Introduction

Cervical cancer remains a substantial global health burden, with an estimated 604,000 new cases and 342,000 deaths reported worldwide in 2020 [1]. In Japan, approximately 10,000 new cases and 3,000 deaths occur annually, with 42% of cases affecting women under 45 years of age [2]. Given the disproportionate impact on women of reproductive age, fertility preservation has become increasingly critical in early-stage cervical cancer management.

For patients with FIGO stage IB1disease (FIGO stage 2018), recent evidence has shifted the standard of care from radical hysterectomy to a less radical approach. The SHAPE trial demonstrated that simple hysterectomy combined with pelvic lymph node assessment was noninferior to radical hysterectomy in terms of 3-year pelvic recurrence rates (2.52% vs. 2.17%) and was associated with significantly reduced surgical morbidity [3]. The ConCerv trial prospectively evaluated conservative surgeries such as conization with lymph node assessment in patients with low-risk early-stage disease, confirming oncologic safety, with a recurrence rate of 3.5% and a lymph node metastasis rate of 5% [4]. Most recently, the Gynecologic Oncology Group (GOG) in United States conducted the GOG-278 trial, which examined the oncological adequacy, contribution to physical function and quality of life, and reproductive outcomes of simple hysterectomy or cone biopsy plus pelvic lymphadenectomy for early stage IA1-IB1 cervical cancer [5,6]. After a median follow-up of 37 months in 201 eligible patients, only 3 (4%) cone biopsy patients have experienced disease recurrence. In addition, patients treated with cone biopsy plus pelvic lymphadenectomy achieved successful pregnancies. Incorporating these findings from SHAPE, ConCerv, and GOG-278 studies, less invasive surgical options are reasonable for appropriately selected patients with tumors ≤2 cm [3–6].

However, for patients with tumors 2–4 cm in size, radical hysterectomy remains the standard treatment, and the safety of fertility preservation strategies has not been fully established. Although radical trachelectomy with pelvic lymph node dissection can preserve fertility while ensuring oncological safety. However, the postoperative pregnancy rate is lower than that of conization, and the procedure is associated with higher rate of miscarriage and preterm birth [7].

Furthermore, for locally advanced cervical cancer, including patients with tumors >4 cm, neoadjuvant chemotherapy (NAC) followed by surgery has been investigated as a potential strategy for less extensive surgery. Large, randomized trials, including the TATA study and EORTC 55994, have not demonstrated a survival advantage of NAC followed by radical hysterectomy over concurrent chemoradiation therapy (CRT); consequently, NAC is not currently recommended as the standard treatment for locally advanced cervical cancer [8,9]. Although these studies focused on the efficacy of NAC in terms of survival compared to CRT, the potential use of NAC as a downstaging strategy to facilitate fertility-sparing surgery remains unexplored.

Cervical cancer is highly chemosensitive and dose-dense chemotherapy regimens can achieve high tumor response rates. Our group previously conducted a phase II trial to investigate a multidisciplinary strategy utilizing dose-dense paclitaxel and carboplatin (dd-TC) administered both before and after radical hysterectomy in patients with locally advanced cervical cancer [10]. This trial demonstrated an overall response rate of 92%, including a 22% pathological complete response rate. Notably, 98% of the patients successfully underwent planned radical hysterectomy without requiring postoperative radiotherapy.

Based on these promising results, we hypothesize that dd-TC therapy can effectively downstage tumors >2 cm to ≤2 cm, potentially enabling oncologically safe conization as a fertility-sparing procedure for patients who would otherwise be ineligible. Recently, several case series have reported the oncological and obstetric outcomes of NAC followed by cervical conization strategy for FIGO stage IB2-IB3 (FIGO stage 2018) cervical cancer, but no prospective studies have been reported to date [11,12]. This innovative approach may expand fertility preservation options, reduce the reliance on radical trachelectomy, and improve reproductive and obstetric outcomes.

Patients and methods (Figs 1 and 2)

1. Study design

This is a single-center, prospective, open-label, single-arm, Phase II interventional study that will prospectively enroll eligible participants. All eligible participants will undergo the specified interventions.

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Fig 1. SPIRIT schedule of Fertility-preserving treatment.

https://doi.org/10.1371/journal.pone.0340963.g001

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Fig 2. Fertility-preserving treatment algorithm.

AUC: area under the curve.

