1. Introduction

Cervical cancer remains a prevalent malignancy in women. One-third of patients present with locally advanced disease (IB2-IVA), where definitive chemoradiation (weekly cisplatin + external beam radiotherapy + brachytherapy) constitutes the gold standard. This strategy achieves high pathological complete response rates (70-90%) with 5-year progression-free and overall survival of 68% and 74%, respectively. Adjuvant chemotherapy following chemoradiation (OUTBACK trial) has shown no survival benefit, leaving the standard paradigm unchanged for two decades (1,3).

The phase III GCIG INTERLACE study has redefined treatment for high-risk cases. In 500 LACC patients, induction chemotherapy (6 weekly cycles of paclitaxel + carboplatin) followed by standard chemoradiation significantly improved survival outcomes versus chemoradiation alone. This approach frequently induces marked tumor response before radiotherapy, raising questions about target volume adaptation (2).

¹⁸F-FDG PET/CT is now widely used for initial staging and early treatment response assessment. Patients achieving complete metabolic response post-treatment demonstrate superior prognosis, though 10-20% recurrence rates persist even among complete responders, underscoring the aggressiveness of specific subtypes (4).

2. Case report

A 69-year-old woman presented with multiple comorbidities, including hypertension, stage IIIa chronic kidney disease (eGFR 45 mL/min by CKD-EPI), and ischemic heart disease treated with apixaban. She was also receiving clonazepam for well-controlled epilepsy and levothyroxine for hypothyroidism. Her surgical history included bilateral hip replacements, partial colectomy, and cardiac surgery. Current medications also comprised furosemide with potassium chloride supplementation, atorvastatin, and zopiclone. The patient had a known penicillin allergy.

Initial symptoms of pelvic pain prompted an ultrasound revealing a 55 mm cervical mass. Initial biopsy suggested CIN2 with p16 expression, while imaging (pelvic MRI and PET-CT) confirmed a tumor infiltrating the upper third of the vagina with associated lombo-aortic and iliac lymphadenopathy. A definitive repeat biopsy could not be performed due to significant bleeding, leading to a clinico-radiological diagnosis of squamous cell carcinoma.

Figure 1: Initial pelvic T1/T2-weighted MRI. A uterine cervical mass measuring approximately 55 mm in anteroposterior diameter, 55 mm in transverse diameter, and 5 cm in height. The tumor remains visible despite metallic artifacts, particularly on: left – sagittal T2 sequence, center – axial T1 sequence, right – sagittal T1 sequence

Figure 2: Baseline ^18F-FDG PET/CT – axial slice. A large, intensely hypermetabolic uterine mass confined to the lower uterine segment, with a maximum standardized uptake value (SUVmax) of 24 and measuring approximately 8 cm in greatest diameter.

She received six cycles of weekly induction chemotherapy with carboplatin (AUC = 2) and paclitaxel (80 mg/m²). Overall tolerance was relatively good: the only notable toxicities were moderate anemia (hemoglobin ≈ 9 g/dL, requiring transfusion of two units of packed red blood cells) and grade 2 neutropenia. No early treatment interruptions were necessary. A follow-up ^18F-FDG PET/CT performed four weeks after completion of induction chemotherapy showed absence of abnormal uptake in the cervical tumor and pelvic lymph nodes (residual SUVmax < 2.5), consistent with a complete metabolic response.

Figure 3: ^18F-FDG PET/CT at four weeks post-induction chemotherapy – axial slice. Resolution of hypermetabolism at the primary cervical lesion and in the initially involved subdiaphragmatic lymph node sites, indicative of a complete metabolic response.

