Abstract
Background/Aim: Although peripheral neuropathy (PN) is a common adverse event in patients treated with oxaliplatin as first-line chemotherapy (1st-OX) for advanced gastric cancer, the effect of PN on the efficacy of paclitaxel at second-line chemotherapy (2nd-PTX) remains unclear. We investigated the association between PN induced by 1st-OX and efficacy of 2nd-PTX in patients with advanced gastric cancer (AGC). Patients and Methods: The study subjects were patients with AGC who received 1st-OX followed by 2nd-PTX at Gifu University Hospital between January 2015 and December 2019. Primary outcome was time to treatment failure (TTF) of 2nd-PTX. Secondary outcomes included overall survival (OS), response rate and adverse events during the period of 2nd-PTX. The association between incidence of grade ≥2 peripheral neuropathy (G2PN) and TTF or OS was also evaluated using Cox proportional hazards analysis. Results: A total of 54 patients with AGC who received 1st-OX followed by 2nd-PTX were eligible. Incidence rates of G2PN at the start of 2nd-PTX was 20.3% (11/54). Median duration of TTF and OS were not significantly longer in patients with G2PN than in those without it (TTF: 4.7 months vs. 3.7 months, p=0.264, OS: 10.6 months vs. 8.5 months, p=0.706). Cox proportional hazards analysis indicated that there was no significant relationship between the incidence of G2PN and TTF, or between the incidence of G2PN and OS. However, development of grade ≥3 PN was significantly higher in patients with G2PN than in those without it (45.5% vs. 2.3%, p<0.001). Conclusion: G2PN induced by 1st-OX may not affect efficacy of 2nd-PTX in patients with AGC but could be a risk for grade ≥3 PN of 2nd-PTX.
Chemotherapy is the standard treatment for advanced gastric cancer (AGC). The most common first-line treatment for patients with AGC is fluoropyrimidine [e.g., fluorouracil, S-1 (tegafur-gimeracil-oteracil potassium), and capecitabine] plus a platinum agent therapy [e.g., cisplatin (CDDP), oxaliplatin (OX)] (1-3). In patients with AGC, paclitaxel (PTX) plus ramucirumab (RAM), an anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody, has been shown to prolong survival when given as second-line chemotherapy (4). Nanoparticle albumin-bound paclitaxel (Nab-PTX) is a second-line treatment option because the ABSOLUTE trial showed the non-inferiority of Nab-PTX (weekly administration) to PTX alone (5). Fluoropyrimidine plus a platinum agent followed by RAM plus PTX or Nab-PTX is recommended as a standard treatment strategy for AGC. Compared to CDDP, which requires prolonged hydration and often inpatient treatment, OX can be performed on an outpatient basis. Therefore, when gastric cancer is treated with outpatient chemotherapy, OX is generally administered as first-line therapy and PTX or Nab-PTX as second-line therapy. However, Otsuka et al. reported that OX initiated as primary therapy for gastric cancer resulted in earlier onset of grade 2 peripheral neuropathy (PN), which forced a reduction or discontinuation of PTX for AGC compared to CDDP (6). PN occurs as an overlapping and cumulative adverse event between OX and PTX/Nab-PTX (2, 4). The severity of PN can lead to a decrease in quality of life (QOL) as well as to a dose reduction, interruption, or discontinuation of anticancer agents. This type of PN is characterized by dose-dependent severity and a long duration of symptoms (7, 8).
PN develops in up to 10% of patients at a cumulative OX dose of 510-765 mg/m2 (9, 10). In addition, daily activities are affected in approximately 50% of patients with a cumulative OX dose higher than 1,000 mg/m2. With taxane-based anticancer agents such as PTX and Nab-PTX, the incidence and severity of PN are also related to the cumulative dose (11).
Given reports that the chronic symptoms of PN induced by first-line chemotherapy (1st-OX) persist for months to years (12), it plausible that the PN of 1st-OX may affect the efficacy of PTX at second-line chemotherapy (2nd-PTX). To our knowledge, however, the effect of PN induced by 1st-OX on the efficacy of PTX at 2nd-PTX has not been investigated.
