A retrospective observational study from St. John’s Medical College Hospital in Bengaluru, published in Supportive Care in Cancer, now quantifies how often this viral awakening complicates one specific and increasingly common scenario: radiotherapy for gynaecological cancers. The research team, led by radiation oncologists Deepu C Tom and Avinash H Udayashankara together with biostatistician John Michael Raj, reviewed the records of 391 women aged 18 years or older with histologically confirmed gynaecologic malignancies who received definitive or adjuvant radiotherapy between January 2016 and October 2025. Their central question was deceptively simple. Among women whose pelvic tumors were being bombarded with fractionated ionizing radiation, how frequently did herpes simplex virus or varicella zoster virus reactivate from latency, and what distinguished the patients in whom reactivation occurred?

The answer was that herpetic reactivation, abbreviated HRA in the study, occurred in 5.6 percent of the cohort, or 22 of the 391 patients analyzed. That figure alone is notable, but the distribution of cases within the cohort is what gives the study its analytical bite. Every single reactivation event occurred in women being treated for carcinoma of the uterine cervix. Among the 291 cervical cancer patients, the incidence was 7.6 percent, a statistically significant excess compared with other gynaecologic cancers such as endometrial, ovarian, vulvar and vaginal malignancies, where no reactivations were recorded at all. The association carried a p value of 0.018, and it suggests that something specific about cervical cancer, its biology or its treatment, rather than gynaecological radiotherapy in general, creates the permissive conditions for viral escape.

The technical details of the radiation treatment themselves emerged as risk factors. Patients who received higher doses of external beam radiotherapy, or EBRT, were more likely to reactivate, with a p value of 0.020. So were women treated with intensity-modulated radiotherapy or volumetric-modulated arc therapy, the IMRT and VMAT techniques that dominate modern radiation oncology, with a p value of 0.008. These findings align with a mechanistic framework that radiation virologists have been assembling for years. Ionizing radiation delivered to a field that overlaps the sacral and pelvic sensory ganglia, which harbor the latent viruses relevant to genital and sacral dermatomal disease, induces local tissue injury, mucosal breakdown and a localized immunosuppressive milieu. Radiation also depletes the tissue-resident T cells and dendritic cell populations that patrol latently infected neurons and their axonal targets. Previous reviews, including a 2018 overview in the Journal of Clinical Virology by Ramirez-Fort and colleagues, have documented radiotherapy-induced reactivation of neurotropic human herpesviruses across tumor sites, and individual case reports of radiation-associated herpes zoster continue to accumulate in the literature.

Concurrent chemotherapy added another layer of risk. Among women who received chemotherapy simultaneously with their radiotherapy, 8.1 percent experienced reactivation, compared with zero percent among those who did not, a difference with a p value of 0.002. Chemotherapeutic agents suppress rapidly dividing hematopoietic and mucosal progenitor cells, compounding the radiation-induced depletion of the immune effectors that normally prevent lytic reactivation. The combination of pelvic radiation and concurrent platinum-based chemotherapy is standard of care for locally advanced cervical cancer, which means the very treatment regimen that offers the best oncological outcomes for these patients also stacks the immunological deck against viral latency.

Perhaps the most striking risk factor in the dataset was the presence of other sexually transmitted infections. Among the 18 patients with documented STIs, 5 experienced herpetic reactivation, an incidence of 27.8 percent, compared with 4.6 percent, or 17 of 373 patients, among women without documented STIs. The difference was highly significant, with a p value below 0.001. The mechanistic logic here is well established from the HIV literature, where Gianella and colleagues have described the sordid affair between human herpesviruses and HIV as a bidirectional dance of immune dysregulation. Co-infecting pathogens sustain systemic inflammation, perturb mucosal immunity and deplete the CD4 T cell compartment, all of which lower the threshold for herpesvirus reactivation. In the context of cervical cancer, where human papillomavirus and other STIs share epidemiological space, this finding identifies a clinically actionable subpopulation that might warrant closer monitoring or even prophylactic antiviral coverage.

