Over a decade, the use of immune-checkpoint inhibitors (ICIs) for metastatic melanoma appears to have led to a shift in the pattern of second primary cancers, according to a population-based cohort study.
"Cancer immunotherapy has significantly improved clinical outcomes," said Dr. Wen Jiang of the University of Texas Southwestern Medical Center, in Dallas. "As a result, patients with metastatic melanoma that were previously considered as terminal now live for extended period of time. This resulted in many of these patients now increasingly being diagnosed with a second primary cancer down the road."
"Our study," he told Reuters Health by email, "showed that the advent of cancer immunotherapy has also changed how these second primary cancers manifest, in terms of the type of second cancer a survivor who was treated with immunotherapy may develop later in life."
Dr. Jiang and his colleagues tapped into the Surveillance, Epidemiology, and End Results (SEER) database to assess differences before and after the U.S. Food and Drug Administration (FDA) first approved use of ICIs. Ipilimumab was approved in 2011 for metastatic melanoma, followed by other ICIs such as nivolumab and pembrolizumab.
The researchers used data on more than 5000 patients who were diagnosed between 2005 and 2016. From 2005 to 2010, the standardized incidence ratio (SIR) for small-intestine cancer was 3.24 and this rose to 9.23 between 2011 and 2016.
Corresponding SIRs for lung and bronchus cancer were 1.93 and 1.54 and for myeloma 7.29 and 5.90.
Compared to the general population, in those who survived the first primary melanoma in the earlier period, the overall risk of developing a second primary cancer was 65% higher. Between 2011 and 2016, this risk was 98% higher.
Thus, concluded Dr. Jiang, "the clinical implication of our study is that long-term follow-up in these cancer survivors, particularly those treated with immunotherapy would be needed to find these second primary cancers early, and provide rationale of potential screening in high-risk patients."
Dermatologist Dr. Michael A. Marchetti of Memorial Sloan Kettering Cancer Center, in New York City, was not convinced by the findings. He told Reuters Health by email that "there wasn't a robust signal to suggest a statistically or clinically significant change in the risk of second primary cancers (SPCs) in the pre- and post-ICIs periods."
"I disagree with the authors' conclusions that additional screening tests for SPCs are warranted in this population, given the low absolute risk of SPCs and the high absolute risk of all-cause death," he said.
Dr. Marchetti, who has studied metastatic melanoma and immune-checkpoint inhibitors, concluded, "Observational studies like these suffer from many limitations, as the authors pointed out, and analyses of the incidence rates of some individual second primary cancers were particularly limited by small numbers of observed cases."
Immune checkpoint inhibitors (ICIs) increase the risk of cardiac events, including fatal heart attack and stroke, in patients with cancer, an analysis of Danish national registry data suggests.
About 10% of 743 registry participants with lung cancer and 6.6% of 145 with malignant melanoma experienced a cardiac event in the 12 months after starting treatment with either of the programmed death-1 (PD-1) inhibitors pembrolizumab or nivolumab. Similarly, 7.5% of 212 patients with malignant melanoma who received the CTLA-4 inhibitor ipilimumab experienced a cardiac event, report Maria D'Souza, MD, a postdoctoral research fellow in cardiology at Herlev og Gentofte Hospital, Hellerup, Denmark, and colleagues.
Within 6 months of treatment initiation, the patients with lung cancer or malignant melanoma who received PD-1 inhibitors had increased rates of cardiac events, compared with those who did not receive the treatment (hazard ratios [HRs], 2.14 and 4.30, respectively). The risk increased nearly fivefold in those who received the CTLA-4 inhibitor (HR, 4.93).
After 6 months, the risk increased slightly in those with lung cancer receiving a PD-1 inhibitor (HR, 2.26), but was no longer statistically significant for those with melanoma who received a PD-1 inhibitor and decreased slightly for those receiving the CTLA-4 inhibitor (HR, 3.48).
Cardiac events associated with immune checkpoint inhibition included heart failure, arrhythmia, myocarditis, pericarditis, and heart-related death, the researchers note.
Their findings were reported online December 9 in the European Heart Journal.
The researchers looked at 25,573 consecutive patients in the Danish national registries who were diagnosed with lung cancer or malignant melanoma between 2011 and 2017.
"We found that these risks were higher than previously estimated by drug safety studies, which have suggested that around 0.03-1% of people treated with immune checkpoint inhibitors develop myocarditis or pericarditis within one year; our results show that 1.8% will," D'Souza explains in a press statement.
She and her colleagues also observed that cardiac events continued to occur beyond the initial 6 months after treatment, contrary to prior findings showing that most adverse heart effects occur within the first few weeks or months after treatment initiation.
"The findings urge increased awareness of cardiac events in patients receiving ICI," they conclude.
In an accompanying editorial, Matthias Totzeck, MD, of the West German Heart and Vascular Center, University Hospital Essen, Germany, and colleagues concur and suggest adding the term "ICI-related cardiovascular disease" to the list of potential ICI complications, and ramping up efforts to increase awareness of these toxicities.
"Longer term steps include broadening collaborations with our oncology and pharmaceutical partners, and expanded clinical research efforts in parallel and based on innovative basic experimental insights," they write. "These and other steps are needed to move this forward so we can improve cardiovascular outcomes among our cancer patients treated with an ICI."
This study was supported by The Danish Heart Foundation and The VELUX Foundation. D'Souza reported grants from these foundations during the course of the study. The editorial was supported by the National Institutes of Health/National Heart Lung, and Blood Institute. Totzeck reported personal funding and advisory fees from Bayer Vital, Astra Zeneca, Daiichi Sankyo, and Bristol Myers Squibb.
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