The relationship between peripheral neuropathy and efficacy in second-line chemotherapy for unresectable advanced gastric cancer: a prospective observational multicenter study protocol (IVY)

The primary objective of this prospective observational multicenter study is to evaluate the incidence and development of CIPN in patients with and without CIPN at the start of second-line chemotherapy for unresectable advanced GC.

This study is conducted in accordance with the World Medical Association Declaration of Helsinki and Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects [25]. The trial protocol has been approved by the Institutional Review Board of all participating institutions and the Kawasaki Medical School Hospital. The protocol of this study has been registered in the University Hospital Medical Information Network’s Clinical Trials Registry (registration number, UMIN000033376).

The primary endpoint is the incidence of grade 3–4 CIPN in second-line chemotherapy. The secondary endpoints are ORR, OS, PFS, time to treatment failure (TTF), safety (the incidence of AEs), and the relationship between the degree of CIPN and the efficacy. This study blood samples in two points (before and after second-line treatment) will be collected for ancillary research to explore the biomarker of paclitaxel efficacy and CIPN.

The PNQ and FACT/GOG-Ntx, patient-reported outcome measures, will be used to assess CIPN because these are valid and reliable instruments for assessing CIPN in patients treated with taxane or oxaliplatin [20, 26, 27]. Patients will answer the PNQ and the FACT/GOG-Ntx questionnaires before treatment (baseline) and every treatment cycle. The PNQ includes two questionnaire items: one inquiring sensory neurotoxicity and one inquiring motor neurotoxicity [23]. The questionnaire items are designed to correspond with the neurotoxicity questions included in the CTCAE. The PNQ grades range from grade A (no symptom) to grade E (very severe neuropathy). Grades from A to C indicate an absence of symptoms interfering with activities of daily living, whereas grades from D and E indicate CIPN symptoms that interfere with activities of daily living. The FACT/GOG-Ntx questionnaire comprises 11 items related to neurotoxicity, with each rated on a five-point scale (0 to 4) [24]. The possible score range for the FACT/GOG-Ntx scale is from 0 to 44, with high scores indicating a lower grade of neuropathy. Tumor assessment using diagnostic imaging will be carried out every within 12 weeks (+ 2 weeks), and treatment response will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 [28]. PFS is defined as the time from registration to the time of progression after second-line treatment initiation or death from any cause. OS is defined as the time from registration to the time of death or last contact. The severity of AEs will be assessed using CTCAE 4.0 [29]. To investigate the influence of first-line treatment to second-line tumor response, we will collect data on treatment duration, tumor response, and total dose of platinum agents in first-line chemotherapy.

All recommended regimens in the Japanese Gastric Cancer Treatment guidelines 2018 (ver. 5) and the Pan-Asian adapted European Society for Medical Oncology Clinical Practice Guidelines will be allowed in this study [30]. Each physician will be able to select the appropriate regimen with consideration of each patient’s conditions (Fig. 1). The definitive regimens are as follows. Sb-paclitaxel plus ramucirumab regimen will comprise ramucirumab (80 mg/m2 intravenously on days 1 and 15) with sb-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15) every 4 weeks. Nab-paclitaxel plus ramucirumab regimen will comprise ramucirumab (80 mg/m2 intravenously on days 1 and 15) with nab-paclitaxel (100 mg/m2 intravenously on days 1, 8, and 15) every 4 weeks. Weekly sb-paclitaxel (80 mg/m2) will be administered intravenously on days 1, 8, and 15, every 4 weeks. Weekly nab-paclitaxel (100 mg/m2) will be administered intravenously on days 1, 8, and 15, every 4 weeks. Ramucirumab (8 mg/kg) will be administered intravenously on days 1 and 15, every 4 weeks. Docetaxel (60–70 mg/m2) will be administered intravenously on day 1, every 4 weeks. Irinotecan (150 mg/m2) will be administered intravenously on days 1 and 15, every 4 weeks. Dose reduction and/or cycle delays will be permitted according to the decision of each physician.

As mentioned in the background section, of the patients who enrolled in this study, the patients with or without any degree of CIPN will be estimated 1: 2 population at the start of second-line chemotherapy administration. We estimate the incidence of grade 3–4 CIPN with 8% (SD + 8%) of the enrolled patients without CIPN at the start of second-line chemotherapy administration during the second-line treatment of PTX with Ramucirumab group (control group). Next, hypothetically, patients with CIPN with any grade at the start of second-line chemotherapy administration (test group) will increase the incidence of grade 3–4 CIPN by + 5% during second-line treatment. To confirm the difference of the incidence of grade3–4 CIPN between the two groups with verifying with α = 0.05 (both sides) and the power (1 − β) = 0.8, the sample size is calculated to be 83 cases in total. The participation ratio is 1: 2 for patients with and without CIPN at the start of second-line chemotherapy, resulting in a total sample size of 125. Among patients scheduled to participate in this study, assuming that 70% of participants will receive the standard treatment of PTX with ramucirumab, the target sample size will be 179. The number of cases for a recruit is set to 200, taking into consideration the participation of incorrect cases and cases of dropout. The degree and frequency of CIPN were evaluated by the PNQ, FACT/GOG-Ntx, and CTCAE. PFS will be estimated by the Kaplan-Meier method and compared among groups with the stratified log-rank test. Secondary endpoints are the rate of AEs graded according to the CTCAE version 4.0, ORR according to the RECIST version 1.1., PFS, and OS. Categorical data comparisons according to the degree and frequency of CIPN will be performed using Fisher’s exact and the χ2 tests. To assess the correlation between the PNQ, FACT/GOG-Ntx questionnaires and the physician-rated CTCAE scales, Spearman’s correlation coefficient was utilized for this evaluation.

Disease progression and occurrence of metastasis, synchronous, or metachronous cancer will be monitored by abdominal computed tomography, magnetic resonance imaging, evaluation of increased clinical symptoms, or elevated levels of tumor markers such as carcinoembryonic antigen, carbohydrate antigen (CA) 19–9, and CA125, every 12 weeks during the treatment period. Safety will be assessed by monitoring AEs using physical and laboratory examinations. The survey sheets, including those of safety, efficacy, and compliance with treatment, will be collected at the time of registration and after every treatment cycle. Besides, patient outcomes will be investigated 2 years after study initiation as well as 1 year after the accrual of the last patient. The CIPN assessments will be performed at baseline and before every cycle using the PNQ, FACT/GOG-Ntx, and CTCAE during the treatment period.