Cardiac Monitoring Guidelines in Clinical Trials and Post-Approval Surveillance for Patients Exposed to Anticancer Treatments: Do the Data Support the Recommendations?

Concerns regarding cardiac adverse events during and after cancer care include contractile dysfunction, dysrhythmia, and inflammation. Clinical trials and practice guidelines may require or recommend sequential ejection fraction determinations for early recognition of contractile dysfunction, bio-marker screening where inflammation or contractile dysfunction could be anticipated, and multiple electrocardiograms with timings of cardiac intervals. In some instances, surveillance schedules used in clinical trial protocols have been incorporated in recommendations without revision or critical scrutiny. When adverse events are rare and interpretative parameters imperfect, false positive results may lead to delay or interruption of vital cancer treatment, may suggest that further cardiac testing be undertaken, and may add to patient anxiety. The risks of excessive monitoring also include inconvenience and increased cost. This paper looks at areas where surveillance recommendations may be problematic, specifically, ejection fractions, cardiac biomarkers, and electrocardiographic monitoring are considered. Changes reported following surveillance monitoring of cancer patients using these parameters may reflect true adverse events or clinically relevant future risk, but interpretative uncertainty or true physiologic change that is unrelated to the drug in question should be considered. Clinicians may not be sufficiently aware of the degree to which reported changes may reflect surveillance artifacts. A balance that incorporates both the likelihood of an event that could be prevented along with clinical implications is suggested. The authors recognize that differentiating among these variables is not always possible yet advocate for modifying surveillance schedules to balance the frequency and severity of events that can be mitigated, based on reliable data. SIGNIFICANCE STATEMENT: The authors' concerns regarding the predictive value of surveillance initiatives are explored. Confounding factors and false-positive results may add to the expense of cancer care and/or compromise optimal therapeutic initiatives.

Arrhythmia in Bruton Tyrosine Kinase Inhibitor-Treated Patients: Unanswered Questions.

(No abstract allowed for commentary).

Cardiovascular adverse events in oncology trials: understanding and appreciating the differences between clinical trial data and real-world reports.

Reports of cardiac adverse events from oncology clinical trials often are at variance with reports derived from clinical observations or data-base reviews. These differences may lead to confusion, as different levels of risks abound in the literature, and the true cardiac risk of using some agents is uncertain. Additionally, such discrepancies may lead to the creation of over-cautious surveillance algorithms. Reasons for these reported differences are complex and often reflect subtleties in the criteria for individual patient evaluation. Both clinical trial data and real-world data have potential flaws that make reconciliation problematic. Importantly, however, both provide crucial information regarding the risk of adverse events. Major factors contribute to these differences including different tools used to diagnose events, and how those tools are interpreted. Additionally, differences in the populations of clinical trial participants and real-world populations play a crucial role. This paper looks at these differences and provides a perspective intended to help clinicians interpret reported variations in event rates derived from highly scrutinized clinical trials and broader real-world data.

BERENICE Final Analysis: Cardiac Safety Study of Neoadjuvant Pertuzumab, Trastuzumab, and Chemotherapy Followed by Adjuvant Pertuzumab and Trastuzumab in HER2-Positive Early Breast Cancer.

BERENICE (NCT02132949) assessed the cardiac safety of the neoadjuvant−adjuvant pertuzumab−trastuzumab-based therapy for high-risk, HER2-positive early breast cancer (EBC). We describe key secondary objectives at final analysis. Eligible patients received dose-dense doxorubicin and cyclophosphamide q2w × 4 ➝ paclitaxel qw × 12 (Cohort A) or 5-fluorouracil, epirubicin, cyclophosphamide q3w × 4 ➝ docetaxel q3w × 4 (B) as per physician's choice. Pertuzumab−trastuzumab (q3w) was initiated from the taxane start and continued post-surgery to complete 1 year. Median follow-up: 64.5 months. There were no new cardiac issues and a low incidence of Class III/IV heart failure (Cohort B only: one patient (0.5%) in the adjuvant and treatment-free follow-up (TFFU) periods). Fourteen patients (7.7%) had LVEF declines of ≥10% points from baseline to <50% in Cohort A, as did 20 (10.5%) in B during the adjuvant period (12 (6.2%) in A and 7 (3.6%) in B during TFFU). The five-year event-free survival rates in Cohorts A and B were 90.8% (95% CI: 86.5, 95.2) and 89.2% (84.8, 93.6), respectively. The five-year overall survival rates were 96.1% (95% CI: 93.3, 98.9) and 93.8% (90.3, 97.2), respectively. The final analysis of BERENICE further supports pertuzumab−trastuzumab-based therapies as standard of care for high-risk, HER2-positive EBC.

Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D).

AIM: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. PATIENTS AND METHODS: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac). RESULTS: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups. CONCLUSION: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00490139.

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up.

PURPOSE: APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease-free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], P = .045) for patients with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)-negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up. METHODS: After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab. RESULTS: This interim OS analysis comparing pertuzumab versus placebo did not reach the P = .0012 level required for statistical significance (P = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen. CONCLUSION: This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit.

Cardiac Safety of Osimertinib: A Review of Data.

