Hand-foot syndrome, or PPE, is far more than a cosmetic nuisance. The condition typically begins with tingling, numbness and redness on the palms of the hands and soles of the feet, and can progress in severe cases to swelling, blistering, ulceration and intense pain that makes walking, gripping objects or even buttoning a shirt difficult. Because these symptoms strike exactly the functions patients rely on for daily life, PPE is a leading cause of dose reductions, treatment interruptions and outright abandonment of otherwise effective cancer regimens. Oncologists have long recognized it as a hallmark toxicity of certain targeted therapies and chemotherapy agents, but the true breadth of drugs implicated — and the timing of onset — has remained surprisingly poorly mapped.

To build that map, the researchers turned to FAERS, the FDA’s sprawling spontaneous reporting database, which collects adverse event submissions from healthcare professionals, manufacturers and patients across the United States. They extracted reports spanning the first quarter of 2004 through the first quarter of 2025, removed duplicate submissions, and then applied a family of statistical techniques known as disproportionality analysis. Rather than proving causation in the way a clinical trial would, disproportionality analysis asks a subtler question: does a particular drug appear in reports of a given side effect more often than would be expected by chance? Four complementary algorithms were used to answer that question — the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network and multi-gamma Poisson shrinkage. Requiring agreement across all four methods helps filter out spurious associations that can arise in self-reported data.

The results were striking in both their scale and their specificity. Protein kinase inhibitors — the targeted drugs that block enzymes driving cancer cell growth and tumor blood vessel formation — and antimetabolites, the classic chemotherapy agents that interfere with DNA and RNA synthesis, emerged as the dominant drug classes. Among individual agents, the oral kinase inhibitor regorafenib, the multi-kinase blocker sorafenib and the fluoropyrimidine prodrug capecitabine produced the strongest safety signals. These three drugs are mainstays of treatment for colorectal cancer, hepatocellular carcinoma, renal cell carcinoma and other hard-to-treat malignancies, meaning the toxicity burden is concentrated in some of oncology’s most vulnerable populations. The finding that hundreds of other drugs also appeared in PPE reports underscores that the syndrome is not confined to a short list of notorious culprits.

Perhaps the most clinically actionable discovery concerns timing. The vast majority of PPE cases — 83.4 percent — occurred within the first 90 days of starting treatment, with many surfacing within the initial weeks. This early-onset pattern carries an important message for oncology teams: the highest-risk window for hand-foot syndrome opens almost immediately after a patient begins therapy. The authors argue that this argues for proactive patient education at the very first prescription, so that patients recognize the earliest tingling or redness and report it before it escalates into blistering lesions. It also supports intensified skin assessment during the initial phases of treatment with high-risk drugs, when a timely dose adjustment can often prevent progression without compromising cancer control.

The analysis also uncovered differences in reporting patterns between female and male patients. For two drugs in particular — the HER2-targeted breast cancer therapy lapatinib and capecitabine — PPE signals were stronger in women. The researchers are careful to caution against overinterpreting this finding. Sex-related differences in spontaneous reports can arise from prescribing patterns, with some drugs used predominantly in diseases that affect one sex more than the other, as well as from possible biological factors such as differences in skin structure, drug metabolism or hormonal influences. Disentangling genuine biological susceptibility from the artifacts of who receives which drug and who reports which symptom remains an open challenge for pharmacovigilance, and the authors explicitly call for cautious interpretation and further study.

Mechanistically, hand-foot syndrome is thought to arise from the unique biology of the skin on the palms and soles. These regions are rich in eccrine sweat glands, experience high mechanical pressure and friction, and express high levels of the molecular targets — such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor — that protein kinase inhibitors are designed to block. When those signaling pathways are inhibited in the skin’s blood vessels, capillary damage and local inflammation can follow, and the repeated trauma of walking and gripping amplifies the injury. For antimetabolites like capecitabine, which is converted to 5-fluorouracil inside the body, the toxicity reflects the drug’s interference with rapidly dividing cells, with the concentration of the activating enzyme thymidine phosphorylase particularly high in palm and sole tissue. The convergence of drug exposure and mechanical stress explains why the syndrome has such a distinctive anatomical fingerprint.

