Neoadjuvant Chemoimmunotherapy and Extrafascial Hysterectomy for IB2 Cervical Cancer

Cervical Cancer Clinical Trial

Official title: Neoadjuvant Chemotherapy Plus Cadunilizumab Followed by Extrafascial Hysterectomy for FIGO Stage IB2 Cervical Cancer: a Multicenter, Single-arm, Phase 2 Trial.

Status Not yet recruiting

Clinical Trial Summary

This study is an exploratory clinical trial to investigate the feasibility of neoadjuvant chemoimmunotherapy plus extrafascial hysterectomy and pelvic lymph node dissection in patients with stage IB2 (2018 FIGO) cervical cancer and to observe the response rate to treatment, adverse effects and complications, and to assess the survival rate of patients.

Clinical Trial Description

In China, cervical cancer is the malignant tumor of the female reproductive tract with the highest incidence rate, and there will be about 112,000 new cases of cervical cancer and 14,000 deaths in China in 2022, with the number of incidence cases accounting for 1/5 of the global total. In recent years, with the early detection of cervical cancer and the wide application of HPV vaccine, more and more patients have been diagnosed at an early stage, which has prompted researchers to conduct in-depth studies and investigations into the treatment of early cervical cancer. to conduct in-depth studies and investigations. For a long time, the standard treatment for early-stage cervical cancer has been wide radical hysterectomy combined with pelvic lymph node dissection, with satisfactory results and 5-year overall survival rates ranging from 73% to 98%. The core of radical hysterectomy is wide hysterectomy, which ensures complete removal of the cervix and uterine body and achieves negative margins. However, this procedure is associated with high complications. In addition to ligamentous penetration, there are important neurovascular vessels in the parietal tissues, which will increase the risk of intraoperative complications such as bleeding, nerve injury, urinary tract and bowel injury, etc. Postoperative complications such as urinary retention, urinary incontinence, defecation difficulties, constipation, and sexual dysfunction may also occur in the immediate and long-term future, which will cause serious problems to the patient's quality of life, especially to the family harmony and social role of young patients. Realization brings serious disturbances.

It has been controversial whether radical hysterectomy is necessary to remove paracervical tissue in early-stage cervical cancer. Studies have reported that the probability of paracervical infiltration is less than 1% in patients with tumors less than 2 cm in diameter, no lymphovascular invasion, and no metastasis in the pelvic lymph nodes, which provides a theoretical basis for conservative surgery. Extrafascial total hysterectomy is a conservative surgical procedure that does not involve removal of parietal tissue and may be a safe and effective alternative to radical hysterectomy as an option for patients with unreserved fertility needs in early-stage, low-risk cervical cancer. In 2018, researchers used the SEER database to analyze and collect information from the period of January 1998 to December 2012 on patients who were diagnosed from January 1998 to December 2012 who were <45 years of age with stage IB1 cervical cancer, comparing the two surgical modalities of performing non-radical excision and radical excision for cervical cancer, showed no significant difference in disease-free survival between the two groups. Thus, radical surgery did not show better oncologic outcomes compared to cervical conization, hysterectomy, or hysterectomy alone in patients with stage IB1 disease. Based on the ConCerV trial, the first multicenter prospective trial to evaluate the use of conservative surgery for early-stage, low-risk cervical cancer, the 2023 NCCN guidelines suggest that early-stage, low-risk cervical cancer should be treated with radical hand surgery if it meets the ConCerv criteria (tumor size ≤2 cm, depth of infiltration ≤10 mm, and no metastatic lesions on imaging), a conservative surgical approach is feasible, i.e, cone excision with negative margins + pelvic lymph node dissection or SLN mapping for those who will preserve fertility, and total extrafascial hysterectomy + pelvic lymph node dissection or SLN mapping for those who will not preserve fertility. In particular, at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, an international randomized controlled phase III trial (SHAPE) initiated by the Canadian Cancer Trials Group compared the prognostic profile of patients with early-stage, low-risk cervical cancer who underwent radical hysterectomy and pelvic lymph node dissection with those who underwent hysterectomy and pelvic lymph node dissection alone, which showed that patients who underwent simple hysterectomy had a non-inferior 3-year pelvic recurrence rate to those who underwent radical hysterectomy, and that the simple hysterectomy group had a significantly lower incidence of acute adverse events and postoperative urinary retention and improved vaginal function. The above clinical trials provide strong clinical evidence for conservative surgery for early-stage, low-risk cervical cancer and have led to a series of major guideline updates as well as an expansion of our focus to conservative surgical management of patients with early-stage cervical cancer at stage 1B1 or higher.

For stage IB2 cervical cancer with tumor diameters of 2-4 cm, the current standard of care is radical hysterectomy, with a 5-year recurrence-free survival rate of 87%.An analysis of the 2018 SEER database showed that tumor lesion size ≥2 cm was an independent risk factor for disease progression, and other studies and literature reviews have shown that lesion size is one of the most important predictors of prognosis, with a statistically significantly higher risk of recurrence for lesions ≥2 cm. This may be related to the fact that larger tumor diameters simultaneously increase the proportion of vascular-positive, deep interstitial infiltration, etc., thereby increasing postoperative risk factors and the proportion of patients requiring adjuvant therapy after surgery. Thus, current guidelines only recommend non-extensive total extrafascial hysterectomy for low-risk early-stage cervical cancer, which has not been extended to patients with stage IB2, and direct conservative surgery in this population is rarely reported in the literature.

