Initial Safety Analysis of CapeOx for Elderly Patients With
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ANTICANCER RESEARCH 42: 2683-2687 (2022)
doi:10.21873/anticanres.15746
Initial Safety Analysis of CapeOx for Elderly Patients With
Advanced Gastric Cancer Patients: A Phase II Trial
KEISHO CHIN1, DAISUKE TAKAHARI1, RYOHEI KAWABATA2, HISASHI HOSAKA3, SO SAITOU4,
TAKESHI SHIRAISHI5, HIROSHI YABUSAKI6, MASAHIRO GOTO7, MASATO NAKAMURA8,
HIROSHI IMAMURA9, YOSHIAKI SHINDO10, FUMIO NAGASHIMA11, WATARU ICHIKAWA12,
TAKASHI SAOTOME13, WATARU YAMAMOTO14, NAOKI ISHIZUKA15 and KENSEI YAMAGUCHI1
1Department
of Gastroenterological Chemotherapy,
Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan;
2Department of Surgery, Osaka Rosai Hospital, Osaka, Japan;
3Department of Gastroenterology, Gunma Prefectural Cancer Center, Gunma, Japan;
4Department of Internal Medicine, Misawa City Hospital, Aomori, Japan;
5Department of Medical Oncology, Matsuyama Red Cross Hospital, Ehime, Japan;
6Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, Niigata, Japan;
7Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan;
8Comprehensive Cancer Center, Aizawa Hospital, Nagano, Japan;
9Department of Gastroenterological Surgery, Toyonaka Municipal Hospital, Osaka, Japan;
10Department of Gastroenterological Surgery, Nakadori General Hospital, Akita, Japan;
11Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan;
12Division of Medical Oncology, Showa University Fujigaoka Hospital, Yokohama, Japan;
13Department of medical Oncology, Matsudo City General Hospital, Chiba, Japan;
14Senju Central Clinic, Tokyo, Japan;
15Department of Clinical Trial Planning and Management,
Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
Abstract. Background: Safety of combination chemotherapy courses due to adverse events. Among the other 15 patients,
using platinum and fluorouracil has not been evaluated dose reduction due to toxicity were needed in 10 and treatment
adequately for advanced gastric cancer (AGC) in elderly delay for adverse events also occurred in 12 patients during
patients. Patients and Methods: We initiated a phase II study the first two courses. Conclusion: Early analyses of safety
to evaluate the efficacy and safety of capecitabine plus suggest that the CapeOX regimen was not tolerated without
oxaliplatin (CapeOX) as first-line therapy for patients with dose reduction for elderly patients with AGC in this study.
AGC aged ≥70 years. Planned assessment of toxicity was made
upon recruitment of the first 20 patients. Results: In five out of In recent decades, systemic chemotherapy for advanced gastric
20 patients, unacceptable toxicity was observed, including cancer (AGC) has been developed and the prognosis of AGC
three patients who were unable to complete the initial two 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
Correspondence to: Keisho Chin, Department of Gastroenterology, oxaliplatin (CapeOX) (5-7). For patients with epidermal
Cancer Institute Hospital of the Japanese Foundation for Cancer growth factor receptor 2-positive disease, the addition of
Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Tel: +81 trastuzumab to chemotherapy is recommended (8). Gastric
335200111, Fax: +81 335700343, e-mail: kchin@jfcr.or.jp cancer is predominantly a disease of elderly people: more than
half of all newly diagnosed patients are aged >60 years (9).
Key Words: Gastric cancer, elderly, oxaliplatin, capecitabine,
However, limited data are available on chemotherapy against
chemotherapy, phase 2 trial.
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.
This article is an open access article distributed under the terms and
Therefore, we initiated a multicenter, single-arm, phase-II
conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0
international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
2683ANTICANCER RESEARCH 42: 2683-2687 (2022)
study to evaluate the efficacy and safety of CapeOX as first- Table I. Baseline characteristics of patients with advanced gastric
line therapy for elderly patients with AGC. A planned cancer (n=20) who participated in the phase II trial of the CapeOX
regimen.
assessment of toxicity was made after completion of two
courses of chemotherapy for the first 20 patients and, here, we Characteristic Value
report the results of the safety data.
