BACKGROUND: Aromatase inhibitor (ai) therapy has been subjected to numerous cost-effectiveness analyses. However, with most ais having reached the end of patent protection and with maturation of the clinical trials data, a re-analysis of ai cost-effectiveness and a consideration of ai use as part of sequential therapy is desirable. Our objective was to assess the cost-effectiveness of the 5-year upfront and sequential tamoxifen (tam) and ai hormonal strategies currently used for treating patients with estrogen receptor (er)-positive early breast cancer. METHODS: The cost-effectiveness analysis used a Markov model that took a Canadian health system perspective with a lifetime time horizon. The base case involved 65-year-old women with er-positive early breast cancer. Probabilistic sensitivity analyses were used to incorporate parameter uncertainties. An expected-value-of-perfect-information test was performed to identify future research directions. Outcomes were quality-adjusted life-years (qalys) and costs. RESULTS: The sequential tam-ai strategy was less costly than the other strategies, but less effective than upfront ai and more effective than upfront tam. Upfront ai was more effective and less costly than upfront tam because of less breast cancer recurrence and differences in adverse events. In an exploratory analysis that included a sequential ai-tam strategy, ai-tam dominated based on small numerical differences unlikely to be clinically significant; that strategy was thus not used in the base-case analysis. CONCLUSIONS: In postmenopausal women with er-positive early breast cancer, strategies using ais appear to provide more benefit than strategies using tam alone. Among the ai-containing strategies, sequential strategies using tam and an ai appear to provide benefits similar to those provided by upfront ai, but at a lower cost.

[Could infant euthanasia be ever acceptable?]. / ¿Podría ser aceptable la eutanasia infantil?

The recent enactment of a law that allows infant euthanasia in Belgium raises questions with varied answers. To contribute to a better understanding of the topic, euthanasia and legislation concepts are described. After a bioethical analysis, we propose as conclusion that children euthanasia could only be acceptable in very exceptional situations in which palliative measures have failed. The answer should be that it is not acceptable in our setting, not until we have public policies, protocols and palliative care services for terminally ill children.

Cost-effectiveness of intensity-modulated radiotherapy in oropharyngeal cancer.

AIMS: Intensity-modulated radiotherapy (IMRT) is an advanced radiation technique that is particularly suited to treating head and neck cancers because it can conform a high dose to the target volume while preserving the tissue function of neighbouring structures. The objective of this study was to compare the cost and effectiveness of IMRT with three-dimensional conformal radiotherapy (3DCRT) for the treatment of locally advanced oropharyngeal cancer. MATERIALS AND METHODS: We developed a Markov model to estimate the incremental cost per quality-adjusted life-year (QALY) gained by IMRT from the perspective of the Ministry of Health. The costs of IMRT and 3DCRT were estimated through activity-based costing, incorporating input from radiation oncologists, physicists and radiation therapists. We obtained clinical effectiveness estimates from published studies and calculated the number needed to treat to avoid a case of severe long-term xerostomia using data from a randomised controlled trial. RESULTS: The delivery of IMRT produced 0.48 more QALYs than 3DCRT at an additional cost of $2447 (QALY and costs discounted at 5% a year), yielding an incremental cost-effectiveness ratio of $5084 per QALY gained. The cost-effectiveness of IMRT was sensitive to the costs of radiotherapy and the effect of IMRT on health-related quality of life. The cost of IMRT will probably decrease with the addition of volumetric modulated arc therapy, an increasingly used technology, because volumetric modulated arc therapy reduces treatment time. We need to treat less than two patients with IMRT to avoid a case of severe, long-term xerostomia (dry mouth), and the incremental cost to avoid a case of severe, long-term xerostomia was $4532. CONCLUSIONS: In the treatment of locally advanced oropharyngeal carcinoma, the IMRT strategy appears to be cost-effective when compared with 3DCRT.

Cost-effectiveness of intensity-modulated radiotherapy in prostate cancer.