The scale of the new study gives it particular weight in a field where much of the evidence comes from small clinical trials that may not capture rare or slowly accumulating toxicities. By pooling more than two decades of real-world reports, the analysis captures the experience of a far more diverse patient population than any single trial — patients with comorbidities, concurrent medications and varying ethnic backgrounds. At the same time, the authors and pharmacovigilance experts alike emphasize the inherent limitations of spontaneous reporting: not all adverse events are reported, reporting rates are influenced by media attention and litigation, and the database cannot establish how frequently PPE occurs relative to the total number of patients treated. Disproportionality signals are a starting point for hypothesis generation, not a verdict on causation.

Even with those caveats, the study’s implications for clinical practice are concrete. Oncologists prescribing regorafenib, sorafenib or capecitabine now have robust, data-driven backing for early and sustained skin monitoring, and the identification of 427 drugs with PPE reports should prompt awareness beyond the usual suspects, particularly as newer kinase inhibitors reach the market. For patients, the message is empowering: symptoms in the hands and feet during cancer treatment should never be dismissed as minor, because early recognition opens the door to dose modification, topical therapies, cooling measures and supportive care that can keep treatment on track. The research team concludes that enhanced vigilance and tailored monitoring schedules — matched to each drug’s risk profile and to the early onset window — are the most promising route to reducing the burden of this debilitating toxicity while preserving the anticancer benefits of the drugs patients depend on.

Subject of Research: Drug-induced palmar-plantar erythrodysaesthesia syndrome associated with antineoplastic agents identified through FDA adverse event reporting data

Article Title: Antineoplastic agent-induced palmar-plantar erythrodysaesthesia syndrome: insights from the FDA adverse event reporting system

Article References: Cheng, H., Li, Q., Hong, X., Zhang, Z., Chen, L., Yang, X., Wang, S., & Pan, W. (2026). Antineoplastic agent-induced palmar-plantar erythrodysaesthesia syndrome: insights from the FDA adverse event reporting system. Journal of Cancer Research and Clinical Oncology. https://doi.org/10.1007/s00432-026-06547-0

Image Credits: AI Generated

DOI: 10.1007/s00432-026-06547-0

Keywords: hand-foot syndrome, palmar-plantar erythrodysaesthesia, FAERS, pharmacovigilance, protein kinase inhibitors, capecitabine, regorafenib, sorafenib, antineoplastic agents, disproportionality analysis, adverse drug reactions, oncology

The study systematically extracted data spanning nearly a decade, from the first quarter of 2014 through the last quarter of 2023, identifying a total of 1,112 cases involving 1,134 adverse event reports specifically linked to ICI-associated noninfectious myocarditis and pericarditis (NM/P). This scope of data—carefully curated from a vast pharmacovigilance repository—provides an unparalleled real-world insight into the epidemiology and risk factors underpinning these life-threatening complications.

A key finding of the research lies in the demographic and clinical profiles of affected patients. The median age was 67 years, indicating a preponderance of older adults in the reported cases, consistent with the typical cancer patient population receiving ICIs. Men were disproportionately represented, suggesting potential sex-related susceptibility that warrants further immunological and pharmacogenomic investigation. The median body weight was recorded at 65 kilograms, although an intriguing trend emerged: patients weighing 75 kilograms or more appeared to face heightened risk, indicating that body mass might modulate drug pharmacodynamics with implications for dosage and monitoring.

Temporal analysis revealed a median onset time of just 28 days from initiation of ICI therapy to the manifestation of myocarditis or pericarditis symptoms. This rapid timeline underscores the necessity for vigilant cardiac monitoring early in treatment courses, as delayed recognition can culminate in severe morbidity or mortality. Indeed, the mortality risk associated with these cardiac irAEs was markedly elevated, particularly in patients treated with nivolumab and pembrolizumab, two of the most widely prescribed programmed death-1 (PD-1) inhibitors.