Here, to test this possibility, we investigated the association between PN induced by 1st-OX and efficacy of 2nd-PTX in patients with AGC.
Patients and Methods
Patients. The study was performed under a retrospective observational design using data obtained from patient electronic medical records at our hospital. Study subjects were patients with AGC at Gifu University Hospital between January 2015 and December 2019. They received either a capecitabine plus OX (CAPOX) regimen or S-1 plus OX (SOX) regimen, followed by a weekly PTX regimen. Exclusion criteria were a reduction in the initial dose of TAS-102 due to poor performance status (≥2 according to the Eastern Cooperative Oncology Group) or discontinuation without image evaluation. Efficacy and safety were compared between patients with and without grade ≥2 PN (G2PN) at the start of 2nd-PTX. Subjects with or without RAM in the 2nd-PTX were included.
Adverse events. Adverse events, including PN, nausea, vomiting, dysgeusia, stomatitis, diarrhea, fatigue, leukopenia, neutropenia, anemia, thrombocytopenia and febrile neutropenia, were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (13). The incidence of PN (grade ≥3) was used as the primary indicator of the safety of chemotherapy.
Efficacy of chemotherapy. Time to treatment failure (TTF), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and relative dose intensity (RDI) were used as indicators of the efficacy of chemotherapy. The primary endpoint was TTF of 2nd-PTX. TTF was defined as the time from the start to the end of therapy with 2nd-PTX. OS was defined as the time from the start of therapy with 2nd-PTX to death. Tumor response was assessed as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) using the patient’s computed tomography scan, in accordance with the Response Evaluation Criteria in Solid Tumors guideline version 1.1. (14). ORR was defined as CR plus PR, and DCR was defined as CR+ PR+SD.
Statistical analyses. Patient characteristics were described as median with 25th and 75th percentiles for continuous variables, and by frequency and percentage for categorical variables. The effect of G2PN on TTF or OS of 2nd-PTX was assessed using a Cox proportional hazards regression model with adjustment for covariates including age, sex, NLR and mGPS. Efficacy and safety were compared between patients with and without G2PN at start of 2nd-PTX. TTF and OS with and without G2PN at start of 2nd-PTX was estimated by Kaplan-Meier analysis and assessed by the log-rank test. The incidence of adverse events and tumor response were compared using the chi-squared test.
Statistical analyses were conducted using IBM SPSS version 22 (IBM Japan Ltd., Tokyo, Japan), R software version 3.5.1 and GraphPad Prism version 6.0 (GraphPad Software, San Diego, CA, USA). p-Values less than 0.05 were considered significant.
Ethics approval and consent to participate. The study was carried out in accordance with the guidelines for human studies adopted by the Ethics Committee of Gifu University Graduate School of Medicine and the Japanese Government and approved by the Medical Review Board of Gifu University Graduate School of Medicine (approval no. 2021-A172 Institutional Review Board). Informed consent was not obtained because this was a retrospective observational study. We posted information about the study on the website of the hospital (opt-out enrollment method).
Results
Patient demographics. A total of 54 patients with AGC who received 1st-OX followed by 2nd-PTX were eligible (Figure 1). Among these 54 patients, 32 (59.3%) were male and 22 (40.7%) were female. In the 1st-OX regimen before 2nd-PTX, the CAPOX and SOX regimens accounted for 20.3% and 79.6%, respectively. The percentage of patients who were concurrently using RAM was 85.1%. Among the 54 studied patients, the number with and without G2PN at the start of 2nd-PTX was 11 (20.4%) and 43 (79.6%), respectively. The incidence of peripheral neuropathy of grade 0, grade 1, grade 2, and grade 3 before paclitaxel initiation was 23, 20, 8, and 3, respectively. Demographics of patients with and without G2PN at the start of 2nd-PTX are shown in Table I.
CONSORT flow diagram.
Demographics and baseline characteristics in patients with and without G2PN at the start of 2nd-PTX.