AIMS: To compare the costs and effectiveness of intensity-modulated radiotherapy (IMRT) with three-dimensional conformal radiotherapy (3DCRT) for the radical treatment of localised prostate cancer at elevated doses (>70 Gy). MATERIALS AND METHODS: A cost-effectiveness analysis model was developed using clinical effectiveness estimates from a systematic review. The base case analysis assumes equal biochemical survival for IMRT and 3DCRT, but lower frequency of gastrointestinal toxicity for IMRT. The costs of IMRT and 3DCRT were estimated through activity-based costing, incorporating input from radiation oncologists, physicists and treatment planners. RESULTS: The delivery of IMRT produced 0.023 more quality-adjusted life-years (QALY) than 3DCRT at an additional cost of $621 (QALY and costs discounted at 5% per year), yielding an incremental cost-effectiveness ratio of $26 768 per QALY gained. The treatment cost of IMRT was $1019 more than 3DCRT, but IMRT resulted in less frequent gastrointestinal toxicity, thus avoiding $402 in the treatment of toxicity. In the scenario that compared a higher dose of IMRT (75.6 Gy) to 3DCRT (68.4 Gy), IMRT improved disease control with equal toxicity incidence, and the IMRT strategy dominated (less costly and more effective). In the base case scenario (no survival difference), the cost-effectiveness of IMRT was most sensitive to the treatment cost difference between IMRT and 3DCRT. CONCLUSION: For radical radiation treatment (>70 Gy) of prostate cancer, IMRT seems to be cost-effective when compared with an equivalent dose of 3DCRT.

Experience with high frequency oscillation ventilation during the 2009 H1N1 influenza pandemic in Australia and New Zealand.

During the 2009 H1N1 pandemic, large numbers of patients had severe respiratory failure. High frequency oscillation ventilation was used as a salvage technique for profound hypoxaemia. Our aim was to compare this experience with high frequency oscillation ventilation during the 2009 H1N1 pandemic with the same period in 2008 by performing a three-month period prevalence study in Australian and New Zealand intensive care units. The main study end-points were clinical demographics, care delivery and survival. Nine intensive care units contributed data. During 2009 there were 22 H1N1 patients (17 adults, five children) and 10 non-H1N1 patients (five adults, five children), while in 2008, 18 patients (two adults, 16 children) received high frequency oscillation ventilation. The principal non-H1N1 high frequency oscillation ventilation indication was bacterial or viral pneumonia (56%). For H1N1 patients, the median duration of high frequency oscillation ventilation was 3.7 days (interquartile range 1.8 to 5) with concomitant therapies including recruitment manoeuvres (22%), prone ventilation (41%), inhaled prostacyclins (18%) and inhaled nitric oxide (36%). Seven patients received extracorporeal membrane oxygenation, six having H1N1. Three patients had extracorporeal membrane oxygenation concurrently, two as salvage therapy following the commencement of high frequency oscillation ventilation. In 2008, no high frequency oscillation ventilation patient received extracorporeal membrane oxygenation. Overall hospital survival was 77% in H1N1 patients, while survival in patients having adjunctive extracorporeal membrane oxygenation was similar to those receiving high frequency oscillation ventilation alone (65% compared to 71%, P = 1.00). Survival rates were comparable to published extracorporeal membrane oxygenation outcomes. High frequency oscillation ventilation was used successfully as a rescue therapy for severe respiratory failure. High frequency oscillation ventilation was only available in a limited number of intensive care units during the H1N1 pandemic.

Extracorporeal membrane oxygenation for cardiorespiratory failure in four patients with pandemic H1N1 2009 influenza virus and secondary bacterial infection.

We report four patients with pandemic H1N1 2009 influenza virus and secondary bacterial infection who were treated with extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure. Three of the four patients had profound shock, necessitating support with venoarterial ECMO. Two patients died during ECMO support. The two survivors had prolonged hospital stays, which were complicated by renal failure and limb ischaemia.

Stage one Norwood procedure results: the green lane experience.

AIMS: This study examined the presentation outcome, morbidity and mortality of infants who have undergone the stage one Norwood procedure for single ventricle reconstruction. METHODS: A retrospective review was done on the first 20 patients to undergo this procedure at Green Lane Hospital, Auckland, New Zealand. Seven patients were diagnosed antenatally. Fetal cardiology records in the same time period were reviewed. RESULTS: Twelve of the 20 patients (60%) have survived, and all of these patients have undergone their bi-directional Glenn procedure with no mortality. Eight patients died, with five of the deaths occurring in the perioperative period. Initial surgical mortality was 75%, decreasing to 25% since 1998. Antenatal diagnosis has not improved surgical outcome to date. CONCLUSION: With advances in surgical technique and pre- and postoperative care, neonates born with single ventricle anatomy have an acceptable surgical option. Babies who survive the Norwood operation have a good chance of surviving the later stages of the cardiac reconstruction process, and they have a reasonable outlook in the intermediate term.