The study also uncovered an unexpected temporal signal that connects cancer care to the recent history of the COVID-19 pandemic. Women treated after the pandemic were significantly more likely to develop reactivation than those treated before it, with an incidence of 8.8 percent versus 1.7 percent and a p value of 0.002. The authors note this as an interesting observation, and it resonates with a growing body of literature documenting herpesvirus reactivation during and after COVID-19 infection itself, as well as after mRNA and adenoviral vector vaccination. Systematic reviews and meta-analyses published in Rev Med Virol and the Journal of Medical Virology have catalogued reactivation events in COVID-19 patients, and researchers have proposed that SARS-CoV-2-induced immune dysregulation, lymphopenia and sustained inflammatory signaling can destabilize herpesvirus latency. Whether the post-pandemic excess in this cohort reflects prior SARS-CoV-2 infection, pandemic-era changes in immune status, altered healthcare-seeking patterns or residual confounding cannot be determined from a retrospective design, but the signal is strong enough to demand prospective investigation.

The clinical consequences of reactivation were not trivial. Among the treatment interruptions recorded in the cohort, 53.3 percent were attributable to herpetic reactivation events. This is the number that transforms the study from a virological curiosity into a matter of oncological urgency. Radiotherapy for cervical cancer is a dose-escalated, fraction-dependent endeavor in which the therapeutic ratio depends on delivering the prescribed dose within a defined overall treatment time. Interruptions prolong the schedule, allow tumor repopulation and are associated in multiple series with inferior local control and survival outcomes. A viral complication that accounts for more than half of all interruptions in a cohort is therefore not a side note in supportive care. It is a determinant of treatment efficacy.

The authors frame their conclusions carefully, acknowledging the inherent limitations of a retrospective single-institution design, including the possibility of under-ascertainment of mild or atypical reactivation events and the absence of systematic viral screening. No datasets were generated or analyzed beyond the clinical records, and the study received no dedicated funding. Yet the risk factor profile they assembled, encompassing cervical cancer as the dominant tumor type, higher EBRT dose, modern conformal techniques, concurrent chemotherapy, coexisting STIs and the post-pandemic era, offers a coherent mechanistic narrative. Radiation and chemotherapy degrade local and systemic immune surveillance; co-infections sustain the inflammatory milieu that destabilizes latency; and the sacral ganglia, sitting within or adjacent to the radiation field, provide the viral reservoir from which lytic replication erupts.

What follows from this study is a question of clinical policy rather than laboratory science. Should patients with cervical cancer and documented STIs, or those receiving high-dose conformal pelvic radiotherapy with concurrent chemotherapy, be considered for prophylactic acyclovir or valacyclovir during treatment, in line with the AGIHO guideline framework already applied to patients with hematologic malignancies and solid tumors? Should radiation oncologists incorporate herpetic reactivation into their differential diagnosis when pelvic or sacral dermatomal eruptions appear mid-course? The incidence of 5.6 percent overall, and 7.6 percent among cervical cancer patients, is high enough that the answer to both questions may be yes, pending prospective validation. For a virus that has coexisted with humans for millennia, hiding in neurons behind a barrier that even the most sophisticated immune system struggles to penetrate, the lesson of this study is that the tools of modern cancer therapy can occasionally reach into that sanctuary and turn latency back into disease.

Subject of Research: Radiotherapy for cervical cancer may wake dormant herpes viruses, study finds

Article Title: Herpetic reactivation during radiotherapy treatment for gynaecological cancers—a retrospective observational study

Article References: Tom, D. C., Udayashankara, A. H., S, N., F, H. N. A., R, J., Garg, S., & Raj, J. M. (2026). Herpetic reactivation during radiotherapy treatment for gynaecological cancers—a retrospective observational study. Supportive Care in Cancer, 34(9), Article 907. https://doi.org/10.1007/s00520-026-11152-5

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11152-5

Keywords: Herpetic, reactivation, during, radiotherapy, treatment, gynaecological, cancers, retrospective, observational, scientific research