Sex
Patients and Methods Male 11
Female 9
Inclusion criteria. The inclusion criteria were: Histologically proven Age, years
gastric adenocarcinoma and epidermal growth factor receptor 2 Median (range) 75.5 (70-84)
Performance status
(HER2)-negative cancer or of unknown cause; unresectable,
0 10
metastatic, or recurrent disease; adequate self-supported nutritional
1 10
intake; age ≥70 years; Eastern Cooperative Oncology Group
Histological type
performance status of 0 or 1; no history of chemotherapy, or Intestinal 11
radiotherapy; adequate organ function, as defined by hemoglobin ≥8 Diffuse 9
g/dl, white blood cell count ≤12,000/mm3, absolute neutrophil count Disease status at study entry
≥1,500/mm3, platelet count ≥100,000/mm3, total bilirubin ≤1.5 mg/dl, recurrence/metastatic 5
serum transaminase ≤100 IU/l, serum creatinine ≤1.5 mg/dl, and 15
creatinine clearance ≥50 ml/min; an evaluable lesion according to the Gastrectomy
Response Evaluation Criteria In Solid Tumors (RECIST v1.1) (10). Yes 8
No 12
Treatment plan. Treatment consisted of capecitabine (1,000 mg/m2, No. of metastasis site
b.i.d., on days 1-14 of each course) and oxaliplatin (130 mg/m2, i.v., on 1 9
day-1 of each course) every 3 weeks. Prophylactic antiemetic therapy 2 10
for oxaliplatin was administered. Treatment delays, suspensions, or ≥3 1
dose modifications were undertaken in reference to the J-CLASSIC Peritoneal metastasis
study (11). Capecitabine was also suspended in the event of any Yes 14
hematologicaI toxicity of grade ≥3 or nonhematological toxicity of No 6
grade ≥2 except first grade 2 nausea or vomiting judged to be related Liver metastasis
to capecitabine and was not resumed until the toxicity had resolved to Yes 8
grade ≤1. After the occurrence of hematological toxicity of grade ≥3 or No 12
most nonhematological toxicity grade ≥2, the capecitabine dose was Lymph node metastasis
Yes 8
reduced to 75% of the original dose. In patient with a second episode
No 12
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- median OS is equal to an expected value of 13.5 months, at a power
related allergic reaction or peripheral neuropathy occurred, capecitabine of 80%, and α (two-sided) of 5%. To ensure maintenance of the
could be continued as monotherapy. statistical power, 110 patients were required. Safety analyses were
planned at completion of an initial two courses of chemotherapy for
Evaluation. Pretreatment evaluation comprised taking a medical history, the first 20 patients. An Independent Data Monitoring Committee
physical examination, complete blood cell count, serum chemistry, (IDMC) considered the tolerability of chemotherapy from initial
esophagogastroduodenoscopy, and computed tomography of the chest, safety data. The approximate criterion they used was that 30%
abdomen, and pelvis. Clinical examination and biochemical tests were (6/20) or more of patients would need two levels of dose reduction
required before and during each treatment course. Tumor assessments for an AE, in addition to suspension or cessation of chemotherapy.
were performed with computed tomography ≤28 days before If it were decided that CapeOx were intolerable, the trial would be
registration and every 8 weeks. Images for tumor responses were continued with dose modification.
evaluated according to RECIST v1.1 (10). Adverse events (AEs) during Because the study is ongoing, only safety data for the first 20
chemotherapy were evaluated using the National Cancer Institute cases are reported here.
Common Terminology Criteria for Adverse Events, v4.03 (12).
Ethical approval of the study protocol. This study was carried out in
Endpoints and statistical analyses. The primary endpoint was the accordance with the Helsinki Declaration (and its amendments) and
median OS using the CapeOX regimen. The secondary endpoints the Clinical Trial Act (Act No. 16 of April 14, 2017) of Japan. The
were progression-free survival (PFS), time to treatment failure, study protocol was approved by the Ethics Review Boards of
response rate, relative dose intensity, and toxicity. The required participating centers and Certified Review Board (jRCTs051180126).
sample size was calculated to be 105 patients. This was based on All eligible patients provided written informed consent to
the null hypothesis that the true median OS is equal to a threshold participation. This trial was registered with the University Hospital
value of 10 months versus the alternative hypothesis that the true Medical Information Network (UMIN000022450)
2684Chin et al: Safety Analysis of CapeOX in Elderly Patients With AGC
Table II. Adverse events observed in elderly patients with advanced gastric cancer (n=20) treated with the CapeOX regimen.