Efficacy and safety of the PTX regimen in AGC patients. The relative dose intensity (RDI) of PTX was 0.69 [interquartile range (IQR)=0.55-0.86]. Median TTF and OS were 4.06 months (IQR=3.5-4.9) and 8.78 months (IQR=7.0-12.2), respectively. ORR and DCR were 25.9% and 53.7%, respectively. The incidence rate of grade ≥3 PN, stomatitis, neutropenia, leukopenia, anemia, thrombocytopenia, and febrile neutropenia was 11.1%, 3.7%, 59.3%, 44.4%, 18.5%, 1.9%, and 5.5%, respectively.
Comparison of efficacy between patients with and without G2PN at start of 2nd-PTX. Median TTF and OS did not significantly differ between patients with and without G2PN at the start of 2nd-PTX [TTF, 4.7 vs. 3.7 months; HR=0.70 (95%CI=0.38-1.27), p=0.264. OS, 10.6 vs. 8.5 months; HR=0.88 (95%CI=0.46-1.69), p=0.708] (Figure 2). The Cox proportional regression analysis showed that G2PN at the start of 2nd-PTX was not a significant risk for TTF or OS in AGC patients who received 2nd-PTX [TTF: HR=0.61 (95%CI=0.29-1.24), p=0.17. OS: HR=0.83 (95%CI=0.41-1.69), p=0.60] (Table II and Table III). As shown in Table IV, there were no significant differences between the two groups in other efficacy outcomes.
Kaplan–Meier curves comparing time to treatment failure (A) and overall survival (B) in patients with advanced gastric cancer who received paclitaxel at second-line chemotherapy (2nd-PTX). The solid line represents patients without grade ≥2 peripheral neuropathy (G2PN) at the start of 2nd-PTX and the dashed line represents those with G2PN at the start of 2nd-PTX.
Cox proportional hazards analysis of TTF in AGC patients receiving paclitaxel-based chemotherapy.
Cox proportional hazards analyses of OS in AGC patients receiving paclitaxel-based chemotherapy.
Comparison of response rate, disease control rate, and relative dose intensity.
Comparison of safety between patients with and without G2PN at the start of 2nd-PTX. Patient groups with and without G2PN at the start of 2nd-PTX showed no difference in the incidence of hematological toxicity (grade ≥3), such as neutropenia, leukopenia, anemia, and thrombocytopenia. In non-hematological toxicity (grade ≥3), PN only was significantly higher in patients with G2PN at the start of 2nd-PTX compared with those without G2PN at the start of 2nd-PTX (45.5% vs. 2.3%, p<0.001) (Table V). The number of patients with peripheral neuropathy of grade 0, grade 1, grade 2, and grade 3 at the end of 2nd-PTX was 7, 20, 22, and 5, respectively. Reasons for the discontinuation of 2nd-PTX in patients with and without G2PN at the start of 2nd-PTX were PD in 90.9% and 93.0%, PN in 9.1% and 2.3%, and sepsis in 0% and 4.7%, respectively.
Comparison of the incidence of adverse events (Grade ≥3) in patients with and without G2PN at the start of 2nd-PTX.
Discussion
In this study, we found no significant association between efficacy, including TTF and OS, and G2PN at the start of 2nd-PTX in patients with AGC who initially received an OX-based regimen followed by a weekly PTX-based regimen. The incidence of PN (grade ≥3) was significantly higher in patients with G2PN than in those without G2PN at the start of 2nd-PTX. These findings suggest that it is important to prevent the onset of PN during 1st-OX in patients with AGC.
Recent studies have described the effectiveness of chemotherapy in the treatment of AGC (1, 2, 15-17). In AGC, S-1 plus CDDP therapy (SP) was the first recommended fluoropyrimidine plus platinum agent therapy. Subsequently, the G-SOX trial reported that SOX therapy, which does not require hydration, was equivalent to SP as first-line chemotherapy for patients with AGC (2). However, OX has been reported to have a higher incidence of PN than CDDP. Additionally, PTX therapy, which is recommended as a second-line chemotherapy for AGC, also has a higher incidence of PN (2, 6). Accordingly, administration of PTX after OX may not only increase the severity of PN but may also result in an insufficient dosage of PTX due to PN.