From a pharmacovigilance standpoint, the study applied two sophisticated disproportionality analysis techniques: the Bayesian Confidence Propagation Neural Network (BCPNN) and the Reporting Odds Ratio (ROR). These statistical methods serve to detect and quantify signals of potential drug-associated adverse effects by contrasting observed reports against expected baselines. The results pointed to a hierarchy of risk, where pembrolizumab exhibited the strongest signal (ROR: 12.32, IC 025: 3.45), followed closely by nivolumab (ROR: 11.23, IC 025: 3.30), indicating more than a tenfold increase in reporting frequency for NM/P compared to other agents. Similarly, atezolizumab, ipilimumab, and durvalumab displayed significant but slightly lower signals, suggesting that while the risk is inherent to the ICI class, it may vary based on specific molecular targets or drug structures.

Importantly, the combination of nivolumab and ipilimumab—a regimen increasingly favored for its synergistic antitumor efficacy—emerged as a notable risk factor. The amplified immune activation achieved by dual checkpoint blockade appears to come at the cost of increased cardiac irAEs, demanding a fine balance between therapeutic benefit and safety vigilance. This insight compels oncologists and cardiologists to collaborate closely in managing patients slated for combination immunotherapy.

The underlying mechanisms driving ICI-induced myocarditis and pericarditis remain an active area of scientific inquiry. It is hypothesized that immune checkpoint blockade disrupts self-tolerance by unleashing autoreactive T-cells against cardiac tissues, thereby initiating inflammatory cascades and tissue injury. This autoimmune-like pathology differs fundamentally from infectious or ischemic causes and necessitates targeted immunosuppressive interventions to reverse cardiac inflammation and preserve function.

Emerging evidence also suggests that certain patient-specific factors, such as baseline immune status, genetic predispositions, and concurrent medications, could modulate the risk profile for cardiac toxicities. The present pharmacovigilance analysis provides a foundational dataset that could inform future prospective studies aimed at delineating predictive biomarkers and personalized risk stratification tools.

The geographic distribution of reports highlights a predominance from the United States and Japan, reflecting both the widespread clinical adoption of ICIs in these regions and possibly differences in pharmacovigilance infrastructure and reporting cultures. Engaging diverse populations globally in active surveillance will be critical to ascertain the universality of these findings and to address potential disparities.

As the oncology community embraces ICIs as mainstays in treating a range of solid tumors and hematologic malignancies, this study serves as a clarion call to integrate cardiac safety monitoring protocols into routine clinical workflows. Early detection of myocarditis and pericarditis—through biomarkers such as troponins, echocardiography, and cardiac MRI—paired with prompt intervention can mitigate severe outcomes.

Ultimately, the balance between therapeutic efficacy and toxicity management defines the future of cancer immunotherapy. The insights gleaned from this large-scale FAERS analysis emphasize the need for heightened awareness, proactive monitoring, and multidisciplinary care to safeguard patients from potentially fatal cardiac adverse events.

The implications of this research resonate beyond clinical oncology. They prompt pharmaceutical developers to innovate next-generation ICIs with reduced off-target immune activation and encourage regulatory agencies to refine post-marketing surveillance frameworks that incorporate sophisticated analytics like BCPNN and ROR. Moreover, the establishment of international registries dedicated to immune-related cardiotoxicity could expedite knowledge dissemination and best practice formulation.

In conclusion, immune checkpoint inhibitor-associated myocarditis and pericarditis represent formidable challenges in cancer therapeutics. This comprehensive pharmacovigilance study illuminates significant risk signals, identifies susceptible patient subgroups, and underscores the urgency of integrating cardiology expertise into oncologic care paradigms. As immunotherapy continues to evolve, such data-driven insights are indispensable to maximizing patient benefit while minimizing harm, ultimately advancing the frontier of personalized cancer treatment.

Article Title: Immune checkpoint inhibitor-associated myocarditis and pericarditis: a pharmacovigilance study based on the FAERS database

Article References:
Yao, G., Zhang, Y., Zhang, H. et al. Immune checkpoint inhibitor-associated myocarditis and pericarditis: a pharmacovigilance study based on the FAERS database. BMC Cancer 25, 1294 (2025). https://doi.org/10.1186/s12885-025-14668-x

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14668-x