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

Immune checkpoint inhibitors have dramatically transformed oncology by empowering the body’s own immune defenses to recognize and eradicate malignant cells. These drugs achieve their effect by blocking inhibitory pathways that cancer cells exploit to evade immune attack, effectively reactivating T cells to target tumors. However, this immune reinvigoration comes at a cost, as it can inadvertently prompt a damaging inflammatory response within the heart muscle, leading to conditions such as myocarditis, a potentially fatal inflammation of the heart.

At the forefront of this research is Assistant Professor Pilar Martín, a leading immunologist and head of the Regulatory Molecules of Inflammation Laboratory at the Spanish National Center for Cardiovascular Research (CNIC), who collaborated closely with CIBER-CV. Professor Martín’s team focused on analyzing the interplay between immune cell populations in cancer patients before and after administration of immune checkpoint inhibitors. Their aim was to decipher immune signatures that might predict cardiotoxicity early in the course of treatment.

Data was collected from an extensive cohort of 215 cancer patients enrolled in the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT), encompassing a diverse spectrum of malignancies such as lung, breast, and skin cancers. Patients received a variety of immune checkpoint inhibitors including agents targeting PD-1, PD-L1, and CTLA-4, with blood samples drawn at multiple intervals—prior to treatment, and subsequently at 2-4 weeks, 10-12 weeks, 6 months, and one year post-treatment initiation. The longitudinal nature of the study provided an unparalleled window into the dynamic immune landscape influenced by these therapies.

A striking discovery emerged early in treatment: a rapid decline in regulatory T cells (Tregs), a subset of immune cells instrumental in maintaining immunological tolerance and preventing excessive inflammation. These CD69-positive Tregs, identified by their expression of the activation marker CD69, appear to function as a critical protective barrier against immune-mediated tissue damage. Their swift depletion post-treatment indicates a vulnerable period wherein the immune system’s ability to restrain harmful inflammation wanes significantly.

Further stratification of patients based on their baseline levels of CD69-positive Tregs uncovered a compelling pattern. Patients with inherently low circulating levels of this protective biomarker prior to starting immunotherapy exhibited a pronounced decline in these regulatory cells and concurrently showed a marked expansion of cytotoxic and pro-inflammatory immune populations. This skewed immune profile correlated strongly with an increased risk of developing myocarditis and other cardiovascular toxicities.

The underlying mechanism points to an imbalance between immune activation and regulation. While immune checkpoint blockade unleashes effector T cells to attack cancer, the simultaneous loss of regulatory T cells disrupts the immune equilibrium, permitting unchecked inflammation that can damage cardiac tissue. This nuanced immunopathophysiology underscores the double-edged nature of immune checkpoint inhibitors — remarkable efficacy paired with serious potential collateral damage.

Professor Martín emphasized the clinical promise of these findings, suggesting that measuring CD69 expression on regulatory T cells through a relatively simple and cost-effective blood test might soon become part of routine screening before immunotherapy initiation. Identifying patients predisposed to immune dysregulation would allow for tailored monitoring protocols and early intervention strategies designed to mitigate heart injury. This personalized approach could vastly improve patient outcomes by balancing cancer control against cardiovascular safety.

Nevertheless, Professor Martín cautions that further research is essential to validate CD69 as a reliable biomarker and to comprehensively characterize the immune alterations during treatment. Integrating these insights with functional cardiac assessments and molecular profiling will enhance the predictive accuracy and mechanistic understanding of immunotherapy-induced cardiotoxicity.

The implications extend beyond prognostication. Understanding the immunological shifts offers a roadmap for developing adjunct therapies that could restore regulatory T cell function or otherwise modulate the immune response to protect cardiac health without compromising anti-tumor activity. This dual therapeutic goal represents the next frontier in cardio-oncology, striving to harmonize effective cancer eradication with preservation of cardiovascular integrity.

The research was formally presented at the European Cardio-Oncology 2025 congress, hosted by the European Society of Cardiology, which serves as an important forum for multidisciplinary collaborations addressing the intersection of cancer treatment and heart disease. The study’s contribution highlights the critical need for ongoing vigilance and innovation at this crossroads of immunology and cardiology.

In summary, this pioneering study sheds light on the pivotal role of regulatory T cells and their biomarker CD69 in mediating the cardiac side effects of immune checkpoint inhibitors. By elucidating early immune cell dynamics that confer risk, it opens the door to predictive testing, personalized patient management, and novel interventional strategies, ultimately aiming to maximize the therapeutic benefits of immunotherapy while minimizing its life-threatening cardiac complications.

Subject of Research: Immune system changes in cancer patients receiving immune checkpoint inhibitors linked to risk of cardiotoxicity
Article Title: Not provided
News Publication Date: Not provided
Web References:
– Spanish National Center for Cardiovascular Research (CNIC): https://www.cnic.es/en/about-cnic-0
– CIBER-CV: https://www.cibercv.es/en
References:
1. Cruz-Adalia A, Jiménez-Borreguero LJ, Ramírez-Huesca M, Chico-Calero I, Barreiro O, López-Conesa E, Fresno M, Sánchez-Madrid F, Martín P. CD69 limits the severity of cardiomyopathy after autoimmune myocarditis. Circulation. 2010 Oct 5;122(14):1396-404. doi: 10.1161/CIRCULATIONAHA.110.952820.
2. Zatarain-Nicolás E, Martín P, Márquez Rodas I, Virizuela J, et al. Cardiovascular toxicity of checkpoint inhibitors: review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity. Clin Transl Oncol. 2023 Nov;25(11):3073-3085. doi: 10.1007/s12094-023-03217-2. PMID: 37227656.
Image Credits: Not provided
Keywords: Cancer, Cardiology, Immune checkpoint inhibitors, Regulatory T cells, CD69 biomarker, Cardiotoxicity, Myocarditis, Immunotherapy, Cardio-oncology