Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Mepitel Film for the Prevention of Acute Radiation Dermatitis in Breast Cancer: A Randomized Multicenter Open-Label Phase III Trial.

PURPOSE: Radiation dermatitis (RD) is common in patients undergoing breast radiotherapy. Mepitel film (MF) can reduce RD, but the results from two randomized controlled trials are conflicting. We aimed to conduct a confirmatory randomized controlled trial in patients at risk of RD. METHODS: Patients were randomly assigned to receive MF or standard care (2:1 ratio). Patients with large breasts after lumpectomy (bra size ≥ 36 inches or cup size ≥ C) or after mastectomy were eligible. Stratification factors included surgery type, dose fractionation, and administration of boost/bolus. The primary end point was grade (G) 2 or 3 RD using the Common Terminology Criteria for Adverse Events v5.0. Secondary end points included patient- and clinician-reported outcomes. RESULTS: Between January 2020 and May 2022, 376 patients were included in the modified intention-to-treat analysis. The incidence of G2 or 3 RD was significantly lower in MF patients compared with standard care (n = 39/251, 15.5%; 95% CI, 11.3 to 20.6% v n = 57/125, 45.6%; 95% CI, 36.7 to 54.8% respectively, odds ratio (OR): 0.20, P < .0001). Benefits of MF remained significant in patients who developed G 3 RD (n = 7, 2.8%; 95% CI, 1.1 to 5.7% v n = 17, 13.6%; 95% CI, 8.1 to 20.9%, OR: 0.19) and moist desquamation (n = 20, 8.0%; 95% CI, 4.9 to 12.0% v n = 24, 19.2%; 95% CI, 12.7 to 27.1%, OR: 0.36). When evaluating the combined patient and health care provider score using Radiation-Induced Skin Reaction Assessment Scale, the MF arm had significantly lower scores (P < .0001). Individual items on the Radiation-Induced Skin Reaction Assessment Scale also favored the MF for both patient- and clinician-reported outcomes. Blistering/peeling, erythema, pigmentation, and edema were significantly reduced in the MF arm. Three patients removed the film prematurely because of rash (n = 2) and excessive pruritus (n = 1). CONCLUSION: MF significantly reduces RD in patients undergoing breast radiotherapy.

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial.

OBJECTIVE: To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer. DESIGN: Multicentre, open label, randomised controlled trial. SETTINGS: 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020. PARTICIPANTS: 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection. INTERVENTIONS: Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only. MAIN OUTCOME MEASURES: Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population. RESULTS: The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1). CONCLUSIONS: Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT01455831.

Access Denied? The Unintended Consequences of Pending Drug Pricing Rules.

The government of Canada now plans to bring into force new federal drug pricing regulations on 1 July 2022. We do not take issue with the goal of medication affordability, which is vital in healthcare the world over. Our concern is that the new guidelines are being implemented without due consideration for three major unintended consequences: regulatory changes will lower the number of clinical trials for new medications in Canada, fewer clinical trials will mean lower research and development investments, and changes will reduce patients' access to new medications. Access to effective medications is a cornerstone of healthcare for Canadian patients. As physicians, our duty to patient care demands that we tell the government to protect the right of Canadians to timely access to life-changing medicines.

Remote, proactive, telephone based management of toxicity in outpatients during adjuvant or neoadjuvant chemotherapy for early stage breast cancer: pragmatic, cluster randomised trial.