Four weeks after this evaluation, the patient began external beam radiotherapy with concurrent chemotherapy. Treatment was delivered using volumetric modulated arc therapy (VMAT) on a 6 MV linear accelerator. The clinical target volumes included the cervical tumor and uterus (GTVp), extended to the invaded right parametrial tissue, as well as bilateral pelvic lymph nodes (CTVn) from the obturator level through the internal and external iliac chains. A 7 mm margin was added to constitute the planning target volume (PTV). Organs at risk delineated were the bladder, rectum, small bowel loops, pelvic bones, and lumbar bone marrow. Dose constraints adhered to published guidelines: bladder D2cc ≤ 80 Gy EQD2, rectum D2cc ≤ 75 Gy EQD2, small bowel maximum dose < 50 Gy (EBRT), and mean dose to lumbar bone marrow < 40 Gy.

She received 45 Gy in 25 fractions (1.8 Gy per fraction), five days per week, combined with five weekly cycles of cisplatin at 32 mg/m², corresponding to a 20% reduction from the standard dose of 40 mg/m², due to moderate renal insufficiency.

High‑dose‑rate (HDR) intracavitary uterovaginal brachytherapy was initiated two weeks after completion of IMRT. Four fractions of 7 Gy each were delivered, yielding a cumulative EQD₂ of approximately 84.7 Gy. In addition, focal “hot spots” (D₀.₁ cc ≳ 105 Gy EQD₂) enabled the effective D₉₀ for the tumor volume to reach 90–92 Gy, in line with guidelines for optimal locoregional control.

Overall, the treatment was well tolerated. Genitourinary and gastrointestinal toxicities were limited to mild grade 1 cystitis and grade 2 proctitis, managed with local hygiene measures and dietary modifications. Cisplatin-related neutropenia remained moderate (grade 1–2) without febrile episodes. No significant treatment interruptions were required. Only brief pauses (1–2 days) were needed on two occasions due to transient neutropenia (grade 2), but treatment was resumed without dose reduction. Three months after completion, the patient was asymptomatic, and follow-up ^18F-FDG PET/CT confirmed the absence of active residual disease, indicating a sustained complete metabolic response. At 15 months of follow-up to date, she remains progression-free.

Figure 4: Pelvic MRI at 3 months post-treatment – sagittal and axial T2-weighted sequences. No residual lesion or visible sign of recurrence, consistent with a complete local radiographic remission.

Figure 5: PET scan 3 months after completion of treatment – Axial slice: complete gynecological metabolic remission.

Figure 6: Pelvic MRI performed 1-year post-treatment – Sagittal and axial T2-weighted sequences.

Figure 7: PET scan 1 year after completion of treatment – Axial slice: complete gynecological metabolic remission.

3. Discussion

This case report describes the management of a locally advanced squamous cell carcinoma of the cervix in a multimorbid patient with chronic renal insufficiency, ischemic heart disease, and epilepsy. The initial biopsy had indicated a low-grade intraepithelial lesion (CIN2), whereas MRI and ^18F-FDG PET/CT revealed a cervical mass highly suggestive of invasive cancer. Systematic anatomo-radiological correlation allowed prompt revision of the diagnosis to invasive squamous carcinoma, thus avoiding understaging as highlighted by Siegel et al., who reported that nearly 20 % of lesions initially classified as CIN2/3 conceal invasive carcinoma when imaging is not integrated into the diagnostic workup (1,5,6,7).

Induction Chemotherapy According to the INTERLACE Protocol

The patient underwent induction chemotherapy identical to the INTERLACE regimen, consisting of six weekly cycles of carboplatin (AUC = 2) plus paclitaxel at 80 mg/m². This approach aimed to achieve early tumor debulking and micrometastatic control prior to radiotherapy. In the phase III INTERLACE trial published in The Lancet in 2024, 92 % of patients completed at least five induction cycles, with a median interval of seven days before initiating radiotherapy, demonstrating both feasibility and tolerability of this schedule (2). In our case, the patient tolerated induction without interruption, and post-induction PET/CT confirmed a complete metabolic response, consistent with the superior 5-year progression-free survival (72 % vs. 64 %, HR 0.65) and overall survival (80 % vs. 72 %, HR 0.60) observed in the induction arm (2).