PURPOSE: Osimertinib is a third-generation, CNS-active, irreversible, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits both EGFR-TKI-sensitizing and T790M resistance mutations. We assess the cardiac failure risk in patients receiving osimertinib by evaluating the available data. METHODS: Post hoc analyses of cardiac data from (1) studies in patients with advanced non-small-cell lung cancer, FLAURA (osimertinib, n = 279; comparator EGFR-TKI, n = 277) and AURA3 (osimertinib, n = 279; chemotherapy, n = 140), and (2) a pooled data set of patients treated with osimertinib 80 mg from across the clinical trial program (n = 1,142), including cardiac failure-related adverse events and left ventricular ejection fraction (LVEF) reductions. An LVEF pharmacokinetic or pharmacodynamic analysis of the pooled data set was performed. The sponsor's global safety database was analyzed for cardiac failure-related adverse events, and a literature search was conducted. RESULTS: Decreases in LVEF from a baseline of ≥ 10 percentage points to an absolute value of < 50% following osimertinib treatment were observed in 8 (3.1%) and 14 (5.5%) patients in FLAURA and AURA3, respectively, and in 35 (3.9%) patients in the pooled population. Most events were asymptomatic and resolved without treatment of the event or osimertinib discontinuation. The pharmacokinetic or pharmacodynamic analysis did not indicate a relationship between exposure to osimertinib and decreases in LVEF from baseline. The database and literature search showed no specific trend or pattern that was suggestive of a safety issue in patients receiving osimertinib. CONCLUSION: These data do not suggest a causal relationship between osimertinib and cardiac failure. However, because of LVEF decreases that were observed in patients with cardiac risk factors before osimertinib treatment, cardiac monitoring, including an assessment of LVEF at baseline and during osimertinib treatment, is advised.

An overview of a different type of cardio-oncology gathering: summary of the COMP (cardio-oncology multidisciplinary practice) meeting held in Houston Texas, January 2020.

An innovative Cardio-Oncology meeting was held in Houston, Texas in January of 2020. This gathering was intended to broaden the scope of Cardio-Oncology to include major presentations by clinicians and researchers beyond physicians, as well as to provide comprehensive reviews by established experts aimed at a variety of levels of professional practitioners. The unique perspective of this meeting is presented in the overview that follows. This overview is intended to contribute to a broader view of Cardio-Oncology, and to provide perspective for the expanding group of providers relative to their individual areas of expertise. These perspectives can and should be incorporated in cardio-oncology centers.

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial.

BACKGROUND: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. METHODS: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. RESULTS: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55-3.51]). CONCLUSIONS: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

Cancer patients in cardiology: how to communicate with patients with special psychological needs and manage their cardiac problems in daily clinical practice.

: Cancer patients are increasingly referred for cardiology evaluations. These patients differ from those routinely seen in cardiology clinics because of their psychological burden and because the therapies and cancer itself can cause cardiac symptoms. A humane approach is critical to managing these patients. Cardiologists may see patients who are newly diagnosed with cancer or are in various phases of treatment; these patients may or may not have preexisting cardiac disease, and may develop cardiotoxicity from chemoimmunotherapy or radiotherapy. Each of these situations presents unique communication challenges for cardiologists. Although some oncology centers provide training in communication skills for their personnel, including cardiologists, this training is not widely available to physicians in general hospitals or private practice. This article examines the psychological aspects of cardio-oncology. It offers practical suggestions on how to best communicate with cancer patients in different phases of oncology care, and discusses when professional psychological help is needed.

Helping the cardio-oncologist: from real life to guidelines.

Guidelines for the diagnosis, management, and surveillance of cancer patients have evolved with the single goal of improving patient care based on established data when available, or in the absence of firm data, on the standard practices of those with broad experience in actual hands-on patient care. Two initiatives intended to disseminate information to cardio-oncologists, were discussed in this session: the first, from the American Society of Clinical Oncology was focused on available data and the confidence level of that data; the second, from The European Society of Cardiology was a position paper. Interestingly, notwithstanding the somewhat different focus, there is considerable agreement between these two initiatives. Nevertheless, guidelines my not be applicable to all afflicted patients, and may raise questions as to when deviations from published standards should be considered. Such deviations may result in allegations of failure to meet standards of care or legal liability.

Mechanisms and clinical course of cardiovascular toxicity of cancer treatment I. Oncology.

The opening session of Second International Colloquium on Cardio-Oncology addressed two areas of vital interest. The first reviewed new thoughts related to established agents. While anthracycline cardiotoxicity has been studied and reviewed extensively, ongoing research attempting to understand why it appears the mechanism(s) of toxicity differs from that of oncologic efficacy continue to evoke comment and intriguing speculation. Better understanding of the role of ß-topoisomerase II in toxicity has advanced our understanding of the cascade of events that lead to heart failure. Additionally, the cardioprotective role of dexrazoxane fits well with our new understanding of how ß-topoisomerase II works. Beyond the anthracyclines, new insight is providing us insight to better understand the impact on cardiac function seen with other agents including those targeting HER2 and several tyrosine-kinase inhibitors. Unlike the anthracyclines, these agents affect cardiac function in ways that are less direct, and therefore have different characteristics and should be thought of in alternate ways. This new knowledge regarding established agents furthers our understanding of the spectrum of cardiotoxicity and cardiac dysfunction in the cancer patient. The session also addressed cardiovascular toxicities of newer and established agents beyond myocardial dysfunction including effects on the vasculature. These agents cause changes that may be temporary or permanent, and that range from subclinical to life-threatening. The session ended with a discussion of the cardiac effects of immune checkpoint inhibitors. These agents can cause rare and sometimes fatal cardiac inflammation, for which long-term follow up may be required.

Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis.

Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.