Grade, n
Adverse event 1 2 3 4 All grades, n (%) Grade 3/4, n (%)
Leukocytopenia 4 3 0 0 7 (35%) 0 (%)
Neutropenia 2 5 3 0 10 (50%) 3 (15%)
Anemia 2 2 0 0 4 (20%) 0 (%)
Thrombocytopenia 10 1 0 0 11 (55%) 0 (%)
Nausea 6 3 2 - 11 (55%) 2 (10%)
Vomiting 2 0 0 0 2 (10%) 0 (%)
Anorexia 4 5 2 0 11 (55%) 2 (10%)
Diarrhea 4 2 2 0 8 (40%) 2 (10%)
Fatigue 8 4 0 - 12 (60%) 0 (%)
Hand-foot syndrome 1 1 0 - 2 (10%) 0 (%)
Creatinine 1 0 0 0 1 (5%) 0 (%)
AST 9 0 0 0 9 (45%) 0 (%)
ALT 8 0 1 0 9 (45%) 1 (5%)
T.BIL 0 0 0 0 0 (0%) 0 (%)
Peripheral neuropathy 10 2 0 0 12 (60 0 (%)
ALT: Alanine aminotransferase; AST: aspartate transaminase; T.BIL: total bilirubin.
Results of their second course, treatment was subsequently discontinued
for four. Two patients needed two levels of dose reduction.
Patients. Between September 2016 and May 2017, 20 patients
were enrolled in this study. After completion of 2 initial Delay of administration. Three out of 15 patients were
courses of chemotherapy, safety analysis was conducted in administered chemotherapy without delay until the start of the
accordance with the protocol. The characteristics of these 20 third course (Figure 2), including one patient with dose
patients are shown in Table I. Their median age was 75.5 reduction at the −1 level. In eight out of 19 patients, the second
years. Half of the patients had an Eastern Cooperative course was suspended due to AEs, and in seven patients, the
Oncology Group performance score of 0. 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,
Safety. All 20 patients underwent safety analyses. Table II lists suspension was for >7 days. In the three out of five patients
the AEs and the proportion of patients experiencing them who did not have a dose reduction, the third course started with
during the first and second course of chemotherapy. One a delay of 5, 7, and 14 days, respectively.
serious AE of nausea was associated with chemotherapy.
There was no treatment-related death. Discontinuation. Out of 20 patients, five patients were
unable to complete the initial two courses of chemotherapy.
Exposure to chemotherapy. Fifteen patients completed the In three of these patients, withdrawal or investigator’s
first two courses of CapeOX chemotherapy and started the discretion were due to AE-related reasons, while grade 2
third course. The relative dose intensities of capecitabine and nausea or diarrhea was observed at discontinuation even
oxaliplatin in the initial two courses were 0.78 (95% though dose reduction was applied for two of them. CapeOx
confidence interval=0.66-0.90) and 0.92 (95% confidence was discontinued in the other two patients due to progressive
interval=0.86-0.98), respectively. disease. The second course was started with dose reduction
and a delay due to AEs in two patients.
Dose reduction. At beginning of the third course, five out of 15
patients were administered chemotherapy without dose IDMC recommendations. Although not meeting the criterion
reduction (Figure 1). Due to AEs, the oxaliplatin dose was mentioned before, it was necessary to reduce the dose (10/15)
reduced for five patients at the start of the second course, and or suspend the start of the subsequent course (12/15) due to
for six patients at the start of the third course. The capecitabine toxicity in the first two courses of the remaining patients
dose was reduced in nine patients at the start of the second (Figure 1 and Figure 2). The IDMC recommended that the
course, and for eight patients at the start of the third course for study should be continued using a reduced dose at the −1
AEs. Of the nine patients whose dose was reduced at the start level of capecitabine (750 mg/m2, b.i.d., on days 1-14 of each
2685ANTICANCER RESEARCH 42: 2683-2687 (2022)
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
Figure 1. Summary of study dose reduction of either oxaliplatin or
capecitabine. (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.
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
Figure 2. Delay of course start. *Delay in either second or third course Taiho. MN has received honoraria from Bayer, BMS, Chugai,
in patients to whom the third course of chemotherapy was administered. 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
course) and oxaliplatin (100 mg/m2 on day 1 of each course). Yakult Honsha, and has received honoraria from Chugai, Takeda and
With these reduced doses, this trial has been ongoing. Yakult Honsha. WI has received grants from Chugai and has
received honoraria from Chugai and Yakult Honsha. KY has received
Discussion 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.
Few prospective studies using combination chemotherapy
including platinum have been performed for patients with AGC
Authors’ Contributions
aged 70 years or over, especially in Japan. The safety data for
CapeOX in the first 20 patients of our study may be meaningful All Authors contributed to the protocol treatment except N.
for daily practice in elderly patients with AGC, despite the small Ishizuka. K. Yamaguchi, K. Chin, D. Takahari, and N. Ishizuka
population evaluated. It is an important issue whether an initial participated in designing the protocol and management of the study.
2686Chin et al: Safety Analysis of CapeOX in Elderly Patients With AGC
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