Radiotherapy safety may hinge on sex, but the evidence is thin

Radiation oncology is one of the most safety-critical corners of modern medicine: high-energy beams are planned on three-dimensional models, verified through layers of quality assurance, and delivered across weeks of fractions in which a small error can mean lasting harm. A new scoping review now asks a question that has rarely been asked systematically in this field: do a patient’s sex or gender influence how safely that pathway unfolds? The answer, according to a team of German radiation oncologists and a medical physicist, is a qualified yes for sex, and a striking silence for gender.

The review, conducted by working groups on patient safety and women in radiation oncology of the German Society of Radiation Oncology, was published in Frontiers in Oncology. The researchers searched PubMed on 22 July 2026, combining terms for radiotherapy, sex- or gender-related differences, and patient safety, quality, toxicity, and adverse events. No date restriction was applied, and backward reference-list searching was added to catch studies the database query missed. From 159 PubMed records, 32 database-identified studies survived screening; citation searching contributed five more, bringing the total to 37 original studies published between 1990 and 2026, with sample sizes ranging from 34 to 11,774 participants.

Those 37 studies yielded 49 reportable empirical findings: 33 described a difference or association, 10 were mixed, and six were statistically non-significant. Forty-four of the findings were clinical or technical outcome signals with potential safety relevance, while only five directly concerned care processes. When the team mapped every finding onto a published patient-safety framework for radiation oncology, which organizes the care pathway into four categories and 27 subcategories, all 49 findings landed in just six patient-specific subcategories: radiation planning and plan evaluation; presentation, consent, indication and prescription; prevention of adverse effects; symptom management; therapy completion and follow-up; and monitoring of non-tumor-targeting medications. Twenty-one of the 27 subcategories contained no retrieved evidence at all.

The classification of the studies themselves was equally revealing. Twenty were classified as analyses of sex, meaning the variable was identified as sex and its ascertainment was described or unambiguous. Seventeen were classified as unclear, typically because they used the word gender for a binary female/male demographic field without defining how it was measured or operationalized. Not a single study operationalized multidimensional gender, meaning identities, roles, relations, behaviors, or structural conditions. This matters because sex and gender are not interchangeable: sex refers to biological attributes such as anatomy, hormones, and chromosomes, while gender encompasses social constructs that may shape symptom reporting, communication, treatment choices, and access to supportive services. Without clear definitions, biological and social explanations become conflated, and apparent differences may actually reflect diagnosis, treatment selection, body composition, or confounding.

The planning-related evidence came from three clinically distinct settings. In a retrospective single-center cohort of 94 patients with post-radiotherapy cardiac events, men had higher maximum atrial doses, while women showed higher unadjusted odds of heart failure, although dose mediation was not demonstrated. A cohort of 53 patients treated with high-dose fractionated radiotherapy to fields encompassing the cauda equina produced model-derived estimates suggesting five-year tolerance doses were higher for women than men, but those estimates rested on only 13 neurotoxicity events, more than half of which occurred five or more years after treatment. In 710 patients receiving radiochemotherapy for locally advanced rectal cancer, women had a higher total-body mean dose per unit body mass, yet deposited energy, weight-normalized tumor-region dose, tumor regression, residual DNA damage, and treatment outcome were all comparable.

Treatment toxicity showed the review’s most consistent theme: direction depends entirely on context. In rectal-cancer radiochemotherapy, all seven grade 4 toxicities in one cohort occurred in women with a body mass index below 22 kilograms per square meter, and separate cohorts found more severe hematologic toxicity, anemia, diarrhea, and skin toxicity among women. In head and neck cancer, women had more grade 3 or higher dermatitis, 12.7 percent versus 5.3 percent, in one cohort, while another found female sex independently associated with more pain but mucositis, weight loss, and dysphagia driven mainly by treatment intensification and other factors. By contrast, toxicity and survival did not differ materially between women and men in palliative lung-cancer radiotherapy, and pooled neoadjuvant trials in resectable stage III non-small-cell lung cancer found severe adverse events similar, even though women had longer event-free and overall survival.

