First-line osimertinib for patients with EGFR-mutated advanced non-small cell lung cancer: efficacy and safety during the COVID-19 pandemic.

Background: The FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Patients diagnosed with EGFR-mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models. Results: The cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged ≥75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1-26.2] and 25.4 months (95% CI: 20.3-not reached), respectively. On multivariable analysis, age ≥75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), programmed death ligand 1 (PD-L1) expression ≥50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. A proportion of 16.5% of the cohort developed grade ≥3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94-7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19. Conclusions: In a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS ≥2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.

Safety and efficacy of pembrolizumab for advanced nonsmall cell lung cancer: before and during the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic changed diagnostic and treatment pathways in oncology. We compared the safety and efficacy of pembrolizumab amongst advanced nonsmall cell lung cancer (NSCLC) patients with a PD-L1 tumor proportion score (TPS) ≥ 50% before and during the pandemic. METHODS: Advanced NSCLC patients initiating pembrolizumab between June 2015 and December 2019 ("pre-pandemic cohort") and between March 2020 and March 2021 ("pandemic cohort") at BC Cancer were identified retrospectively. Multivariable logistic regression evaluated risk factors for immune-related adverse events (irAE) ≥ grade 3 at the 6 week, 3 month, and 6 month landmarks. Cox regression models of overall survival (OS) were constructed. RESULTS: The study population comprised 417 patients in the pre-pandemic cohort and 111 patients in the pandemic cohort. Between March and May 2020, 48% fewer advanced NSCLC cases with PD-L1 TPS ≥ 50% were diagnosed compared to similar intervals in 2018-2019. Telemedicine assessment [new patient consultations (p < 0.001) and follow-up (p < 0.001)] and extended interval pembrolizumab dosing (p < 0.001) were more common in the pandemic cohort. Patients initiating pembrolizumab after February 2020 (vs. before January 2020) experienced similar odds of developing severe irAE. 2/111 (1.8%) patients receiving pembrolizumab during the pandemic tested positive for COVID-19. On multivariable analysis, no association between pembrolizumab treatment period (before vs. during the COVID-19 pandemic) and OS was observed (p = 0.18). CONCLUSION: Significant changes in healthcare delivery in response to the pandemic did not result in increased high grade toxicity or lower survival outcomes in patients with advanced NSCLC treated with pembrolizumab.

Web-Based Peer Navigation for Men with Prostate Cancer and Their Family Caregivers: A Pilot Feasibility Study.

This study assessed the feasibility, acceptability and potential effects of True North Peer Navigation (PN)­a web-based peer navigation program for men with prostate cancer (PC) and their family caregivers. A one-arm, pre-post pilot feasibility study was conducted at two cancer centres in Canada. Participants were matched through a web-app with a specially trained peer navigator who assessed needs and barriers to care, provided support and encouraged a proactive approach to health for 3 months. Descriptive statistics were calculated, along with paired t-tests. True North PN was feasible, with 57.9% (84/145) recruitment, 84.5% (71/84) pre-questionnaire, 77.5% (55/71) app registration, 92.7% (51/55) match and 66.7% (34/51) post-questionnaire completion rates. Mean satisfaction with Peer Navigators was 8.4/10 (SD 2.15), mean program satisfaction was 6.8/10 (SD 2.9) and mean app usability was 60/100 (SD 14.8). At 3 months, mean ± SE patient/caregiver activation had improved by 11.5 ± 3.4 points (p = 0.002), patient quality of life by 1.1 ± 0.2 points (p < 0.0001), informational support by 0.4 ± 0.17 points (p = 0.03), practical support by 0.5 ± 0.25 points (p = 0.04) and less need for support related to fear of recurrence among patients by 0.4 ± 19 points (p = 0.03). The True North web-based peer navigation program is highly feasible and acceptable among PC patients and caregivers, and the associated improvements in patient and caregiver activation are promising. A randomized controlled trial is warranted to determine effectiveness.

Assessing the nutritional needs of men with prostate cancer.

BACKGROUND: Nutrition is important for prostate cancer (PC) survivorship care to help achieve a healthy weight, reduce treatment side effects and reduce the risk of developing other chronic diseases. We aimed to advance the understanding of the nutritional needs of men with PC and services that could be potentially implemented to address them. METHODS: We conducted a needs assessment of nutrition services for men with PC drawing on four perspectives; 1) patient evaluation of a nutrition education session in British Columbia (BC), 2) survey of BC health professionals, 3) an environmental scan of existing nutrition services across Canada and 4) a scoping literature review. RESULTS: Patients expressed a need for more nutrition information and a desire for additional nutrition services. More than 60% of health professionals believed there is a need for more nutrition services for men with PC, and reported the focus should be on weight management or management of PC progression. The environmental scan revealed few existing services for men with PC across Canada, most were inclusive of multiple cancers and not tailored for men with PC. Eighteen completed studies were identified in the scoping literature review. The majority provided combined diet and exercise programs with various formats of delivery such as individual, group and home-based. Overall, 78% of studies reported improvements in one or more of the following measures: dietary intake/ diet quality, body composition, self-efficacy, quality of life, fatigue, practicing health behavior goals and physical function/ exercise. Four studies assessed feasibility, adherence or satisfaction with all reporting positive findings. CONCLUSION: Despite the high prevalence of PC in Canada, and the perceived need for more support by patients and health professionals, there are limited nutrition services for men with PC. Evidence from the literature suggests nutrition services are effective and well-accepted by men with PC. Our findings define a need for standardized nutrition services for men with PC that assess and meet long term nutritional needs. Our findings also provide insight into the type and delivery of nutrition services that may help close the gap in care for men with PC.

A randomised phase 2 trial of intensive induction chemotherapy (CBOP/BEP) and standard BEP in poor-prognosis germ cell tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604).

BACKGROUND: Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required. OBJECTIVE: To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial. DESIGN, SETTING, AND PARTICIPANTS: We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres. INTERVENTION: BEP (bleomycin 30,000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15,000 IU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates. RESULTS AND LIMITATIONS: A total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61-85) with CBOP/BEP, 61% with BEP (90% CI, 48-73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33-1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS. CONCLUSIONS: The primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial. PATIENT SUMMARY: In this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration. TRIAL REGISTRATION: ISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604.

Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).

BACKGROUND: Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. METHODS: In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 µg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. FINDINGS: 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). INTERPRETATION: Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. FUNDING: Cancer Research UK, MRC Clinical Trials Unit.

Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214).

PURPOSE: Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. PATIENTS AND METHODS: Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). RESULTS: Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). CONCLUSION: These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up.

BACKGROUND: From July 1, 1989, through March 31, 2001, 2466 patients with stage I seminoma were evaluated in three randomized noninferiority trials: the TE10, TE18, and TE19 trials. We analyzed mature results of these studies. METHODS: The TE10 trial randomly assigned 478 patients to para-aortic and ipsilateral iliac lymph node (dogleg field) or para-aortic only radiation therapy (total dose = 30 Gy). The TE18 trial randomly assigned 1094 patients to a total dose of 30 or 20 Gy of radiation therapy, predominantly to a para-aortic field. The TE19 trial randomly assigned 1477 patients to radiation therapy or a single injection of carboplatin at a dose of seven times the area under the curve. Time to relapse was determined from Kaplan-Meier curves, and such data were compared by use of Cox regression models. Noninferiority in TE18 and TE19 required the upper limit of the 90% confidence intervals (CIs) (reflecting the one-sided test for noninferiority at a 5% statistical significance level) to exclude a hazard ratio (HR) of greater than 2.0 and a doubling of the 5-year relapse rates observed in the control arm. The TE10 trial was not powered to exclude clinically relevant differences in overall relapse rates but was assessed against the same criteria. RESULTS: Median follow-up times were 6.4-12 years in the three trials. We identified the noninferiority of the following treatments: 20 Gy of radiation therapy in the TE18 trial (HR of relapse = 0.63, 90% CI = 0.38 to 1.04) and carboplatin in the TE19 trial (HR of relapse = 1.25, 90% CI = 0.83 to 1.89). Para-aortic radiation therapy in the TE10 trial was associated with a hazard ratio of relapse of 1.15 (90% CI = 0.54 to 2.44). Relapse occurred after 3 years in only four (0.2%) of all 2466 patients. Computed tomography scans had little impact on the detection of relapse after radiation therapy; seven of the 904 patients allocated radiation therapy in TE19 had a relapse detected by this method. CONCLUSION: This large and mature dataset from three randomized trials has provided support for the use of either radiation therapy or carboplatin therapy as adjuvant treatment for stage I seminoma.

Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer.

OBJECTIVE: To assess the hormonal effects of Fem7 (Merck, KGaA, Darmstadt, Germany) 100 microg transdermal oestrogen patches on men undergoing first-line androgen-deprivation therapy for prostate cancer. PATIENTS AND METHODS: PATCH is a multicentre, randomized, phase II trial for men with locally advanced or metastatic prostate cancer, comparing luteinizing hormone-releasing hormone agonist therapy with oestrogen patches. To assess the dosing schedule for the patches, as this was the first time that this brand of patch had been used in men, and to reassure patients and participating clinicians, the Independent Data Monitoring Committee agreed to early release of hormonal data from this study. RESULTS: Oestradiol, testosterone and prostate-specific antigen (PSA) levels are presented for the first group of 14 patients who received the patches (with 1 withdrawal) and for whom there were > or =12 weeks of follow-up by March 2007. After 12 weeks, testosterone levels (nmol/L) in eight of the 13 patients were <1.7, two were 1.7-2 and three were >2. The median (range) serum oestradiol levels was 442 (52.1-1542) pmol/L and all patients had a PSA response, with eight having a PSA level of <4 ng/mL. CONCLUSION: These results confirm that oestrogen patches produce castrate levels of testosterone and concomitant PSA responses. They also highlighted the potential differences between different brands of oestrogen patches, and the need to monitor hormonal response, toxicity and efficacy until more experience with oestrogen patches for this clinical indication is obtained. The number of patches recommended in the PATCH study has now been increased.