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Results and discussion

This study aimed to evaluate the feasibility, oncological safety, and reproductive outcomes of a novel fertility-preserving treatment strategy for women with early and locally advanced cervical cancer without parametrial invasion (FIGO 2018 stage IB2–IB3) who desired to retain their reproductive potential. We hypothesized that neoadjuvant dd-TC could effectively downstage tumors larger than 2 cm to ≤2 cm, thereby facilitating oncologically safe cervical conization with laparoscopic pelvic lymphadenectomy. Notably, the target patients are different from those in the SHAPE, ConCerv, and GOG-278 trials, which initially targeted patients with tumors ≤2 cm [3–6]. This approach is designed to expand fertility preservation options for patients who would otherwise require radical hysterectomy or definitive chemoradiotherapy, both of which result in permanent infertility.

This study incorporates two experimental approaches: NAC using dd-TC and less radical surgery aimed for fertility preservation. While this presents a dual experimental approach, the favorable oncological outcomes of less radical surgery in stage IA–IB1 cervical cancer have already been demonstrated in multiple clinical studies [3–6]. Therefore, the risk of combining less radical surgery with dd-TC, which has a proven high response rate, is considered acceptable provided that strict discontinuation criteria are established. Our protocol incorporates radiologic and histopathologic assessments at multiple time points to ensure patient safety. The primary objective of this study is to determine whether cervical cancers downstaged to <2 cm by NAC can be treated identically to cervical cancers originally <2 cm in size. Importantly, successful uterine preservation in this study is not viewed as an isolated metric but is evaluated in close conjunction with oncological safety endpoints, such as 2-year RFS, to ensure that fertility-sparing does not jeopardize patient survival.

In this protocol, instead of sentinel lymph node biopsy (SLNB) and ultrastaging, we performed radiological lymph node evaluation using PET-CT and MRI after NAC was performed, followed by pathological confirmation via laparoscopic complete pelvic lymphadenectomy after cervical conization. However, we recognize the inherent limitations of imaging-based assessment, as PET-CT and MRI may not fully detect occult micro-residual disease or small-volume nodal involvement after NAC. The rationale for this is that, at the time of the study initiation, only Techne® Phytate (used in the RI method) was covered by public health insurance in Japan, and the SLNB procedure itself had not yet been approved. Although the fluorescent dye tracer indocyanine green was subsequently approved in July 2025, and SNLB approval is expected to follow, there are currently no data regarding the efficacy and safety of performing SLNB either before or after dd-TC. Introducing SLNB would therefore constitute an additional experimental variable. Consequently, the future application of SLNB in this study requires careful discussion.

Patients with FIGO stage IB2–IB3 cervical cancer (FIGO stage 2018), inherently carry an estimated recurrence risk of approximately 10% [15,16]. Accordingly, we prioritized patient safety throughout both the interventions and study procedures. To this end, explicit criteria were established to determine eligibility for proceeding to each subsequent intervention step. Additionally, an interim safety analysis was planned after the enrollment of the first five patients. Depending on the results of this interim evaluation, the study design allowed for protocol modification or, if deemed necessary, trial discontinuation to safeguard participants [17].

The small sample size, single-center design, and relatively short follow-up period (2 years) inherently limit the generalizability of this feasibility study. However, these limitations are acceptable given that the present study was designed as an exploratory investigation to generate preliminary data for future multicenter phase II or III trials. We believe that the present design represents a practical and feasible framework for evaluating the safety and preliminary efficacy of this novel fertility-sparing approach.

This study aims to clarify the oncological safety and obstetric outcomes of this novel fertility-preserving approach, and to identify the types of assisted reproductive technology required. Medically, this study may establish a new treatment paradigm that balances oncologic control with fertility preservation in patients currently deemed ineligible for conservative surgery, thereby improving the quality of life and long-term reproductive outcomes. Furthermore, we intend to assess its social acceptability and determine the extent of patient and societal demand for such fertility-preserving strategies. From a societal perspective, this study may reduce the psychological and economic burdens associated with infertility in young women with cervical cancer, facilitate family planning, and contribute to broader reproductive health equity. These findings may also inform international guidelines and stimulate further research into fertility-sparing strategies for bulky cervical cancer.

Supporting information

Acknowledgments

We thank Editage (www.editage.jp) for their assistance with English language editing.