Neoadjuvant chemotherapy is commonly used in the preoperative treatment of patients with cervical cancer with local tumor diameter >4 cm. Neoadjuvant chemotherapy can reduce the size of the tumor lesion, decrease the risk of deep mesenchymal infiltration of paracervical tissue, paracervical metastasis, and positive margins for lymph node metastasis, increase the feasibility of radical surgery, and decrease the proportion of postoperative adjuvant therapy. There is increasing data to support that in patients with tumors ≥2 cm in diameter, cervical conization or radical hysterectomy after neoadjuvant chemotherapy preserves fertility and that the proportion of patients with intermediate and high risk factors requiring postoperative radiotherapy decreases significantly, with better oncologic and fertility outcomes. This also brings a new dawn for patients with stage 1B2 cervical cancer to undergo conservative surgery. With the rapid development of immunotherapy phase and treatment, the neoadjuvant treatment modality in combination with immune checkpoint inhibitors can significantly improve the EFS, pathological remission rate, etc. in numerous solid tumors. Immunotherapy has achieved remarkable results in the treatment of advanced cervical cancer, and the treatment strategy of immune checkpoint inhibitors combined with chemotherapy has become the first-line treatment for advanced or recurrent PD-L1 expression-positive cervical cancer, and cimeplizumab has been added as a preferred regimen for the second-line medication for recurrent metastatic cervical cancer in the new NCCN guideline of 2024, which is not limited to PD-L1 expression-positive population. The latest studies in cervical cancer have shown that the introduction of immunotherapy into the neoadjuvant treatment phase greatly improved the pathological remission rate of patients with locally advanced cervical cancer (IB3, IIA2 and tumor diameter ≥4cm stage IIB/IIIC1r) to 38%, and further analysis of the patients' postoperative pathological factors showed that the incision margin positivity rate was only 1. 2%, and the rate of paracervical tissue infiltration was only 2.5%, meanwhile, 69% of the neo-adjuvant immunotherapy tumor diameter ≤2 cm, and more than 50% of patients had deep mesenchymal infiltration ≤1/3. Mechanistically, more and more studies have shown that chemotherapy has an immunomodulatory effect, and chemotherapeutic agents commonly used in neoadjuvant chemotherapy for cervical cancer, including cisplatin and paclitaxel, can modulate the effector T-cell response by increasing tumor antigenicity, inducing the death of immunogenic cells, disrupting the immunosuppressive pathway, and enhancing the effector T-cell response to regulate antitumor T-cell responses. Further studies have shown that sequential administration of chemotherapy followed by immunotherapy preserves the ability of PD-L1 inhibitors to activate the immune response and may be a superior dosing strategy. Therefore, based on the application of neoadjuvant chemotherapy in conservative surgery for cervical cancer and the latest findings and theoretical basis of immunization combined with neoadjuvant chemotherapy, we expect to achieve conservative surgical treatment for patients with stage IB2 cervical cancer through the application of neoadjuvant immunotherapy in stage IB2 cervical cancer by reducing the risk factors of patients to achieve therapeutic ConCerV criteria that meet the criteria for extrafascial total hysterectomy.

Cardunolizumab is the world's first PD-1/CTLA-4 bispecific tumor immunotherapy that achieves immune cell activation by "double de-braking", i.e., indirectly releasing and activating immune cells by simultaneously inhibiting the two immune signaling checkpoint pathways of PD-1 and CTLA-4, thereby enhancing immune activity and strengthening the anti-tumor effect. Anti-tumor activity. Cadunilizumab, the world's first new dual antibody drug for tumor immunotherapy and the first new bispecific antibody drug in China, was approved by the State Drug Administration in June 2022 for the treatment of patients with recurrent or metastatic cervical cancer who have previously failed platinum-containing chemotherapy. In the Phase II clinical trial, the anti-tumor activity of cardunculus monotherapy was encouraging and the long-term survival benefit was significant. At a median follow-up of 14.6 months, the objective remission rate of cardunculus monotherapy in patients with advanced cervical cancer who had failed prior platinum-containing chemotherapy was 32.3%, with 14.1% (14 cases) achieving complete remission, 18.2% (18 cases) achieving partial remission, and the median OS had not yet been reached, with an 18-month OS rate of 51.2%. In addition, cardunolizumab has demonstrated excellent efficacy and safety in clinical trials in a variety of tumors, including hepatocellular carcinoma, lung cancer and neuroendocrine tumors.

This study is an exploratory clinical trial based on recent studies of immune checkpoint inhibitors and neoadjuvant chemotherapy in patients with stage IB2 (2018 FIGO) cervical cancer, to evaluate the feasibility of extrafascial hysterectomy plus pelvic lymph node dissection in patients after cardunilizumab in combination with platinum-containing chemotherapy as neoadjuvant immunotherapy, to observe the treatment response rate, adverse effects and complications, and to assess patient survival. ;

Related Conditions & MeSH terms

• Cervical Cancer
• Fertility Preservation
• Radical Hysterectomy
• Uterine Cervical Neoplasms

• NCT number: NCT06289751
• Study type: Interventional
• Source: Tongji Hospital
• Contact: Gang Chen
• Phone: 086-027-8362
• Email: gumpc@126.com
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 1, 2024
• Completion date: January 1, 2031