Symptom and quality-of-life findings were similarly time- and endpoint-dependent. In the longitudinal rectal-cancer analysis, women entered treatment with poorer quality-of-life scores and showed greater deterioration in nausea, appetite, and diarrhea, but most symptoms returned toward baseline within ten weeks. In head and neck cancer, men reported more pain-related burden during treatment while women reported more weight loss and dry mouth, with the pattern shifting again at three months. Among post-radiotherapy survivors, men had poorer unadjusted mental-health measures, but those associations attenuated once optimism was considered. Male sex predicted worsening pain after stereotactic radiosurgery for brain metastases, yet two secondary analyses of palliative bone-metastasis trials found baseline symptom differences did not translate into any female/male difference in analgesic response.

Follow-up and care-process findings added their own signals. Pediatric late-effect studies pointed in opposite directions: one historical cohort of childhood acute lymphoblastic leukemia survivors reported more severe cognitive impairment, short stature, and weight gain among girls, while a pediatric brain-tumor cohort associated lower IQ with male sex, with tumor size the stronger predictor, and a further leukemia cohort found no sex association with central-nervous-system alterations. After historical Hodgkin lymphoma treatment, women irradiated young had higher risks of breast and other solid second malignancies, whereas men showed patterns including leukemia and non-Hodgkin lymphoma. One study evaluated a follow-up process directly: despite standardized information and administrative support, rehabilitation was initiated by 25.1 percent of source-defined women versus 9.6 percent of men after radiotherapy. And in a prospective survey of 112 radiotherapy patients, women reported more complementary-medicine use and more frequent exposure to products with possible or known interaction potential, though actual interactions and adverse drug events were not measured.

The authors are careful about what these findings do and do not establish. An outcome association alone does not demonstrate preventability, and no included study established that a sex- or gender-targeted pathway improves patient outcomes. Seven findings concerning survival, recurrence, or local control were retained only as indirect prognostic signals. The review also carries methodological limitations: it relied on a single database with a phrase-dependent query, five studies came only from citation searching, studies reporting sex solely as a covariate may have been captured selectively, full texts were restricted to English and German, no formal risk-of-bias or certainty assessment was performed, and only seven studies were radiotherapy-specific while in ten multimodal studies the radiotherapy contribution could not be separated. Trial randomization, the authors note, does not randomize sex.

For current practice, the review supports accurate documentation of sex and gender variables, universal risk-adapted symptom monitoring, routine medication reconciliation including complementary products, and individualized planning based on anatomy and dose rather than sex alone. It does not support routine sex-specific thresholds or pathways, which would require prospective validation against both safety and tumor-control outcomes. The authors call for future studies that prespecify sex-by-treatment and sex-by-dose interactions, test whether sex adds predictive value beyond anatomy, dose, systemic therapy, body composition, and comorbidity, measure multidimensional gender directly rather than inferring it from an administrative field, and prospectively evaluate whether clearly defined sex- and gender-informed care processes actually improve safety. The empty subcategories, they caution, reflect the limits of the search as much as the literature itself, and should not be read as evidence that sex or gender is irrelevant across the rest of the radiation-oncology pathway.

Subject of Research: Sex- and gender-related aspects of patient safety in radiation oncology

Article Title: Sex- and gender-related aspects of patient safety in radiation oncology: a scoping review

Article References: Grohmann, M., Trommer, M., Besserer, A., & Baehr, A. (2026). Sex- and gender-related aspects of patient safety in radiation oncology: a scoping review. Frontiers in Oncology, 16, 1962214. https://doi.org/10.3389/fonc.2026.1962214

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1962214

Keywords: radiation oncology, patient safety, scoping review, radiotherapy, sex differences, gender, toxicity, symptom management, treatment planning, rehabilitation, complementary medicine, health equity