The study is being conducted in China. The study protocol was approved by Shanghai Jiaotong University School of Medicine affiliated with Ruijin Hospital Ethics Committee (N-2018-239). All the group members have GCP certificates. Any recorded results will be anonymized in our study database.
This is a prospective, randomized, open-labeled, multicentered phase III study. The 2-year progression-free survival in stage IIB-IVA cancer patients treated with CCRT is approximately 65% according to the literature. The desired 2-year progression-free survival treated with NACT followed by CCRT will be 80%. We assume an 8% loss to follow-up, and we seek a power of 80% at a two-sided significance level of 0.05. To detect a 15% difference, we will need 150 patients (per group). Based on an institutional volume of 80 patients per year and 20 patients per year in other centers, this trial will require 3 years to complete the recruitment of 300 patients. The objective is to explore the overall survival rate, disease-free response rate, response rate 3 months after treatment completion, survival outcomes, quality of life and severity of side effects of dose-dense NACT followed by CCRT. The potential biomarkers for predicting treatment response will be studied.
The study was designed by a team of researchers from Shanghai Jiaotong University Medical School affiliated with Ruijin Hospital. It is being conducted at 5 sites in China: Shanghai Jiaotong University Medical School affiliated with Ruijin Hospital, Renji Hospital, The First People’s Hospital, Shanghai Tongji University affiliated with Oriental Hospital, and Fujian Medical University affiliated with Union Hospital.
Our group and its individual members have substantive experience in conducting studies on LACC. We have a multidisciplinary group to assess the stage and status of the patients precisely, to assure the patients meet the inclusion criteria, to treat the patients and monitor the side effects, and to follow the patients on a regular basis. Researchers will manage the whole process, and experienced statisticians will participate in the study design and data analysis.
We plan to recruit adult patients who have cervical cancer with the following inclusion and exclusion criteria.
Each participant must meet all the following criteria to participate in this study: (1) age, 18~70 years; (2) histologically confirmed squamous carcinoma, adenocarcinoma or adeno-squamous carcinoma of the cervix; (3) FIGO (2009) stage IIB-IVA as evaluated by two senior gynecological oncologists; (4) performance status: Eastern Cooperative Oncology Group (ECOG) ≤2; (5) body weight ≥40 kg; (6) adequate bone marrow function (WBC ≥4.0×109/L, neutrophils ≥2.0 × 109/L, HB ≥70 g/L and platelets ≥100.0×109/L); adequate liver function (serum bilirubin, ALT, AST and ALP ≤1.0 N); adequate renal function (urea nitrogen ≤1.0 N, Cr≤1.0 N); (7) no active tuberculosis; (8) no pregnancy or lactation; (9) negative HIV test; and (10) written informed consent before enrollment and before initiation of any procedure.
Individuals who meet any of the following criteria will be excluded from the study: (1) previous pelvic malignant diseases treated with chemotherapy or radiotherapy; (2) pelvic or abdominal radiotherapy; (3) suprarenal lymph node metastasis or distant metastasis detected by PET/CT or chest/abdominal CT; (4) acute infection or uncontrolled severe medical; (5) pregnant or lactating; (6) intestinal perforation or acute ileus; (7) uncontrolled cardiac disease (defined as a cardiac function that would preclude hydration during cisplatin administration and any contraindication to paclitaxel); (8) adrenocortical insufficiency; (9) bone marrow metastasis; or (10) not meeting requirements for chemotherapy.
Study procedures and treatments
The patients will be allocated in a 1:1 ratio to one of two intervention arms (Fig 1-2). The randomization scheme will be prepared by the study statistician using a random number table, with the results entered by a study manager not involved with patient recruitment. During treatment, patients will have gynecological oncologist visits before each day of chemotherapy during NACT and weekly visits during CCRT.
Clinical data The data collected will include general medical information (age, childbirth, family history of cancer, and chronic diseases), tumor stage, tumor type, and chemo-/radiotherapy-related adverse events. At baseline, all patients will be physically examined by two gynecological oncologists and will have computed tomography (CT-scans) of the chest and upper abdomen or 18-fluoro-2-deoxy-D-glucose positron emission tomography ([18F] FDG-PET) with computed tomography (CT) (PET/CT) and magnetic resonance imaging (MRI)/computed tomography of the pelvis (within the previous 4 weeks). Full blood counts, liver and renal function tests will also be performed, and human papillomavirus (HPV) type and tumor marker (SCCA, CA 125, CA 199) values will be determined. In all cases, a detailed drawing of the lesion will be registered, and glomerular filtration rate (GFR), computed tomography urography (CTU), cystoscopy and sigmoidoscopy will be performed when necessary. All histology slides will be reviewed by the same panel of pathologists.
Control arm Patients will undergo radiation with concomitant cisplatin (CCRT) treatment as follows: cisplatin (40 mg/m2) will be given with hydration over 1 h (before radiation), weekly for 5 cycles. Radiotherapy to the whole pelvis will be given to a total dose of 45 Gy in 5 weeks. Extended fields will be used to treat positive common iliac and/or para-aortic lymph nodes with a total dose of 55-60 Gy. Brachytherapy will be given following completion of external beam radiation therapy. Patients will receive image-guided adaptive brachytherapy (IGBRT) with a high-risk clinical target volume (HRCTV) of 85 Gy in 3-4 fractions.