In the randomized, open-label, international multicenter phase III RAINBOW trial, Wilke et al. reported a median progression-free survival (PFS) and OS for 2nd-PTX plus RAM of 4.4 and 9.6 months, respectively (4). These values are consistent with the median OS and TTF in our present study (OS, 8.78 months; TTF, 4.06 months). In addition, the incidence of PN (grade ≥3) in our study of 11.1% was similar to the 8.0% in the RAINBOW study (4).
Our study showed that there was no significant association between G2PN at the start of 2nd-PTX and the efficacy of 2nd-PTX in AGC patients after 1st-OX. In contrast, PN (grade 3) was significantly more frequent in patients with G2PN than in those without G2PN at the start of 2nd-PTX. Otsuka et al. showed that among 50 patients with AGC after 1st-OX, 27 patients (54%) experienced a dose reduction in 2nd-PTX, while in 6 patients (12%) the dose of 2nd-PTX was reduced due to PN (6). In other words, they reported that PN was the reason for the low rate of 22.2% (6/27) of PTX dose reductions.
In this study, neutropenia of grade 3 or higher was frequent, occurring in 54.5% of patients with G2PN and 60.5% of those without G2PN. Grade ≥3 neutropenia frequently resulted in a dose reduction in PTX. Further, more than 90% of patients in both groups discontinued chemotherapy because of PD, suggesting that G2PN at the start of PTX did not affect the dose intensity of 2nd-PTX.
However, the proportion of patients whose PN worsened to grade 3 was significantly higher in patients with G2PN than in those without G2PN at the start of 2nd-PTX. Severe PN is considered to be associated with a decrease in patient QOL. Yamazaki et al. examined the non-inferiority for PFS of FOLFIRI (folinic acid, bolus/continuous fluorouracil, and irinotecan) plus bevacizumab (BEV) and mFOLFOX6 (folinic acid, bolus/continuous fluorouracil, and oxaliplatin) plus BEV as first-line chemotherapy for mCRC (18). They reported that neurotoxicity-related QoL was apparently better in FOLFIRI + Bev than in mFOLFOX6 + Bev for 18 months. In addition, the FACT/GOG-Ntx scale - a specific scale for neurotoxicity-related QoL - showed that sensory neuropathy worsened QoL immediately after the initiation of mFOLFOX6 + Bev for the initial 9 months, from which the patients did not sufficiently recover during the subsequent 9 months (18). To avoid compromising QOL, decision making for treatment strategies using 1st-OX and 2nd-PTX should aim to prevent PN. Possibilities include the use of a stop-and-go strategy for OX administration (19) and frozen gloves on extremities for PTX administration (20).
Several limitations of our study should be mentioned. First, the study was conducted under a retrospective design and analyzed data from a single center. Second, because the sample size was small and the number of factors included in the multivariable analysis was limited to avoid overfitting, consideration of confounding factors may have been insufficient. Third, the patient’s QOL was not assessed.
In conclusion, although we found no significant relationship between G2PN at the start of PTX and the efficacy of 2nd-PTX in AGC patients after 1st-OX, the incidence of severe PN was significantly higher in patients with G2PN at the start of PTX than in those without G2PN. Appropriate measures to avoid PN should be implemented for AGC patients who receive 1st-OX followed by 2nd-PTX.
Footnotes
↵* These Authors contributed equally to this study.
Authors’ Contributions
Hironori Fujii conceptualized this study. Hironori Fujii, Shiori Sadaka and Kanae Ajisawa acquired the clinical data. Naoki Okumura, Akitaka Makiyama, Hirotoshi Iihara, Itaru Yasufuku, Koichi Ohata, Ryo Kobayashi, Yoshihiro Tanaka, Hideki Hayashi, and Akio Suzuki were responsible for the data interpretation. Hironori Fujii and Shiori Sadaka drafted the manuscript. All Authors have read and approved the current version of the manuscript.
Conflicts of Interest
Akitaka Makiyama has received honoraria for lectures from Eli Lilly and Company., Taiho Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd. The other Authors have no conflicts of interest to declare in relation to this study.
- Received July 20, 2022.
- Revision received July 28, 2022.
- Accepted July 29, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
