Abstract
Background: Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients. Patients and Methods: We initiated a phase II study to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapeOX) as first-line therapy for patients with AGC aged ≥70 years. Planned assessment of toxicity was made upon recruitment of the first 20 patients. Results: In five out of 20 patients, unacceptable toxicity was observed, including three patients who were unable to complete the initial two courses due to adverse events. Among the other 15 patients, dose reduction due to toxicity were needed in 10 and treatment delay for adverse events also occurred in 12 patients during the first two courses. Conclusion: Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.
In recent decades, systemic chemotherapy for advanced gastric cancer (AGC) has been developed and the prognosis of AGC has improved. At present, a regimen that combines a platinum-based agent and fluorouracil-based agent is regarded as acceptable first-line treatment (1-4), such as capecitabine plus oxaliplatin (CapeOX) (5-7). For patients with epidermal growth factor receptor 2-positive disease, the addition of trastuzumab to chemotherapy is recommended (8). Gastric cancer is predominantly a disease of elderly people: more than half of all newly diagnosed patients are aged >60 years (9). However, limited data are available on chemotherapy against AGC in such patients. In pivotal clinical trials (1-4, 8), the number of elderly patients was small, and they have not been representative of the patients with AGC seen in daily practice. Therefore, we initiated a multicenter, single-arm, phase-II study to evaluate the efficacy and safety of CapeOX as first-line therapy for elderly patients with AGC. A planned assessment of toxicity was made after completion of two courses of chemotherapy for the first 20 patients and, here, we report the results of the safety data.
Patients and Methods
Inclusion criteria. The inclusion criteria were: Histologically proven gastric adenocarcinoma and epidermal growth factor receptor 2 (HER2)-negative cancer or of unknown cause; unresectable, metastatic, or recurrent disease; adequate self-supported nutritional intake; age ≥70 years; Eastern Cooperative Oncology Group performance status of 0 or 1; no history of chemotherapy, or radiotherapy; adequate organ function, as defined by hemoglobin ≥8 g/dl, white blood cell count ≤12,000/mm3, absolute neutrophil count ≥1,500/mm3, platelet count ≥100,000/mm3, total bilirubin ≤1.5 mg/dl, serum transaminase ≤100 IU/l, serum creatinine ≤1.5 mg/dl, and creatinine clearance ≥50 ml/min; an evaluable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) (10).
Treatment plan. Treatment consisted of capecitabine (1,000 mg/m2, b.i.d., on days 1-14 of each course) and oxaliplatin (130 mg/m2, i.v., on day-1 of each course) every 3 weeks. Prophylactic antiemetic therapy for oxaliplatin was administered. Treatment delays, suspensions, or dose modifications were undertaken in reference to the J-CLASSIC study (11). Capecitabine was also suspended in the event of any hematologicaI toxicity of grade ≥3 or nonhematological toxicity of grade ≥2 except first grade 2 nausea or vomiting judged to be related to capecitabine and was not resumed until the toxicity had resolved to grade ≤1. After the occurrence of hematological toxicity of grade ≥3 or most nonhematological toxicity grade ≥2, the capecitabine dose was reduced to 75% of the original dose. In patient with a second episode of hematological toxicity of grade ≥3 or most nonhematological toxicity of grade ≥2, the capecitabine dose was reduced to 50% of the original dose. After the occurrence of any oxaliplatin-related nonhematological toxicity of grade 3, the oxaliplatin dose was reduced to 100 mg/m2 in the subsequent course. Oxaliplatin and capecitabine were discontinued in the event of nonhematological toxicity of grade ≥4. If an oxaliplatin-related allergic reaction or peripheral neuropathy occurred, capecitabine could be continued as monotherapy.
Evaluation. Pretreatment evaluation comprised taking a medical history, physical examination, complete blood cell count, serum chemistry, esophagogastroduodenoscopy, and computed tomography of the chest, abdomen, and pelvis. Clinical examination and biochemical tests were required before and during each treatment course. Tumor assessments were performed with computed tomography ≤28 days before registration and every 8 weeks. Images for tumor responses were evaluated according to RECIST v1.1 (10). Adverse events (AEs) during chemotherapy were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03 (12).
