Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Albumin-Bound Paclitaxel

Cisplatin

Tubulin Modulators

Antimitotic Agents

neoadjuvant chemotherapy + Cadonilimab + Radical hysterectomy/Extrafascial hysterectomy

10 mg/kg (body weight), 60 min, IV. Repeat every 3 weeks for a total of 3 cycles

Cadonilimab

260 mg/m2 for 30 min. Repeat every 3 weeks for a total of 3 cycles.

Paclitaxel-albumin

75-80 mg/m2, IV, 1 mg/min. Repeat every 3 weeks for a total of 3 cycles.

Extrafascial hysterectomy + pelvic lymphadenectomy (or SLN mapping)

Extrafascial hysterectomy

Gang Chen

Jing Chen

Kezhen Li

Ding Ma

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.

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\&#39;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 \&lt;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 \&gt;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\&#39; 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\&#39;s first PD-1/CTLA-4 bispecific tumor immunotherapy that achieves immune cell activation by \&#34;double de-braking\&#34;, 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\&#39;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.

Neoadjuvant Chemoimmunotherapy and Extrafascial Hysterectomy for IB2 Cervical Cancer

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

Defined as the proportion (%) of all patients who met all ConCerV criteria approximately 2-4 weeks after completion of neoadjuvant chemoimmunotherapy. ConCerV criteria: no LVSI, negative margins, squamous cell carcinoma (any grade), adenocarcinoma (common type) or adenosquamous carcinoma (G1 or G2), tumor size ≤2 cm, depth of infiltration ≤10 mm, no metastatic lesions seen.

the proportion of patients who had either complete response or partial response, assessed by independent central reviewers according to RECIST, version 1.1.

according to the criteria for postoperative adjuvant therapy in the 2024 NCCN Guidelines, with tumor size based on size assessed by imaging prior to conization of the uterine cervix, and other pathological findings based on a combination of conization and hysterectomy results

A treatment-emergent adverse events (TEAE) is defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a study drug.

Intraoperative bleeding, vascular injuries, bladder injuries, rectal injuries, and ureteral injuries were measured by the need for suture repair; occlusive nerve injuries were measured by complete severance, and vascular injuries required documentation of the site of injury. Postoperative complications included: cervical stenosis, cervical insufficiency, ureteral/bladder/rectal/vaginal fistula, internal hemorrhage, pelvic infection, lymphocyst, lymphatic fistula, lower extremity edema, lower extremity venous thrombosis, urinary retention, nerve injury, and bowel obstruction.

Pathologic complete response (PCR) refers to the absence of invasive/in situ cancer and/or lymph nodes

the chances of staying free of disease progression for patients with cervical cancer.

The First Affiliated Hospital of China University of Science and Technology (Anhui Provincial)

Women Hospital, School of Medicine, Zhejiang University

Southwest Hospital, China

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Sichuan Cancer Hospital and Research Institute

Qilu Hospital of Shandong University

Beijing Friendship Hospital

Tianjin Medical University

West China Second University Hospital

Xiangya Hospital of Central South University

Gansu Provincial Maternal and Child Health Care Hospital

Zhejiang Cancer Hospital

Shengjing Hospital

Tongji Hospital

Professor

Type A hysterectomy with 1 - 2cm of vaginal cuff plus level 1 pelvic lymph-node dissection according to Querleu and Morrow classification.

Type B2 hysterectomy with 1 - 2cm of vaginal cuff plus level 1 pelvic lymph-node dissection according to Querleu and Morrow classification.

Hysterectomy plus Pelvic Lymph-Node Dissection

Extrafascial Hysterectomy

Modified radical hysterectomy

This study is an open-label, multicenter, randomized, phase II non-inferiority trial (proof of concept study). Its purpose is to evaluate the safety and efficacy of extrafascial hysterectomy plus pelvic-lymph node dissection compared with the standard modified radical hysterectomy in patients with stage IA2-IB1 cervical cancer ≤ 2cm.

The purpose of this study is to evaluate the safety and efficacy of extrafascial hysterectomy compared with modified radical hysterectomy, both plus level 1 pelvic lymph-node dissection, in patients with early stage IA2-IB1 cervical cancer ≤ 2cm. The experimental procedure will be considered to be promising for treatment of stage IA2-IB1 cervical cancer ≤ 2cm if the Bayesian posterior probability of "the difference of the 3-y DFS rate is less than the non-inferiority margin of 5%" is at least 50%. Thus, using this proof of concept design, the planned sample size is 40, with 20 cases per arm, which provides 72% chance of satisfying the above criteria, under the hypothesis that the lowest 3-y DFS rate in each arm is 90%. As required, adjuvant therapy will include cisplatin-based chemo-radiation or pelvic radiation alone (EBRT +/- intracavitary brachytherapy) indicated according to the #GOG92 and #GOG109 criteria.

Proof of concept design (phase II non-inferiority trial)

Due to the surgical nature of the study, only participants were masked to treatment allocation

LESs Surgical Radicality for EaRly Stage Cervical Cancer

A Proof of Concept Non-inferiority Trial Evaluating the Safety and Efficacy of Extrafascial Hysterectomy Plus Pelvic Lymph-node Dissection in Patients With Stage IA2-IB1 Cervical Cancer ≤ 2cm

QoL according to EORTC C30 questionnaire (v3.0)

Cisplatin-based chemo-radiation or pelvic radiation alone (EBRT +/- intracavitary brachytherapy) indicated according to the #GOG92 and #GOG109 criteria

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant Chemoimmunotherapy and Extrafascial Hysterectomy for IB2 Cervical Cancer	NCT06289751	Cervical Cancer Neoadjuvant Che... Radical Hystere... Fertility Prese...	Cadonilimab Paclitaxel-albu... Cisplatin Extrafascial hy...	18 Years - 70 Years	Tongji Hospital
LESs Surgical Radicality for EaRly Stage Cervical Cancer	NCT02613286	Uterine Cervica...	Extrafascial Hy... Modified radica...	18 Years - 70 Years	Hospital de Câncer de Pernambuco
LESs Surgical Radicality for EaRly Stage Cervical Cancer	NCT02613286	Uterine Cervica...	Extrafascial Hy... Modified radica...	18 Years - 70 Years	Hospital de Câncer de Pernambuco
Neoadjuvant Chemoimmunotherapy and Extrafascial Hysterectomy for IB2 Cervical Cancer	NCT06289751	Cervical Cancer Neoadjuvant Che... Radical Hystere... Fertility Prese...	Cadonilimab Paclitaxel-albu... Cisplatin Extrafascial hy...	18 Years - 70 Years	Tongji Hospital

Spots Global Cancer Trial Database for extrafascial hysterectomy