Radiotherapy Planning and Delivery

External beam radiotherapy was planned using volumetric modulated arc therapy (VMAT) to deliver 45 Gy in 25 fractions to the defined target volumes. The primary clinical target volume (CTVp) encompassed the cervix, uterus. It involved parametrial tissue, while the nodal CTV (CTVn) included bilateral pelvic lymph nodes from the obturator region through the internal and external iliac chains. A 7 mm margin was applied to create the planning target volume (PTV). Organs at risk—bladder, rectum, small bowel loops, pelvic bones, and lumbar bone marrow—were delineated and dose constraints strictly observed: bladder D2cc ≲ 75 Gy EQD2, rectum D2cc ≲ 65 Gy EQD2, small bowel maximum < 50 Gy (EBRT), and mean lumbar bone marrow dose < 40 Gy (1). Complementary high-dose-rate intracavitary brachytherapy achieved a cumulative EQD2 of 78–86 Gy to the upper cervical region without excessive exposure of adjacent healthy tissues.

Dose Adaptation and Tolerance

Given the patient’s moderate renal impairment, concurrent cisplatin was reduced by 20 % to 60 mg/m², in line with Tinker et al., who demonstrated preserved cisplatin efficacy despite dose reduction in at-risk populations (8). Renal function was closely monitored, and optimal hydration protocols were employed for each cycle. The patient experienced only mild gastrointestinal toxicity (grade 1–2 diarrhea) and no severe hematologic adverse events, confirming that dose adjustments can maintain a favorable tolerability profile.

Comparison with the Literature and Future Perspectives

Our findings align with the prospective INTERLACE data and contrast with the OUTBACK trial, where adjuvant chemotherapy after chemoradiation failed to improve survival (2,3). A retrospective study by Pfaendler et al. reported complete response rates of approximately 58 % in multimorbid cohorts, underscoring the influence of individual factors such as immune status and comorbidity management (9). Additionally, a recent meta-analysis by Olawaiye et al. suggested that the carboplatin/paclitaxel regimen may offer a more favorable toxicity profile without compromising efficacy, with an objective response rate of 72 % versus 68 % for cisplatin. However, cisplatin remains preferred for squamous histology based on long-term outcomes (10).

Therapeutic Perspectives

The complete metabolic response observed in this multimorbid patient highlights the growing importance of identifying molecular predictors of therapeutic efficacy, particularly in the context of platinum- and taxane-based chemotherapy. Several biomarker-driven approaches are currently being explored to refine patient selection and move toward a more personalized oncologic strategy. For instance, BRCA-like molecular profiles have emerged as potential predictors of enhanced response to platinum agents. Preliminary studies suggest that alterations in DNA repair genes such as BRCA1, BRCA2, and PALB2 may sensitize squamous cell carcinomas to platinum salts. In addition, immune-related markers—such as PD-L1 expression and the density of tumor-infiltrating lymphocytes (TILs)—may help identify patients more likely to benefit from combination regimens involving immunotherapy. Genomic initiatives like the EMBRACE II project are also underway, incorporating serial tumor biopsies to uncover biomarkers associated with treatment response, particularly to image-guided adaptive brachytherapy and systemic chemotherapy(1,11,12).

The recent integration of immune checkpoint inhibitors into cervical cancer management offers promising new avenues for enhancing therapeutic efficacy. The KEYNOTE A18 trial, which investigates the addition of pembrolizumab (a PD-1 inhibitor) to standard chemoradiotherapy, has reported preliminary improvements in progression-free survival. However, the optimal sequencing of therapies—whether through induction chemotherapy followed by immunochemoradiotherapy, or vice versa—remains under investigation. The role of induction chemotherapy is of particular interest, as it may enhance tumor antigen release and modulate the tumor microenvironment, thereby improving the effectiveness of subsequent immunotherapy(13). Nevertheless, patient selection is critical, especially in individuals with comorbidities such as renal impairment, which may predispose them to immune-related adverse events like pneumonitis or colitis. Ongoing studies, including the CALLA trial, are evaluating the use of durvalumab as maintenance therapy following chemoradiotherapy, with results expected in 2026(14).