Endpoints and statistical analyses. The primary endpoint was the median OS using the CapeOX regimen. The secondary endpoints were progression-free survival (PFS), time to treatment failure, response rate, relative dose intensity, and toxicity. The required sample size was calculated to be 105 patients. This was based on the null hypothesis that the true median OS is equal to a threshold value of 10 months versus the alternative hypothesis that the true median OS is equal to an expected value of 13.5 months, at a power of 80%, and α (two-sided) of 5%. To ensure maintenance of the statistical power, 110 patients were required. Safety analyses were planned at completion of an initial two courses of chemotherapy for the first 20 patients. An Independent Data Monitoring Committee (IDMC) considered the tolerability of chemotherapy from initial safety data. The approximate criterion they used was that 30% (6/20) or more of patients would need two levels of dose reduction for an AE, in addition to suspension or cessation of chemotherapy. If it were decided that CapeOx were intolerable, the trial would be continued with dose modification.
Because the study is ongoing, only safety data for the first 20 cases are reported here.
Ethical approval of the study protocol. This study was carried out in accordance with the Helsinki Declaration (and its amendments) and the Clinical Trial Act (Act No. 16 of April 14, 2017) of Japan. The study protocol was approved by the Ethics Review Boards of participating centers and Certified Review Board (jRCTs051180126). All eligible patients provided written informed consent to participation. This trial was registered with the University Hospital Medical Information Network (UMIN000022450)
Results
Patients. Between September 2016 and May 2017, 20 patients were enrolled in this study. After completion of 2 initial courses of chemotherapy, safety analysis was conducted in accordance with the protocol. The characteristics of these 20 patients are shown in Table I. Their median age was 75.5 years. Half of the patients had an Eastern Cooperative Oncology Group performance score of 0.
Baseline characteristics of patients with advanced gastric cancer (n=20) who participated in the phase II trial of the CapeOX regimen.
Safety. All 20 patients underwent safety analyses. Table II lists the AEs and the proportion of patients experiencing them during the first and second course of chemotherapy. One serious AE of nausea was associated with chemotherapy. There was no treatment-related death.
Adverse events observed in elderly patients with advanced gastric cancer (n=20) treated with the CapeOX regimen.
Exposure to chemotherapy. Fifteen patients completed the first two courses of CapeOX chemotherapy and started the third course. The relative dose intensities of capecitabine and oxaliplatin in the initial two courses were 0.78 (95% confidence interval=0.66-0.90) and 0.92 (95% confidence interval=0.86-0.98), respectively.
Dose reduction. At beginning of the third course, five out of 15 patients were administered chemotherapy without dose reduction (Figure 1). Due to AEs, the oxaliplatin dose was reduced for five patients at the start of the second course, and for six patients at the start of the third course. The capecitabine dose was reduced in nine patients at the start of the second course, and for eight patients at the start of the third course for AEs. Of the nine patients whose dose was reduced at the start of their second course, treatment was subsequently discontinued for four. Two patients needed two levels of dose reduction.
Summary of study dose reduction of either oxaliplatin or capecitabine.
Delay of administration. Three out of 15 patients were administered chemotherapy without delay until the start of the third course (Figure 2), including one patient with dose reduction at the −1 level. In eight out of 19 patients, the second course was suspended due to AEs, and in seven patients, the suspension was for >7 days. In 10 out of 15 patients, the third course was suspended due to AEs, and in five of these patients, suspension was for >7 days. In the three out of five patients who did not have a dose reduction, the third course started with a delay of 5, 7, and 14 days, respectively.
Delay of course start. *Delay in either second or third course in patients to whom the third course of chemotherapy was administered.
Discontinuation. Out of 20 patients, five patients were unable to complete the initial two courses of chemotherapy. In three of these patients, withdrawal or investigator’s discretion were due to AE-related reasons, while grade 2 nausea or diarrhea was observed at discontinuation even though dose reduction was applied for two of them. CapeOx was discontinued in the other two patients due to progressive disease. The second course was started with dose reduction and a delay due to AEs in two patients.
