Oncology Must Confront Hidden Side Effects of Breakthrough Cancer Therapies
Key Insights
Current toxicity reporting frameworks like CTCAE fail to capture the duration and functional impact of low-grade but chronic adverse events from novel cancer therapies.
Pan-RAS (search) inhibitor daraxonrasib doubled survival in advanced pancreatic cancer (search), yet full quality-of-life data remain undisclosed due to short follow-up, obscuring non-CTCAE toxicities from clinicians.
Real-world experience with bispecific antibodies like amivantamab reveals that full toxicity profiles emerge only after broader patient exposure, highlighting gaps in clinical trial reporting.
Recent breakthroughs in cancer therapy—including immunotherapies, antibody–drug conjugates, and bispecific antibodies—have transformed oncology care, making treatments more targeted and extending overall survival. Yet as patients live longer, they face lifelong challenges from treatment-induced toxicities whose full scope remains poorly understood. According to a perspective published in Nature Medicine, approaches to recording and managing these toxicities have not evolved at the same pace as therapeutic innovation, and their impact on quality of life for cancer survivors is unclear.
The Hidden Burden of Low-Grade Toxicities
Those who survive cancer must live with the consequences of therapy-induced toxicities and may remain on treatment for the rest of their lives. Even low-grade adverse effects such as rash and diarrhea can become functionally and psychologically devastating when experienced over a long period. Immune-related adverse events in patients treated with immune checkpoint inhibitors can be chronic and persist for years or be irreversible. However, the duration of adverse events is not factored into the existing Common Terminology Criteria for Adverse Events (CTCAE), which was designed for acute toxicities.
"What is deemed manageable according to current criteria might be unacceptable to patients," the authors note. Quality-of-life data are commonly reported years after the primary clinical report has been published and the drug has been approved, meaning these data are not available to new patients making treatment decisions. Patient questionnaires used to assess quality of life may be outdated and may not accurately represent patients' issues.
The Daraxonrasib Case: Survival Gains Without the Full Picture
The latest breakthrough in oncology, the pan-RAS (search) inhibitor daraxonrasib, doubled the survival of patients with aggressive RAS oncogene-driven advanced pancreatic cancer (search)—a disease with historically very limited treatment options. Most patients experienced acneiform rash and, although less common, diarrhea and stomatitis as low-grade therapy-related adverse events. Yet full quality-of-life data, including information on daily functioning and emotional well-being, have not been disclosed owing to short follow-up.
Because functional and psychological disruptions are not factored into CTCAE, non-CTCAE toxicities such as impaired daily functioning and emotional well-being remain hidden from prescribing clinicians in the first years after a therapy's rollout. "Patients may be less accepting of new agents when expected toxicities, short or long term, cannot be disclosed because they are unknown or underappreciated or their severity is underestimated," the authors warn. Without such disclosure, obtaining actual informed consent for treatment with new agents in clinical practice is not possible.
Real-World Evidence Reveals What Trials Miss
Toxicity profiles of novel drugs can differ depending on targets, mechanisms of action, and individual patient factors such as genetic background and comorbidities. For patients historically excluded from trials based on these factors, only real-world data or appropriately designed trials can reveal the toxicities they can expect. Disparities exist in the severity of treatment-related adverse events across malignancies and therapeutic modalities, including gender disparities in adverse events induced by immunotherapy and racial disparities in those induced by chimeric antigen receptor (CAR) T cell therapy.
Real-world experiences with the bispecific antibody amivantamab in lung cancer (search) have demonstrated that the full extent and severity of skin toxicities can come to light only when a broader patient population has been exposed to the drug. Additionally, historical siloing of disciplines has limited knowledge transfer on how to detect, monitor, and manage therapy-induced toxicities—such as cytokine-release syndrome in CAR T cell therapy or immune-related adverse events in immune checkpoint inhibition.
Clinical Perspectives on Managing Toxicities
In a discussion on CancerNetwork, Dr. Park addressed management of low-grade immune-related adverse events, the most common toxicities encountered with checkpoint inhibitors, including dermatitis, pruritus, and gastrointestinal symptoms. She prioritizes supportive care for grade 1 to 2 toxicities when safe to do so, enabling most patients to remain on treatment. Key to success is early symptom reporting, proactive management, and setting expectations upfront. She noted that older patients often value functional independence over maximal treatment intensity, and that treatment breaks or discontinuation do not necessarily compromise outcomes, as responses in cutaneous squamous cell carcinoma (search) tend to be durable.
Dr. Sondak reinforced that disease-related symptoms—including painful or bleeding lesions and neuropathic pain from perineural invasion—can themselves be meaningfully improved by effective treatment. He encourages providers to use both radiation and systemic immunotherapy early when nerve involvement is causing pain. He also reassures patients that treating immune-related adverse events with corticosteroids does not impair antitumor response, and that even patients who discontinue due to severe toxicity have sometimes had the best outcomes. The full care team—nurses, nurse practitioners, and physician assistants—plays a critical role in monitoring patients and catching side effects early.
A Call for Systemic Change
The Nature Medicine perspective calls for new toxicity reporting guidelines developed with input from patients, so that their needs are accurately reflected in drug development. Patient questionnaires must be frequently updated. It is important to include populations at risk in the adaptation of current toxicity and quality-of-life reporting. Global and interdisciplinary efforts to detect and manage novel treatment-related adverse events are required as tissue-agnostic drugs and specific drug classes are approved across cancer types.
Examples of progress include cross-disciplinary working groups that provide guidelines for identifying and treating a rare syndrome associated with immune effector cell-based therapies, and monitoring immune-related side effects through registries such as the Side Effect Registry Immuno-Oncology. "This is a time of unprecedented pace in oncology drug development and clinical translation," the authors conclude. "The opportunity to reconsider current approaches to recording and managing treatment-related toxicities and to involving patients' perspectives early on during clinical development cannot be missed."