Intraoperative frozen section pathology of vaginal margin in radical hysterectomy on the prognosis and quality of life for patients with IB2–IIA2 cervical cancer: study protocol for a multicenter randomized controlled trial

Cervical cancer (CC) is the most common gynecological malignancy in women and the leading cause of cancer death in some developing countries [1]. Despite improvements in screening and prevention, CC remains a significant cause of morbidity and mortality [2]. In the last 2 decades notable advances in surgical procedures, external radiation therapy (RT), brachytherapy techniques, and chemotherapy have led to improved prognosis of CC patients [3]. Significant improvement in cancer treatment increases the number of cancer survivors who face long-term consequences on their sexual and general quality of life (QoL), especially with the application of minimally invasive surgery for CC [4, 5]. Radical hysterectomy (RH) allows tumor removal and identification of risk factors for tailor adjuvant treatments and studies have indicated that the shift from minimally invasive to open RH did not affect 90-day surgery-related morbidity [6].

To date, intraoperative frozen pathology exam of vaginal margin in RH is rarely assessed and there is still no consensus on the length of vaginal resection in RH. To be specific, patients in stage IB2 to IIA2 should undergo a RH to remove at least 3 centimeters of the lower edge of the CC in vagina according to National Comprehensive Cancer Network (NCCN) guidelines.

Parametrial invasion, positive lymph nodes, pelvic and vaginal margins metastasis were high risk factors for CC metastasis. Among them, the positive vaginal margin was an independent risk factor for metastasis of cancer recurrence of vaginal stump. Previous evidence has demonstrated that metastasis rate in CC patients was higher while patients with negative vaginal margins rarely have recurrence of vaginal stump, implying the potential use of the vaginal margin status to reduce surgical complications and the recurrence rate of vaginal stump. Given that intraoperative frozen pathology can provide relatively accurate pathological results quickly during surgery, we considered it as an ideal method to evaluate the involvement of vaginal margins, thus predicting the condition of further vaginal resection. However, there is yet no prospective randomized study investigating the value of intraoperative frozen pathology exam on vaginal margins for determining whether further vagina resection is necessary. In this protocol, we aim to conduct prospective randomized controlled trials (RCTs) to compare the prognosis and QoL between patients who undergo RH with and without extra further vagina resection based on intraoperative frozen section pathology of vaginal margin. Furthermore, we will explore the value of intraoperative frozen pathology exam on vaginal margins to help decide whether further vagina resection is necessary so that low-risk patients could avoid unnecessary further vagina resection while high-risk patients would receive effective treatment to minimize the risk of postoperative RT.

Intraoperative frozen section pathology is highly correlated with the final pathological evaluation after surgery. To be specific, patients in stage IB2 to IIA2 should undergo a RH to remove at least 3 centimeters of the lower edge of the CC in vagina according to NCCN guidelines. RH plus pelvic node dissection are main treatment methods for patients with early-to-mid-stage CC. During the last decade, growing evidence supports the adoption of a minimally invasive approach [4, 7]. However, the radicality of surgery directly affects the extent of sexual dysfunction [8]. Moreover, the direct effects of RT on the vaginal tissues can have lasting sequelae including vaginal dryness, vaginal stenosis, fragility, and dyspareunia [9, 10]. Even mild or Grade 1 vaginal tissue effects can have significant negative impact on sexual function and QoL [10]. The EMBRACE I (external beam radio chemotherapy and MRI based adaptive brachytherapy in locally advanced CC) cohort showed that approximately 90% of patients exhibited at least Grade 1 vaginal mucosal changes [11]. Epithelial loss can persist for months and the process of re epithelialization may take up to 2 years and may never fully regenerate [12]. Due to the difference in vascular supply, the distal vagina is more sensitive to radiotherapy compared to the proximal upper and mid-third vagina [13].

There is strong evidence supporting the use of RT with or without chemotherapy in both definitive and postoperative settings. Brachytherapy is an essential part of definitive management and volumetric planning is recommended. Intensity modulated radiotherapy may be used for the reduction of acute and late toxicity. Radiation remains an essential component for women with CC to achieve cure [14]. Traditionally, positive pelvic lymph node, positive surgical margins, and LVSI are the high-risk factors based on which a recommendation for adjuvant radiotherapy and chemotherapy is made. However, the impact of combining pelvic external irradiation with brachytherapy on OS and DFS is unclear due to inconsistent reports. The rationale for adjuvant brachytherapy is based on the premise that residual disease in vaginal stump is the primary cause of local recurrence and treatment failure, and brachytherapy may improve local tumor control and prevent development of metastases. Yu et al. [15] reported that the combination of external beam RT and brachytherapy can improve local-regional recurrence free survival in post-operative CC patients with risk factors other than positive stump, especially in those meeting Sedlis criteria, but did not show a significant OS benefit. Nonetheless, due to the limitations in technology and equipment, many hospitals in China have yet to offer brachytherapy as treatment for CC. External pelvic RT is currently the main treatment for CC, and is used frequently in China.

Only a limited number of studies support vaginal brachytherapy (VBT) boost to external beam radiotherapy (EBRT) in the adjuvant treatment of CC. Gultekin’s study assessed the impact of the addition of VBT boost to adjuvant EBRT on oncological outcomes and toxicity in patients with CC and found that with a median follow-up time of 56 months (range 33–90), the 5-year OS rate was 82%. There was no difference in 5-year OS (87% vs. 79%, p=0.11), recurrence-free survival (74% vs. 71%, p=0.49), local recurrence-free survival (78% vs. 76%, p=0.16), and distant metastasis-free survival (85% vs. 76%, p=0.09) rates between treatment groups. Therefore, there was no benefit of addition of VBT to EBRT in patients with positive surgical margins. Therefore, adding VBT boost to EBRT did not provide any benefit in local control or survival in patients with CC [16]. Ragab’s study also found that additional utilization of VBT with EBRT was associated with neither OS nor cancer-specific survival [17].

A study primarily involving stage I CC patients (73%) showed that, after adjusting for other covariates, the QoL of patients who received RT, with or without chemotherapy, was significantly lower than that of patients who received surgery alone [18]. Therefore, the surgery should strive to remove the affected vagina as much as possible to achieve negative vaginal margins, which can reduce the adverse effects of postoperative RT on the remaining vagina, and prevent the recurrence and metastasis of lesions in patient with CC.

Based on the above discussion, further randomized clinical trials comparing and analyzing different treatment options and strategies for CC are mandatory. We designed this RCT in which a 3 cm vaginal wall resection will be performed. If frozen pathology shows positive vaginal margins, an additional 1 cm of tissue will be removed laterally until intraoperative frozen pathology indicates negative vaginal margins.

To confirm the results, negative margins should be obtained while minimizing the extent of vaginal resection for preventing sexual dysfunction. This reduces the risk of requiring brachytherapy for positive vaginal margins, while avoiding the disadvantage of traditional radical surgery, which involves removing a longer segment of the vaginal wall and results in a shorter residual vaginal length that may affect sexual QoL. Based on large-scale prospective RCT with multiple centers, the safety and effectiveness of this method will be evaluated to provide higher-level clinical evidence support.