OBJECTIVE: To evaluate the effectiveness of remote proactive management of toxicities during chemotherapy for early stage breast cancer. DESIGN: Pragmatic, cluster randomised trial. SETTING: 20 cancer centres in Ontario, Canada, allocated by covariate constrained randomisation to remote management of toxicities or routine care. PARTICIPANTS: All patients starting adjuvant or neoadjuvant chemotherapy for early stage breast cancer at each centre. 25 patients from each centre completed patient reported outcome questionnaires. INTERVENTIONS: Proactive, standardised, nurse led telephone management of common toxicities at two time points after each chemotherapy cycle. MAIN OUTCOME MEASURES: The primary outcome, cluster level mean number of visits to the emergency department or admissions to hospital per patient during the whole course of chemotherapy treatment, was evaluated with routinely available administrative healthcare data. Secondary patient reported outcomes included toxicity, self-efficacy, and quality of life. RESULTS: Baseline characteristics of participants were similar in the intervention (n=944) and control arms (n=1214); 22% were older than 65 years. Penetration (that is, the percentage of patients who received the intervention at each centre) was 50-86%. Mean number of visits to the emergency department or admissions to hospital per patient was 0.91 (standard deviation 0.28) in the intervention arm and 0.94 (0.40) in the control arm (P=0.94); 47% (1014 of 2158 patients) had at least one visit to the emergency department or a hospital admission during chemotherapy. Among 580 participants who completed the patient reported outcome questionnaires, at least one grade 3 toxicity was reported by 48% (134 of 278 patients) in the intervention arm and by 58% (163 of 283) in the control arm. No differences in self-efficacy, anxiety, or depression were found. Compared with baseline, the functional assessment of cancer therapy trial outcome index decreased by 6.1 and 9.0 points in the intervention and control participants, respectively. CONCLUSIONS: Proactive, telephone based management of toxicities during chemotherapy did not result in fewer visits to the emergency department or hospital admissions. With the rapid rise in remote care because of the covid-19 pandemic, identifying scalable strategies for remote management of patients during cancer treatment is particularly relevant. TRIAL REGISTRATION: ClinicalTrials.gov NCT02485678.

The Operation of Canada's Only Virtually Operated Radiation Oncology Service During the COVID-19 Pandemic.

PURPOSE: Our institution operates a remote radiation oncology service in Northern Ontario, Canada. Since the start of the coronavirus disease 2019 pandemic, this center has operated without radiation oncologists on site owing to safety precautions, and this study seeks to understand the effect of this shift. METHODS AND MATERIALS: Departmental level data reports were used to investigate differences in metrics between April to May of 2019 and April to May 2020. These metrics include the total number of referrals received, average wait time from referral to consult, the number of cases that underwent peer review before beginning treatment, the total number of fractions given over each period, patient-reported outcomes, and patient satisfaction. We also examined the importance of physical examinations and the use of SABR treatment. RESULTS: There was an observed decrease in the number of referrals received, total number of fractions administered, and number of patients providing patient-reported outcomes. We observed no change in patient wait times, cases undergoing peer review before commencing treatment, or overall patient satisfaction. Challenges were identified in the collection of patient- reported outcomes and the conduction of physical examinations. CONCLUSIONS: This paper provides proof of concept that a radiation clinic can function entirely virtually in the short term without sacrificing patient satisfaction, efficiency, or safety.

Oncology education for family medicine residents: a national needs assessment survey.

BACKGROUND: This study aimed to determine the current state of oncology education in Canadian family medicine postgraduate medical education programs (FM PGME) and examine opinions regarding optimal oncology education in these programs. METHODS: A survey was designed to evaluate ideal and current oncology teaching, educational topics, objectives, and competencies in FM PGMEs. The survey was sent to Canadian family medicine (FM) residents and program directors (PDs). RESULTS: In total, 150 residents and 17 PDs affiliated with 16 of 17 Canadian medical schools completed the survey. The majority indicated their programs do not have a mandatory clinical rotation in oncology (79% residents, 88% PDs). Low rates of residents (7%) and PDs (13%) reported FM residents being adequately prepared for their role in caring for cancer patients (p = 0.03). Residents and PDs believed the most optimal method of teaching oncology is through clinical exposure (65% residents, 80% PDs). Residents and PDs agreed the most important topics to learn (rated ≥4.7 on 5-point Likert scale) were: performing pap smears, cancer screening/prevention, breaking bad news, and approach to patient with increased cancer risk. According to residents, other important topics such as appropriate cancer patient referrals, managing cancer complications and post-treatment surveillance were only taught at frequencies of 52, 40 and 36%, respectively. CONCLUSIONS: Current FM PGME oncology education is suboptimal, although the degree differs in the opinion of residents and PDs. This study identified topics and methods of education which could be focussed upon to improve FM oncology education.

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.

BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

Axillary lymph node management in breast cancer with positive sentinel lymph node biopsy.