Study arm Neoadjuvant chemotherapy will be given weekly for 4 weeks (on days 1, 8, 15 and 22) as follows: paclitaxel (60 mg/m2) over 1 h followed by cisplatin (40 mg/m2) over 30 min, given intravenously with hydration for 3 days (3000 ml per day, from the day before the dose to the day after the dose). Both drugs will be delayed if neutrophils are <1.5×109/L and/or platelets are <75×109/L on the day of treatment until hematologic improvement to grade 1 is achieved. The doses of paclitaxel and cisplatin will be reduced by 50% if neutrophils are (0.5-1.0)×109/L and/or platelets are (25-50)×109/L. In the event of further hematological toxicity (neutrophils <0.5×109/L and/or platelets <25×109/L), NACT will be discontinued. Patients with a significant hypersensitivity reaction to paclitaxel or cisplatin will be withdrawn from the study. If NACT is discontinued early, patients who proceed to CCRT will commence when blood counts have recovered. Within 2 weeks after NACT, patients will be treated subsequently by CCRT as the control arm as soon as hematological recovery permits.
Follow-up After completion of treatment, patients will be followed up every 3 months during the first 2 years and every 6 months for the next 3 years. Gynecological oncologist examination will be repeated after NACT, 12 weeks after CCRT and again 3-6 months after treatment. Abdominal ultrasound or upper abdomen CT, pelvic MRI, and tumor marker values will be evaluated. PET/CT, GFR, and CTU will be performed when necessary.
Primary endpoint The primary aim of this trial will be to compare the 2-year disease-free survival (DFS) difference between dose-dense NACT followed by CCRT and CCRT alone. Five-year overall survival (OS) and disease-free survival (DFS) rates will be recorded. We will test the hypothesis: compared with CCRT alone, dose-dense NACT followed by CCRT can significantly improve 2-year DFS and 5-year OS and DFS in stage IIB-IVA cervical cancer patients.
Secondary endpoint The secondary specific aim of this trial will be a comparison of the response rate 3 months after treatment completion. In addition, the response rate for NACT will also be recorded. The response rate will be assessed by two radiologists blinded to the treatment option based on RECIST 1.1 criteria. We will test the hypothesis: dose-dense NACT followed by CCRT will have a higher response rate at 3 months than CCRT alone.
Tertiary endpoint The tertiary specific aim of this trial will be to measure the difference in adverse effects and quality of life between the two groups. All grade III/IV acute and late toxicities will be considered significant. We will measure quality of life with the EORTC QLQ-30 (V3.0) and CX24. We will test the hypothesis: there will be no difference in the incidence and severity of therapy-attributed adverse events between the two groups. Dose-dense NACT followed by CCRT will result in a higher quality of life than CCRT alone.
Quaternary endpoint The quaternary specific aim of this trial will be to identify predictive biomarkers of treatment response. By collecting tissue and blood samples, including samples from recurrent tumors, before and after NACT and before and after CCRT (if there is residual tumor available after treatment), we intend to compare differences in gene expression profiles in responding and nonresponding subgroups in each treatment arm. We will test the hypothesis: there will be different gene expression profiles in responding and nonresponding groups, independent of the treatment group assignment.
Clinicalresponse Clinical remission will be evaluated according to the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST) . A pelvic MRI will be performed at the end of the 4 weeks of NACT to assess the response using the RECIST 1.1 criteria. The overall response will be determined using pelvic MRI 12 weeks after the completion of CCRT. MRI scans will all be reviewed at Ruijin Hospital and assessed by two radiologists blinded to the treatment option based on the RECIST 1.1 criteria. Further radiological assessments will be conducted as clinically indicated. The complete response (CR) is defined as disappearance of all target lesions, and any pathological lymph nodes (whether target or nontarget) must have reduction in the short axis to < 10 mm. Partial remission (PR) is defined as at least a 30% decrease in the sum of the diameters of the target lesions, taking as reference the baseline sum of the diameters. Progressive disease (PD) is defined as at least 20% increase in the sum of the diameters of the target lesions, taking as reference the baseline sum of the diameters, with the smallest sum of increase at least 5 mm. In addition, a relative increase of more or new lesions is also considered progression. Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Patients with CR or PR will be classified as clinical responders, and patients with stable disease and progression of disease will be defined as clinical nonresponders. If the two radiologists reached different conclusions, the results will be rechecked and discussed to reach a consensus.
Adverse effects The adverse effects of adjuvant chemotherapy and chemoradiation will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patients will be monitored for marrow function suppression as well as gastrointestinal and dermatologic side effects. Full blood counts will be performed weekly during NACT and twice weekly during CCRT. Biochemistry and toxicity assessments will be carried out weekly during treatment, then 3 months post-CCRT, and every 12 months for 5 years. A bone density test will be performed before treatment and 3 months after CCRT. Adverse events will be based on the maximum toxicity grade for each type of event. All grade 3/4 acute and late toxicities will be considered significant. Serious adverse events need to be addressed urgently and should be reported to the functionary within 24 h. Adverse events occurring 6 months after the end of treatment will be considered late toxicity. Quality of life will be assessed with the EORTC QLQ-30 (V3.0) and CX24 before treatment, post-NACT, post-CCRT, three months post-CCRT, and every 12 months for 5 years.
Baseline characteristics (age, tumor size, tumor stage, etc.) for both treatment groups will be compared to ensure comparability of the patient populations to rule out selection bias. Means and standard deviations will be used to report continuous variables, and proportions will be used to report categorical variables. Comparisons of categorical outcome measures such as response rate, survival rate, incidence of adverse effects, etc. will be computed using the chi-square test or Fisher’s exact test if any of the expected values in the contingency table are less than 5. Kaplan-Meier survival analysis will be used for 2-year and 5-year overall survival and disease-free survival comparisons. Relative risks, or odds ratios, with their corresponding 95% confidence intervals will be analyzed by multivariable logistic regression. A P-value of <0.05 was considered significant.