Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce cardiovascular toxicities. OBJECTIVES: To prospectively assess the incidence of major cardiovascular events (MACE) on ICIs in solid cancer patients: myocarditis, pericarditis, acute coronary syndrome, heart failure, high-degree conduction abnormalities or sustained ventricular arrhythmias, or cardiovascular death at 6 weeks (early MACE), including asymptomatic clinical changes by an independent adjudication committee using current recommended diagnostic criteria. The secondary objective was the incidence of the above-mentioned events adding atrial fibrillation (AF) at 6 months (late MACE). RESULTS: Participants underwent pre-ICIs and repeated multimodality cardiac imaging (echocardiogram, cardiac magnetic resonance (CMR)), serum biomarkers (ultrasensitive troponin I), and rhythm surveillance (ambulatory ECG monitoring) at 6 weeks and 6 months. Forty-nine patients (38 (77.6%) male; mean age 64.3 (SD 11.0) years old) were included (June 2020-December 2021). Early MACE were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias, or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P = 0.035) predicted early MACE. At 6 months follow-up, 18 MACE were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias, or conduction disorders, and 4 (8.2%) AF. There was a significant decline in LVEF (P < 0.001) in patients with no MACE (P = 0.003) or HF (P = 0.0028). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P = 0.006) predicted HF on multivariate analysis. There were no significant T1 or T2 mapping changes in our study cohort on repeated CMR. CONCLUSIONS: Cardiotoxicity on ICIs is more frequent than previously described when using a thorough detection strategy, consisting mainly in HF and asymptomatic rhythm disorders.

Cost-effectiveness Analysis of Innovative Therapy for Patients with Newly Diagnosed Hormone-Sensitive Metastatic Prostate Cancer.

BACKGROUND: The optimal therapeutic strategies for patients with metastatic hormone-sensitive prostate cancer (mHSPC) followed by metastatic castrate-resistant prostate cancer (mCRPC), in terms of cost and effectiveness, remains unknown. This study aims to compare the cost-effectiveness of various potential strategies, from the start of first-line treatment in mHSPC to the death of the patients. METHODS: Two Markov decision-analysis models were developed, one for cohort A "asymptomatic/mildly symptomatic patients in mCRPC", and one for cohort B "symptomatic patients in mCRPC". Each strategy reflects daily practice for mHSPC until progression in mCRPC from the start of first treatment regimen with either docetaxel or abiraterone acetate plus prednisone (AA) in mHSPC to the death of the patient. The cost-effectiveness analysis was performed from the French public health care system perspective. Only direct medical costs were included. Survival data were extracted from results of published randomized clinical trials. RESULTS: For cohort A, docetaxel followed by AA is the most cost-effective therapeutic strategy (€96,925 for 4.24 life-years). For cohort B, docetaxel followed by docetaxel is the most cost-effective therapeutic strategy (€81,463 for 4.05 life-years). Sensitivity analyses confirmed the robustness of our results except for a price reduction of 70% for AA or enzalutamide. CONCLUSION: Our approach is innovative to the extent that our analysis considers various potential strategies for metastatic prostate cancer (mPC). Our economic evaluation suggests that a price reduction of AA or enzalutamide impacts on the results. This approach must continue, including new drugs for patients with mPC.

Cabazitaxel schedules in metastatic castration-resistant prostate cancer: a review.

Cabazitaxel (25 mg/m2 every 3 weeks) is the standard second-line chemotherapy for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. It is associated with a risk of neutropenic complications, which may be a barrier to its use in daily clinical practice, particularly in frail elderly patients. Here the authors reviewed key studies conducted with cabazitaxel (TROPIC, PROSELICA, AFFINITY, CARD and the European compassionate use program) and pilot studies with adapted schedules. Based on this review, the use of prophylactic granulocyte colony-stimulating factor from cycle 1 appears crucial to maximize the benefit-risk ratio of cabazitaxel in metastatic castration-resistant prostate cancer. Preliminary data with alternative schedules look promising, especially for frail patients. Results of the ongoing Phase III CABASTY trial (ClinicalTrials.gov: NCT02961257) are awaited.

Patients' self-assessment versus investigators' evaluation in a phase III trial in non-castrate metastatic prostate cancer (GETUG-AFU 15).

