The Effect of Metformin on Bladder Cancer Incidence and Outcomes: A Systematic Review and Meta-Analysis

BACKGROUND: Effective oral treatment options for urothelial bladder cancer (BC) are lacking. Metformin, the most frequently used oral drug in type II diabetes mellitus, has putative anticancer properties and could, therefore, influence BC incidence and treatment outcomes. We systematically reviewed the current literature regarding the effect of metformin on BC incidence and oncological outcomes in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). METHODS: This review was conducted according to the PRISMA guidelines. Literature was gathered through a systematic search in PubMed/Medline, EMBASE and the Cochrane library. Risk of bias was determined using the Cochrane risk-of-bias tool for randomized trials and the Newcastle-Ottawa Scale for non-randomized trials. Hazard ratios (HRs) were extracted and pooled in a random-effects meta-analysis. RESULTS: We reviewed 13 studies, including 3,315,320 patients, considering the risk of developing BC after metformin exposure and 9 studies, including 4,006 patients, on oncological outcomes of patients with BC. Metformin did not affect BC incidence (HR 0.97, 95% CI 0.87 -1.09) or oncological outcomes for NMIBC but did show a reduced risk of recurrence (HR 0.52, 95% CI 0.32 -0.84), cancer-specific mortality (HR 0.58, 95% CI 0.43 -0.78) and overall mortality (HR 0.66, 95% CI 0.47 -0.92) in MIBC. CONCLUSIONS: The role of metformin in the prevention and treatment of BC in patients remains unclear. Although a beneficial effect of metformin on treatment outcomes of certain stages of BC may exist, a definitive conclusion cannot be drawn. Prospective clinical trials are needed to assess the efficacy of metformin for BC treatment

Bladder-sparing chemoradiotherapy combined with immune checkpoint inhibition for locally advanced urothelial bladder cancer—a review

Despite current treatment strategies, the 5-year overall survival of muscle-invasive bladder cancer (MIBC) is approximately 50%. Historically, radical cystectomy (RC) with neoadjuvant chemotherapy has been the first-choice treatment for this patient group. Recently, several studies have reported encouraging results of using immune checkpoint inhibitors (ICI) prior to RC. However, in recent years, bladder-sparing alternatives such as CRT have gained popularity. The effect of radiotherapy on the tumor microenvironment is an important rationale for combining CRT with ICI therapy. Worldwide, twelve immunochemoradiotherapy (iCRT) trials are ongoing. Each study employs a different chemotherapy and radiotherapy regimen and varies the timing of ICI administration concurrent to radiotherapy, adjuvant, or both. Five studies have presented (preliminary) results showing promising safety and short-term survival data. The first peer-reviewed publications are expected in the near future. The preclinical evidence and preliminary patient data demonstrate the potential of iCRT bladder-sparing treatment for bladder cancer

Bladder-sparing chemoradiotherapy combined with immune checkpoint inhibition for locally advanced urothelial bladder cancer—a review

Despite current treatment strategies, the 5-year overall survival of muscle-invasive bladder cancer (MIBC) is approximately 50%. Historically, radical cystectomy (RC) with neoadjuvant chemotherapy has been the first-choice treatment for this patient group. Recently, several studies have reported encouraging results of using immune checkpoint inhibitors (ICI) prior to RC. However, in recent years, bladder-sparing alternatives such as CRT have gained popularity. The effect of radiotherapy on the tumor microenvironment is an important rationale for combining CRT with ICI therapy. Worldwide, twelve immunochemoradiotherapy (iCRT) trials are ongoing. Each study employs a different chemotherapy and radiotherapy regimen and varies the timing of ICI administration concurrent to radiotherapy, adjuvant, or both. Five studies have presented (preliminary) results showing promising safety and short-term survival data. The first peer-reviewed publications are expected in the near future. The preclinical evidence and preliminary patient data demonstrate the potential of iCRT bladder-sparing treatment for bladder cancer

Bladder-Sparing Chemoradiotherapy Combined with Immune Checkpoint Inhibition for Locally Advanced Urothelial Bladder Cancer—A Review

Despite current treatment strategies, the 5-year overall survival of muscle-invasive bladder cancer (MIBC) is approximately 50%. Historically, radical cystectomy (RC) with neoadjuvant chemotherapy has been the first-choice treatment for this patient group. Recently, several studies have reported encouraging results of using immune checkpoint inhibitors (ICI) prior to RC. However, in recent years, bladder-sparing alternatives such as CRT have gained popularity. The effect of radiotherapy on the tumor microenvironment is an important rationale for combining CRT with ICI therapy. Worldwide, twelve immunochemoradiotherapy (iCRT) trials are ongoing. Each study employs a different chemotherapy and radiotherapy regimen and varies the timing of ICI administration concurrent to radiotherapy, adjuvant, or both. Five studies have presented (preliminary) results showing promising safety and short-term survival data. The first peer-reviewed publications are expected in the near future. The preclinical evidence and preliminary patient data demonstrate the potential of iCRT bladder-sparing treatment for bladder cancer

Study protocol of a phase II clinical trial of oral metformin for the intravesical treatment of non-muscle invasive bladder cancer

Contains fulltext : 214043.pdf (publisher's version ) (Open Access

Developing a core set of patient-reported outcomes in pancreatic cancer: A Delphi survey

Patient-reported outcomes (PROs) are amongst the most relevant outcome measures in pancreatic cancer care and research. However, it is unknown which out of the numerous PROs are most important to patients and health care professionals (HCPs) in this setting. The aim of this study was to identify a core set of PROs to be incorporated in a nationwide prospective multidisciplinary pancreatic cancer registry. We performed a two-round Delphi survey among 150 patients diagnosed with pancreatic or periampullary cancer (treated either with curative intent or in palliative setting) and 78 HCPs (surgeons, medical oncologists, gastroenterologists, radiotherapists, nurses, and dietitians) in The Netherlands. In round 1, participants were invited to rate the importance of 53 PROs, which were extracted from 17 different PRO measures and grouped into global domains, on a 1-9 Likert scale. PROs rated as very important (score 7-9) by the majority (≥ 80%) of curative and/or palliative patients as well as HCPs were considered sufficiently important to be incorporated in the core set. PROs not fulfilling these criteria in round 1 were presented again to the participants in round 2 along with individual and group feedback. A total of 97 patients (94%) in curative-intent setting, 38 patients (81%) in palliative setting and 73 HCPs (94%) completed both rounds 1 and 2. After the first round, 7 PROs were included in the core set: general quality of life, general health, physical ability, satisfaction with caregivers, satisfaction with services and care organisation, coping and defecation. After the second round, 10 additional PROs were added: appetite, ability to work/do usual activities, medication use, weight changes, fatigue, negative feelings, positive feelings, fear of recurrence, relationship with partner/family, and pancreatic enzyme replacement therapy use. This study provides a core set of PROs selected by patients and HCPs, which may be incorporated in pancreatic cancer care and research. Validation outside the Dutch context is recommended for generalisation and use in international studie

Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer

Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. Objective: To determine the safety of iCRT for MIBC. Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summary: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials

Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer

Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. Objective: To determine the safety of iCRT for MIBC. Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summary: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials

Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer

Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. Objective: To determine the safety of iCRT for MIBC. Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summary: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials