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Abstract
Background Concurrent chemoradiotherapy is the first-line treatment for FIGO stage IIB cervical cancer. Neoadjuvant chemotherapy followed by radical surgery may provide another treatment option.
Primary objective To compare the therapeutic outcomes of neoadjuvant chemotherapy followed by surgery with cisplatin-based concurrent chemoradiotherapy for stage IIB cervical cancer.
Study hypothesis We hypothesize that the therapeutic effect of neoadjuvant chemotherapy combined with surgery and risk-adapted adjuvant treatment will be superior to that of concurrent chemoradiotherapy in stage IIB cervical cancer.
Trial design Patients with stage IIB cervical cancer will be randomized 1:1 to neoadjuvant chemotherapy followed by surgery (Arm A) or concurrent chemoradiotherapy (Arm B). In arm A, patients will receive three cycles of paclitaxel and cisplatin followed by a type C radical hysterectomy and pelvic ±paraaortic lymphadenectomy. Patients showing progression after neoadjuvant chemotherapy will be referred to concurrent chemoradiotherapy. Adjuvant therapy will be recommended according to the presence of pathological risks. In Arm B, all patients will receive definitive concurrent chemoradiotherapy, including external beam pelvic radiotherapy combined with concurrent weekly cisplatin followed by brachytherapy.
Major inclusion/exclusion criteria Patients between 18 and 60 years with histologically confirmed, untreated stage IIB cervical squamous carcinoma, adenocarcinoma, or adeno-squamous carcinoma.
Primary endpoint The primary endpoint is 2-year disease-free survival.
Sample size An estimated sample size of 240 is required to fulfill the study objectives.
Estimated dates for completing accrual and presenting results As of February 2020, 115 eligible patients from four institutions have been enrolled. Enrollment is expected to be completed by December 2022.
Trial registration number ClinicalTrials. gov identifier: NCT02595554.
- cervical cancer
- radiotherapy
- surgery
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Introduction
For women with cervical cancer, FIGO stage IIB is considered a locally advanced disease and some might consider it an unresectable disease. The definition of stage IIB has not changed since 1989.1 The diagnosis criterion of stage IIB is more subjective than those of other stages because the parametrial infiltration, which refers to a histopathological status, must be evaluated primarily by palpation. Such subjective methodology for assigning the stage may lead to inaccuracy in diagnosis and increase the difficulty of treatment planning.
Despite potential heterogeneity among stage IIB patients, the treatments for these patients are consistent and generally undergo cisplatin-based concurrent chemoradiotherapy.2 However, although concurrent chemoradiotherapy can lead to acceptable oncological control in the majority of patients, concerns remain in several aspects. First, young patients will suffer from ovarian failure unless an ovarian transplantation is performed before radiation.3 In addition, persistent vaginal fibrosis may adversely affect sexual activity and may cause considerable distress.4 Next, the true pathologic status of region lymph nodes is largely unknown, so it is impossible to formulate precise individualised radiotherapy treatment plans. Also, in patients who show progression or recurrence after primary radiation, the subsequent management may be challenging, as radiation-induced pelvic fibrosis not only decreases the possibility of salvage surgery but also reduces the efficacy of chemotherapy. Finally, in many developing countries, the devices and technicians for radiotherapy are insufficient, with less than one radiotherapy equipment per million population.5 All these factors contribute to a strong demand for alternative therapy for patients with stage IIB cervical cancer.
Neoadjuvant chemotherapy followed by radical surgery may be an alternative to concurrent chemoradiotherapy for select stage IIB patients. This surgery-based protocol allows for pathological assessment of parametrial and lymphatic involvement and provides additional pathologic information for planning adjuvant treatment. Oncological control may be more efficient if the tumor burden can be decreased before adjuvant radiotherapy. Furthermore, in patients showing complete response to neoadjuvant chemotherapy, radiotherapy may be completely avoided based on reduced postoperative pathological risks, which may improve patient quality of life while preserving a possible therapeutic option for future recurrence. Nevertheless, the disadvantages of neoadjuvant chemotherapy and radical surgery are also noteworthy. Unexpected infiltration and difficulty may be encountered during surgery, which may cause severe blood loss or tumor residue.6 In addition, combining the use of neoadjuvant chemotherapy, radical surgery, and adjuvant chemoradiotherapy will significantly increase the medical cost and treatment-associated morbidities, such as lymphedema, myelosuppression, urinary and rectal fistula, rectal stricture, and bladder dysfunction.7
The data on the survival and morbidity of surgery-based treatment for stage IIB patients remains limited.8–12 The Chinese South-East-Middle (CSEM) Cooperative Group of Gynecological Oncology is an unofficial organization initiated by several top gynecological oncologists in China. CSEM has expanded rapidly in recent years and has incorporated dozens of high-level hospitals from different regions of China to work together for clinical trials. In this report, we present the protocol of the sixth trial of the CSEM Group (CSEM 006), which compares the therapeutic outcomes of neoadjuvant chemotherapy combined with surgery to cisplatin-based concurrent chemoradiotherapy for patients with stage IIB cervical cancer.
Methods
Trial design
CSEM 006 is an open-label, multicenter, randomized controlled trial. The primary goal is to verify if surgical-based treatment is a superior alternative to concurrent chemoradiotherapy for stage IIB cervical cancer patients. Patients with FIGO stage IIB cervical cancer will be randomized 1:1 into either neoadjuvant chemotherapy followed by radical surgery (Arm A) or definitive concurrent chemoradiotherapy (Arm B). This trial has been registered at the ClinicalTrials.gov database (NCT02595554). The study schema is shown in Figure 1.
The study scheme of CSEM 006.
All patients in the CSEM 006 study will be initially evaluated for parametrial involvement by at least two senior gynecological oncologists. In arm A (neoadjuvant chemotherapy followed by radical surgery), patients will receive three cycles of paclitaxel (150 mg/m2) and cisplatin (70 mg/m2) in a 3- week cycle. Tumor response will be evaluated by gynecological examination before each cycle and by MRI after 3 cycles. Patients will be considered to have progressive disease if they meet any of the following criteria: maximum diameter of cervical tumor increases more than 30%; parametrial infiltration increase; moderate or severe dilation of ureter; suspected new pelvic or paraaortic lymph node metastasis (short axis >1 cm); or new distant metastases.
If progression is confirmed, the patient will be re-assessed for surgical treatment or directly referred for standard concurrent chemoradiotherapy. For patients without progression, standard type C radical hysterectomy and pelvic lymphadenectomy will be performed in combination with or without salpingo-oophorectomy. Paraaortic nodes may also be sampled in patients with initial tumor diameter ≥4 cm, high histological grade, or positive nodes accidentally found during operation. However, radical surgery may be abandoned and the patient having a disposition to concurrent chemoradiotherapy if the parametrial status is evaluated as unresectable. Recently, we excluded the laparoscopic approach for radical hysterectomy in consideration of the findings from the Laparoscopic Approach to Cervical Cancer (LACC) study.13 In pathological evaluation, the parametrial tissue and vaginal margins will be independently sampled and examined.
Adjuvant treatment after radical surgery will be determined according to postoperative pathological factors. High pathological risks include lymph node metastasis, positive surgical margin, and parametrial infiltration, while intermediate risks include large tumor volume (≥4 cm), deep stromal invasion, and lymphovascular space involvement. Postoperative concurrent chemoradiotherapy will be planned if the patient has either of the high-risk factors, or more than one intermediate-risk factor. In addition, patients with deep stromal invasion only will be submitted to radiotherapy alone. Patients without any of the pathological risks will receive 3–4 cycles of paclitaxel and cisplatin regimen only.
In Arm B, definitive concurrent chemoradiotherapy will be planned for all patients, including external beam pelvic radiotherapy (point A: 50 Gy/5~6 weeks, point B: 55~60 Gy/6~7 weeks) combined with concurrent weekly cisplatin (30~40 mg/m2) chemotherapy followed by brachytherapy (30~35 Gy/5~6 weeks). The radiation field for retroperitoneal nodes will be adjusted in accordance with dynamic imaging evaluations. Ovarian transplantation will be performed only when it is considered medically necessary and requested by the patient.
After completion of all treatments, patients will be followed up at 30 days and then every 3 months in the first 2 years and 6 months in the next 3 years.
Participants
Eligible patients are women between 18 and 60 years of age with histologically confirmed, untreated FIGO stage IIB cervical squamous carcinoma, adenocarcinoma, or adeno-squamous carcinoma. The assignment of stage IIB disease will be performed by at least two senior gynecological oncologists and MRI examination. Expected survival time at initial diagnosis should be >3 months. All patients should be told the details of the trial protocol and sign informed consents before treatment.
Exclusion criteria include: presence of other life-threatening disease; previous anti-cancer therapy including surgery, chemotherapy, and radiotherapy; abnormal testing in function of liver, kidney, or blood; history of organ transplantation, mental disease, brain dysfunction, or drug abuse; pregnant patients; and suspected pelvic or paraaortic lymph node with short axis >1 cm, or evidence of distant metastasis on imaging examination.
Outcomes
The primary objective of this study is disease-free survival at 2 years. Secondary objectives include quality of life, surgical morbidity and mortality, responses to neoadjuvant chemotherapy, rate of positive margin (parametrial or vaginal) on surgical specimens, medical cost, and overall survival. Quality of life will be assessed with European Organization for Research and Treatment QLQ-C30 at the time of baseline screening, 1 month, and 1 year after all planned treatment completed. Any intraoperative or postoperative complications such as severe blood loss (>800 mL), injury of ureter, bladder or rectum, lymphatic fistula, deep venous thrombosis, and lower-extremity lymphedema, will be recorded.
Randomisation and blinding
Patients will be randomized 1:1 into either neoadjuvant chemotherapy followed by radical surgery or definitive chemoradiation. The randomization sequence was made at Sun Yat-sen University Cancer Center by a computer-generated random number code and sectioned with 20 per fraction. The group allocations will be independently carried out in different institutions using the central envelope method, stratified by diameter of cervical tumor (<4 cm and ≥4 cm). Details of the randomizations were maintained in sequentially numbered, opaque, sealed envelopes prepared by a statistician without clinical involvement in the trial.
Sample size and statistical methods
Based on available data,8–12 the reference 2-year progression-free survival in stage IIB cervical cancer treated by concurrent chemoradiotherapy is estimated as 75%. We planned a recruitment of 240 patients in 5 years and a 3-year additional follow-up after the completion of treatment to record disease progression or death. This calculation is based on the assumption that there will be a 10% benefit in 2-year disease-free survival for the neoadjuvant chemotherapy and surgery (85%) group compared with the concurrent chemoradiotherapy (75%) group with an alpha of 0.05 and a power of 80%. In the two arms, there is an equal number of patients and an estimated dropout rate of <10%.
The hazard ratios of potential prognostic factors will be analyzed using the Cox proportional hazards model. The chemoradiotherapy-associated morbidities of the two arms will be compared using the Fisher exact test or χ2 test, while the surgical complications will be presented only. The quality of life in the two arms will be compared using the t-test or variance analysis.
The final analyzes will contain intention to treat and pre-protocol cohorts. The intention to treat cohort includes patients who fulfill all inclusion criteria and have at least one follow-up interview whatever the treatment received. The per-protocol cohort includes patients who complete all planned treatments without violations of trial protocol. The primary and secondary objectives will be separately measured in proper cohorts, and may be stratified according to patients’ age, primary tumor diameter, response to neoadjuvant chemotherapy, and degree of parametrial infiltration.
The trial has two safety margins. The first one is the recurrence rate in the neoadjuvant chemotherapy/surgery arm, which is set as 50%. The second safety margin is the rate of treatment alteration due to progression after neoadjuvant chemotherapy, which reflects the unfeasibility of surgery-based protocol and is set as 25%. The safety margins will be examined when the first 30, 60, and 120 patients complete the first-year follow-up, and the study will be terminated if either of the safety margins is exceeded. Up to February 2020, 115 eligible patients from four institutions have been enrolled. We anticipate enrollment will be completed by December 2022.