A prospective randomized clinical assessment of a new pigtail central venous catheter in comparison with standard alternatives.

The Cook Pigtail central venous catheter (CVC) has been designed to diminish the risk of vascular perforation and consequent cardiac tamponade. With the participation of 12 consultant anaesthetists and 19 registrars, adults undergoing elective surgery were randomized to receive either a Pigtail (n = 101) or their consultant anaesthetists' "standard" CVC (n = 102). Median ease of insertion was rated 8 for Pigtail CVCs and 9 for standards (10 being best; P = 0.001). Arrhythmias occurred during 16 standard and 33 Pigtail central venous catheter insertions (P < 0.006). No significant difference was found in insertion time or radiographically assessed tip depth for standard and Pigtail central venous catheters. A perforated right atrium of uncertain cause occurred in a patient who received an Arrow triple-lumen central venous catheter. Participating consultant anaesthetists preferred their "standard" central venous catheter for routine use, but five indicated that they would select a Cook Pigtail where long-term use was planned because of in vitro evidence of its greater safety.

[Maternal brain death during pregnancy]. / Muerte cerebral materna durante el embarazo.

The case of a pregnant patient who had a massive intracraneal haemorrhage at 18 weeks of gestation is presented. Patient's neurological damage evolved to brain death, but the fetus continued in good condition. The decision of withdrawing life support or to continue supporting the mother's life to allow fetal development aroused difficult ethical questions, both to relatives and professionals. This is an exceptional situation of a heart beating cadaver and a non viable fetus whose life depends on the continuation of treatments that are considered as experimental. A good decision should be based on the respect to a body in brain death, the fetal right to life, family's wishes and values, the use of experimental treatments, and the rational use of a public hospital's resources. The conclusion was that the continuation of life support treatments was not an ethical obligation. Withdrawing life support to allow fetal death in this case means foregoing an experimental treatment and to respect family's autonomy and the right of the patient's death with dignity. Similar cases need to be discussed with a multidisciplinary analysis in their own particularity.

Neonatal lupus syndrome: a case with chondrodysplasia punctata and other unusual manifestations.

We report a case of a newborn infant whose mother had systemic lupus erythematosus (SLE) diagnosed before pregnancy. The child had clinical manifestations of neonatal lupus as well as chondrodysplasia punctata and other findings that resemble the congenital anomalies associated with the use of oral anticoagulants, with no history of exposure. We speculate that the combined action of the different maternal autoantibodies may produce the whole spectrum of manifestations.

Do not resuscitate orders and pediatric patients: the role of a clinical ethics committee in a developing country.

No published information is currently available about formal "do not resuscitate" (DNR) orders for pediatric patients in developing countries, even though there has been extensive discussion of how to determine who should be involved. This article reports the experience of a clinical ethics committee that recommended DNR orders at a pediatric public hospital in Chile. The committee consisted of four permanent physician members and temporary members including clergymen, nurses, the head of the patient's hospital unit, and the attending physician. Attending physicians submitted cases to the committee on a voluntary basis, and the committee's recommendations were not binding. During the 1990-1993 study period the committee recommended issuing DNR orders for 16 of the 34 patients it evaluated. The hospital records of these 16 patients were retrospectively reviewed for information about the patient's age and diagnosis, the committee's specific recommendations, and the outcome of the case. It was found that the committee typically recommended specific measures to help the child's parents and attending staff in addition to the DNR order. The average patient age was 2 years and 2 months. Nearly all of the patients had chronic and multiple pathologies. In all cases the committee recommendations (taken by consensus) were followed by the attending physician with the consent of the patient's parents. Eleven of the 16 patients for whom DNR orders were issued died during the study period. The five others remained alive despite respiratory insufficiency, severe neurologic damage, or hepatic failure. In general the committee's recommendations appeared useful, providing stronger arguments for DNR decisions and suggesting further support measures for patients, their families, and the attending professionals. This finding supports the idea that clinical ethics committees can provide both valuable support and an opportunity to arrive at better decisions in the public hospitals of developing countries.