The surgical treatment of localized breast cancer has become progressively less aggressive over the years. The management of the axillary lymph nodes has been modified by the introduction of sentinel lymph node biopsy. Axillary dissection can be avoided in patients with sentinel lymph node negative biopsies. Based on randomized trials data, it has been proposed that no lymph node dissection should be carried out even in certain patients with sentinel lymph node positive biopsies. This commentary discusses the basis of such recommendations and cautions against a general omission of lymph node dissection in breast cancer patients with positive sentinel lymph node biopsies. Instead, an individualized approach based on axillary tumor burden and biology of the cancer should be considered.

Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer.

PURPOSE: Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. PATIENTS AND METHODS: Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. RESULTS: Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. CONCLUSION: Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.

Primary extranodal B-cell non-Hodgkin lymphoma mimicking an endodontic lesion: report of 2 cases.

Intrabony oral non-Hodgkin lymphoma (NHL) is rare. We report 2 cases of NHL of the maxilla that initially presented as apical abscesses in endodontically treated teeth. Radiographic findings were nondescript, but tissue biopsy revealed diffuse large B-cell NHL in both instances. No other sites of disease were found. Both patients were treated by chemotherapy and radiation with good results. As primary NHL of the maxilla can mimic a dental inflammatory lesion, tissue biopsy is mandatory in cases where symptoms do not resolve after specific treatment.

Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial.

PURPOSE: In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS: We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS: In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION: This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

Community based intervention to optimize osteoporosis management: randomized controlled trial.

BACKGROUND: Osteoporosis-related fractures are a significant public health concern. Interventions that increase detection and treatment of osteoporosis are underutilized. This pragmatic randomised study was done to evaluate the impact of a multifaceted community-based care program aimed at optimizing evidence-based management in patients at risk for osteoporosis and fractures. METHODS: This was a 12-month randomized trial performed in Ontario, Canada. Eligible patients were community-dwelling, aged ≥55 years, and identified to be at risk for osteoporosis-related fractures. Two hundred and one patients were allocated to the intervention group or to usual care. Components of the intervention were directed towards primary care physicians and patients and included facilitated bone mineral density testing, patient education and patient-specific recommendations for osteoporosis treatment. The primary outcome was the implementation of appropriate osteoporosis management. RESULTS: 101 patients were allocated to intervention and 100 to control. Mean age of participants was 71.9 ± 7.2 years and 94% were women. Pharmacological treatment (alendronate, risedronate, or raloxifene) for osteoporosis was increased by 29% compared to usual care (56% [29/52] vs. 27% [16/60]; relative risk [RR] 2.09, 95% confidence interval [CI] 1.29 to 3.40). More individuals in the intervention group were taking calcium (54% [54/101] vs. 20% [20/100]; RR 2.67, 95% CI 1.74 to 4.12) and vitamin D (33% [33/101] vs. 20% [20/100]; RR 1.63, 95% CI 1.01 to 2.65). CONCLUSIONS: A multi-faceted community-based intervention improved management of osteoporosis in high risk patients compared with usual care. TRIAL REGISTRATION: This trial has been registered with clinicaltrials.gov (ID: NCT00465387).

Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study.

Denosumab increased lumbar spine bone mineral density (BMD) versus placebo in a 2-year, randomized, placebo-controlled, phase 3 study of patients with hormone-receptor-positive, non-metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy. In subgroup analyses at 12 and 24 months, we evaluated factors (duration and type of aromatase inhibitor, tamoxifen use, age, time since menopause, body mass index, T-score) that might influence BMD at the lumbar spine, total hip, femoral neck, and 1/3 radius. Patients were randomized to receive placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months. In all subgroups, 12 or 24 months' treatment with denosumab was associated with larger BMD gains than placebo across multiple skeletal sites. Most increases were statistically significant (P < 0.05). Twice-yearly administration of denosumab, regardless of patient subgroup or skeletal site, resulted in consistent increases in BMD versus placebo at 12 and 24 months.

Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer.

PURPOSE: Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, to protect against aromatase inhibitor-induced bone loss. PATIENTS AND METHODS: Eligible women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (< or = 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). RESULTS: At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. CONCLUSION: In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.