Meanwhile, brachytherapy remains a cornerstone in the treatment of locally advanced cervical cancer, and recent innovations have further refined this modality. MRI-guided adaptive brachytherapy allows for more precise dose delivery, particularly to the high-risk clinical target volume (HR-CTV). The EMBRACE I and II trials recommend delivering an equivalent dose of at least 85 Gy in 2 Gy fractions, which has been associated with local control rates exceeding 90% in patients with small-volume tumors. The INTERLACE trial, for instance, revealed that 30% of patients received three-dimensional volumetric brachytherapy instead of the conventional point A technique, with a median delivered dose of 79.4 Gy. These findings underscore the impact of technical quality on clinical outcomes. For patients with bulky tumors or parametrial extension, hybrid applicators that combine intracavitary and interstitial components have proven essential in achieving adequate target coverage without significantly increasing the risk of late complications, such as fistula formation. Notably, the total treatment time remains a key prognostic factor, with durations exceeding 50 days linked to increased recurrence rates. The induction phase in INTERLACE helped shorten the interval before external beam radiation, with a median delay of just seven days(1,2,16,17).

Ongoing clinical trials continue to push the boundaries of therapeutic optimization. EMBRACE III is targeting high-risk patients (FIGO stages IIIB to IVA) with dose-escalated adaptive brachytherapy, while INTERLACE 2 is evaluating the addition of bevacizumab to the induction phase. Furthermore, technological innovations are paving the way for future improvements. Stereotactic body radiation therapy (SBRT) is currently under investigation as a potential boost modality for residual lymph nodes. Concurrently, artificial intelligence is being harnessed to develop automated treatment planning algorithms that optimize dose distribution while minimizing exposure to organs at risk such as the bladder and rectum, thereby enhancing both precision and reproducibility(18,20,21).

Together, these therapeutic and technological advancements signal a paradigm shift toward more individualized and effective treatment strategies in advanced cervical cancer.

4. Conclusion

This case illustrates the applicability of the INTERLACE induction protocol in a high-risk, multimorbid patient, achieving a durable complete metabolic response at 12 months. It emphasizes the critical importance of personalized, multidisciplinary management of comorbidities to balance oncologic efficacy and treatment safety.

ABBREVIATIONS

AUC – Area Under the Curve

BRCA – Breast Cancer gene

CCRT – Concurrent Chemoradiotherapy

CIN – Cervical Intraepithelial Neoplasia

CKD-EPI –  Chronic Kidney Disease – Epidemiology Collaboration

CT – Computed Tomography

CTV – Clinical Target Volume

D₂cc – Minimum dose to the most exposed 2 cc

D₀.₁cc – Minimum dose to the most exposed 0.1 cc

EBRT – External Beam Radiotherapy

EQD2 – Equivalent Dose in 2 Gy fractions

FIGO – Fédération Internationale de Gynécologie Obstétrique

GTV – Gross Tumor Volume

HDR – High Dose Rate

IMRT – Intensity-Modulated Radiation Therapy

MRI – Magnetic Resonance Imaging

PET/CT – Positron Emission Tomography / Computed Tomography

PTV – Planning Target Volume

SUVmax – Maximum Standardized Uptake Value

TILs -Tumor Infiltrating Lymphocytes

VMAT – Volumetric Modulated Arc Therapy

STATEMENTS

Authors’ Contributions: All authors contributed to the conception, drafting, and revision of the manuscript. NT conducted the literature review, analyzed the clinical data, and contributed to the interpretation of the findings. All authors read and approved the final version of the manuscript.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Informed Consent: Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Conflict of Interest: The authors declare that they have no conflict of interest.

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