Cervical cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide, particularly in low- and middle-income countries (LMICs), where over 85% of the global burden exists. India alone accounts for nearly one-fifth of the global cervical cancer deaths, with the majority of patients presenting at a locally advanced stage (FIGO stage IB3–IVA). There are more than 1.27 lakh reported cases of cervical cancer and approximately 80,000 deaths among women reported in 2022 in India (GLOBOCAN 2022). 

Persistent infection with high-risk human papillomavirus (HR-HPV), especially types 16 and 18, plays a pivotal role in the pathogenesis of cervical cancer. While prophylactic HPV vaccination has demonstrated high efficacy in preventing HPV-associated lesions and invasive cancer when administered before exposure, emerging evidence suggests potential immunomodulatory roles when administered after disease onset. The nonavalent HPV vaccine, targeting nine high-risk HPV types, offers broader immunogenicity and has shown a favorable safety profile.  Recent preclinical and translational studies indicate that HPV vaccination may enhance antitumor immunity even in patients with existing HPV-driven malignancies, potentially aiding in viral clearance, reducing residual tumor burden and improving treatment outcomes. 

One of the key challenges in the post-treatment surveillance of cervical cancer is the lack of sensitive biomarkers to predict response or recurrence. Circulating tumor DNA (ctDNA) and more specifically, circulating HPV cell-free DNA (cfDNA), is a promising non-invasive biomarker that reflects tumor dynamics. Studies have shown that HPV cfDNA levels correlate with tumor burden, response to therapy, and can predict early relapse. However, data on how therapeutic HPV vaccination impacts cfDNA levels and clinical outcomes in conjunction with CRT is limited, representing a critical knowledge gap.

Standard treatment for locally advanced cervical cancer (LACC) comprises concurrent chemoradiotherapy (CRT), which includes external beam radiotherapy with weekly cisplatin and intracavitary brachytherapy.  Despite this established regimen, outcomes remain suboptimal, with recurrence rates as high as 30–40% and significant long-term morbidity. This underscores the urgent need to enhance treatment efficacy, reduce recurrence and explore personalized and immune-targeted strategies. 

This randomized controlled Phase II trial aims to evaluate the clinical and molecular outcomes of adding the nonavalent HPV vaccine to standard CRT in patients with LACC. The primary objectives are to assess tumor response at three months and 12-month progression-free survival (PFS). Secondary objectives include the evaluation of serial HPV cfDNA levels as a biomarker of treatment response and relapse risk and assessment of quality of life using validated patient-reported outcome tools. Participants will be randomized into two arms: standard CRT alone versus CRT plus three doses of the nonavalent HPV vaccine administered at baseline, month two and month six. The study incorporates a prospective collection of blood samples for cfDNA analysis and utilizes RECIST criteria and imaging to evaluate tumor response.

This study is novel in integrating a prophylactic vaccine as a potential therapeutic adjunct in HPV-associated cervical cancer, supported by molecular biomarker surveillance and patient-centred outcomes. If successful, this approach could not only improve survival and quality of life in LACC but also redefine the role of HPV vaccination beyond prevention, supporting a paradigm shift in HPV-driven cancer management.