IDMC recommendations. Although not meeting the criterion mentioned before, it was necessary to reduce the dose (10/15) or suspend the start of the subsequent course (12/15) due to toxicity in the first two courses of the remaining patients (Figure 1 and Figure 2). The IDMC recommended that the study should be continued using a reduced dose at the −1 level of capecitabine (750 mg/m2, b.i.d., on days 1-14 of each course) and oxaliplatin (100 mg/m2 on day 1 of each course). With these reduced doses, this trial has been ongoing.
Discussion
Few prospective studies using combination chemotherapy including platinum have been performed for patients with AGC aged 70 years or over, especially in Japan. The safety data for CapeOX in the first 20 patients of our study may be meaningful for daily practice in elderly patients with AGC, despite the small population evaluated. It is an important issue whether an initial dose reduction is necessary for elderly patients with AGC or not. Recently, the results of the GO2 trial for frail or elderly patients with advanced gastroesophageal cancer were published. The GO2 trial compared three doses of CapeOX (100%, 80%, 60%) (13). Similar PFS for the reduced-dose group compared with the full-dose group was shown, and the primary endpoint (non-inferiority comparison for PFS) was met. The median OS was approximately 7 months and also very close in all three arms and with a similar tendency to PFS. Moreover, they showed good persistence of quality of life and low toxicity by dose reduction for elderly or frail patients with AGC. In the other two randomized controlled trials for elderly patients with AGC, they received chemotherapy with dose reduction at the start of the first course: 80% of the full dose in the 321GO trial (14), and oxaliplatin (110 mg/m2) plus full-dose capecitabine in a Korean study (15). In one non-randomized prospective phase II trial for elderly patients with AGC from China, the CapeOX regimen with capecitabine at a lower dose of 1,700 mg/m2/day (days 1-14) was used, and the authors concluded that reduced-dose chemotherapy was efficacious and fairly tolerable for elderly patients with AGC (16). The findings mentioned above support the notion of administering reduced-dose chemotherapy at initiation for elderly patients with AGC, which our conclusion is compatible with.
There is a limitation to this study because these are only initial safety findings from two courses of chemotherapy from 20 patients, without efficacy findings. Thus, we cannot draw any definite conclusion at this point. In summary, early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study. This study was resumed after reducing the dose of capecitabine and oxaliplatin by one level.
Acknowledgements
The Authors thank the patients and large number of clinicians, research nurses, data managers, and other clinical and support staff at participating centers. The authors would like to thank Mr. Hitoshi Masuda and Ms. Naomi Tsukagoshi for their excellent assistance.
This study was supported by a non-profit organization, The Tokyo Cooperative Oncology Group, with funding from Yakult Honsha Co., Ltd., under a study contract. The above-mentioned company did not have access to data and was not involved in any aspect of the research.
Footnotes
Authors’ Contributions
All Authors contributed to the protocol treatment except N. Ishizuka. K. Yamaguchi, K. Chin, D. Takahari, and N. Ishizuka participated in designing the protocol and management of the study.
Conflicts of Interest
The Authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KC has received honoraria from BMS, Chugai, Ono, and Taiho. MN has received honoraria from Bayer, BMS, Chugai, Daiichi Sankyo, Eli Lilly, Merck, Ono, Otsuka, Sanofi, Taiho, Takeda, and Yakult Honsha. FM has received grants from Astellas, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, J-pharma, Merck, Mochida, MSD, Ono, Sumitomo Dainippon, Taiho, Takeda, and Yakult Honsha, and has received honoraria from Chugai, Takeda and Yakult Honsha. WI has received grants from Chugai and has received honoraria from Chugai and Yakult Honsha. KY has received honoraria from Eli Lilly and Daiichi Sankyo, and has received Grants from Eli Lilly, Ono, Sanofi, Taiho, and Yakult Honsha. All remaining Authors have declared no conflicts of interest.
- Received March 6, 2022.
- Revision received March 29, 2022.
- Accepted March 31, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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