Discussion
Several observational studies have reported that the 5-year survival rates for stage IIB cervical cancer patients undergoing surgery-based treatment ranged from 64.0% to 85.2%, which is comparable to those of patients treated by definitive concurrent chemoradiotherapy (64.0%–81.1%).8–11 Lee et al reported a group of 192 Korean patients treated with surgery- or radiotherapy-based management.8 They found that neoadjuvant chemotherapy prior to radical surgery could improve pathological prognostic factors, however, the rates of adjuvant radiotherapy and 5-year survival remained unchanged. Chai et al reported a series of 438 Chinese patients with stage IIB cervical cancer treated with surgery- (n=148) or radiotherapy- (n=290) based protocols and found that neither the overall nor progression-free survival were significantly different.9 However, all these studies were retrospective and therefore selection bias might exist. For example, doctors might be prone to choose neoadjuvant chemotherapy and surgery for patients with better performance status or less parametrial infiltration that was not considered as a variable in analyzes of matched cohorts. In addition, the regimens for neoadjuvant chemotherapy or adjuvant therapy in these studies were inconsistent and not contemporary.
A recently published prospective, randomized trial from India showed a significant decrease in disease-free survival of locally advanced cervical cancer treated by neoadjuvant chemotherapy (paclitaxel and carboplatin) combined with surgery,12 which has led many to question the rationale of surgery-based protocols. However, in that trial, patients with two or more intermediate risk factors received adjuvant radiotherapy alone without further chemotherapy, while those with only one intermediate risk factor received neither radiotherapy nor chemotherapy. It is also noteworthy that nearly half of the patients in the neoadjuvant chemotherapy group did not receive any treatment after surgery, which may be inadequate for patients with stage IIB cervical cancer. To the best of our knowledge, no randomized controlled study has yet been designed exclusively for stage IIB cervical cancer to compare the outcomes of surgery- and radiotherapy-based treatments.
In CSEM 006 we adopted an intensive policy for planning postoperative adjuvant therapy, with the consideration that the pathological risk factors may have been reduced or covered up due to neoadjuvant chemotherapy. This policy may increase the treatment-associated morbidities: however, it may also provide patients with higher chance of cure for their disease. Based on previous studies, the toxicity of additional chemotherapy is expected to be acceptable.14 15 We will also compare the quality of life and treatment-associated morbidity in the two arms, which are important concerns in this clinical setting.
The accuracy of imaging examinations in assessing parametrial infiltration and lymph node metastasis is another endpoint in this trial. The diagnosis by imaging examination will be compared with the results of physical examination. Unfortunately, it will be impossible to set a standard reference for diagnosis of parametrial infiltration or lymph node metastasis since the pathological results are obtained after neoadjuvant chemotherapy. Nevertheless, we can analyze the consistency and relationship of clinical and imaging examinations, and their roles in the prediction of therapeutic effects, surgical morbidity, and feasibility.
Certainly challenges still lay ahead for CSEM 006. Unlike those trials for single intervention or drugs, CSEM 006 involves a combination of different therapeutic modalities and is liable to generate protocol deviations due to the complexity, uncertainty, and long-duration of treatments. On the other hand, such a complex protocol also puts forward higher requirements for participant centers where experienced, specialized multi-disciplinary teams for clinical trial should be prepared.
The primary aim of the CSEM 006 study is to determine whether neoadjuvant chemotherapy followed by radical surgery can serve as an alternative to concurrent chemoradiotherapy for FIGO stage IIB cervical cancer. In addition to this, we also expect to identify a subgroup of stage IIB patients that may benefit from surgery-based treatment the most. These patients may be of younger age and good performance status, bear small primary tumor, less aggressive parametrial infiltration, imaging negative for nodal diseases, and/or demonstrate a good response to neoadjuvant chemotherapy.
References
Footnotes
HT and HH contributed equally.
Contributors All the authors will participate in the trial and lead it in their respective institution. HT and HH drafted the manuscript and J-H L revised it critically for important intellectual content. QL provided statistical support. All authors validated the final version of the submitted manuscript.
Funding This study was funded by the Health and Medical Cooperation Innovation Special Program of Guangzhou Municipal Science and Technology (NO. 158100075).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
Data availability statement All data relevant to the study are included in the article