BACKGROUND: Toxicity, which is a key parameter in the evaluation of cancer treatments, can be underestimated by clinicians. We investigated differences between patients and physicians in reporting adverse events of androgen deprivation therapy (ADT) with or without docetaxel in a multicentre phase III trial in non-castrate metastatic prostate cancer. METHODS: The 385 patients included were invited to complete a 26-symptom questionnaire 3 and 6 months after the start of treatment, among which eighteen symptoms were also assessed by physicians, reported in medical records and graded using the Common Toxicity Criteria of the National Cancer Institute. Positive and negative agreements as well as Kappa concordance coefficients were computed. FINDINGS: Data were available for 220 and 165 patients at 3 and 6 months respectively. Physicians systematically under-reported patients' symptoms. Positive agreement rates (at respectively 3 and 6 months) for the five most commonly reported symptoms were: 61.0% and 64.3% hot flushes, 50.0% and 43.6% fatigue, 29.4% and 31.1% sexual dysfunction, 24.4% and 14.4% weigh gain/loss, 16.7% and 19.3% for joint/muscle pain. For symptoms most frequently reported as disturbing or very disturbing by patients, the clinicians' failure to report them ranged from 50.8% (hot flushes) to 89.5% (joint/muscle pain) at 3 months, and from 48.2% (hot flushes) to 88.4% (joint/muscle pain) at 6 months. INTERPRETATION: Physicians often failed to report treatment-related symptoms, even the most common and disturbing ones. Patients' self-evaluation of toxicity should be used in clinical trials to improve the process of drug assessment in oncology. FUNDING: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, Astra-Zeneca, and Amgen.

Drug management of prostate cancer: prevalence and consequences of renal insufficiency.

BACKGROUND: The Renal Insufficiency and Anticancer Medications (IRMA) study reported a renal insufficiency (RI) prevalence of 50%-60% in a population of almost 5000 patients with solid tumors, 80% of whom were being treated with anticancer drugs that either necessitated dosage adjustment or were potentially nephrotoxic drugs. A national multicenter study from 15 cancer centers in France analyzed IRMA data on patients with prostate cancer. PATIENTS AND METHODS: Data on patients with prostate cancer from the IRMA study were analyzed. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of RI. Anticancer drugs' potential renal toxicity and need for dosage adjustment were detailed. RESULTS: Of the 222 IRMA patients with prostate cancer, 14.9% had a serum creatinine (SCr) level of > 110 micromol/L. When using Cockcroft-Gault and aMDRD formulas, 62.6% and 55.9%, respectively, of the patients had RI. Of the 228 anticancer drug prescriptions, 82.9% required dose adjustments for RI or were drugs with no available data on their administration in patients with RI. Of the patients treated, 86.9% received >or= 1 such drug, but only 29.1% received nephrotoxic drugs. CONCLUSION: The prevalence of RI in patients with prostate cancer was very high in spite of a normal SCr level in most cases. Some anticancer drugs, particularly some bisphosphonates and platinum salts, might be nephrotoxic and/or need dosage adjustment. However, other important drugs in prostate cancer, such as docetaxel, neither require dose reduction nor present with potential nephrotoxicity. Both issues were significantly more important in the patients with bone metastases compared with those with nonmetastatic disease.

Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study.

BACKGROUND: The Renal Insufficiency and Cancer Medications (IRMA) study is a French national observational study. The results from this study of nearly 5,000 patients demonstrated the high prevalence of renal impairment in a population of patients with solid tumors. METHODS: Every cancer patient who presented at oncology departments that participated in the study over at least 1 of 2 predefined periods during 2004 were included. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulae to estimate the prevalence of renal insufficiency (RI) according to the Kidney Disease Outcomes Quality Initiative-Kidney Disease Improving Global Outcomes definition and stratification. Anticancer drugs were studied with regard to their potential renal toxicity and dosage adjustment. RESULTS: Of the 4,684 patients from the 15 centers, 7.2% had serum creatinine levels >110 micromol/L. However, when they were assessed using Cockcroft-Gault and aMDRD formulae, 57.4% and 52.9% of patients had abnormal renal function or RI, respectively. Of the 7,181 anticancer drug prescriptions, 53.4% required dose adjustments for RI. Of the patients treated, 79.9% received at least 1 such drug. And 80.1% received potentially nephrotoxic drugs. CONCLUSIONS: RI was common in patients with cancer, and drug dosage adjustments often were necessary. Renal function should be evaluated in all cancer patients using either the Cockcroft-Gault formula or the aMDRD formula, including patients with normal serum creatinine levels. In patients who are at high risk for drug toxicity, the dosage should be adapted to renal function, and the use of nephrotoxic therapies should be avoided whenever possible.