Abstract
Background/Aim: This phase II study (MCSGO-1202) aimed to evaluate the initial dose reduction of oxaliplatin in XELOX plus bevacizumab therapy. Patients and Methods: This was a phase II, multicenter, open-label, single-arm, prospective, study conducted at 14 Japanese institutions. The study included patients with metastatic colorectal cancer (mCRC) with performance status (PS) of 1 or 2 who had not undergone chemotherapy. Patients received oxaliplatin (100 mg/m2) plus bevacizumab (7.5 mg/kg) on day 1 and capecitabine (2,000 mg/m2/day) on days 1-14 of a 21-day cycle. The primary endpoint was the objective response rate. The secondary endpoints were progression-free and overall survival, 1-year survival rate, disease control rate, dose intensity, and adverse events. Results: Between April 2012 and March 2016, 56 patients were enrolled. The median age was 71 years (range=44-85 years), and the majority (90.6%) had a PS of 1. A complete response was observed in three patients (5.7%), partial response in 24 (45.3%), stable disease in 22 (43.4%), and progressive disease in one (1.9%). The median progression-free survival and overall survival were 11.4 and 26.5 months, respectively. The most common grade 3-4 adverse events were leucopenia (15.1%), neutropenia (9.4%), neuropathy (9.4%). Conclusion: The dose-reduction strategy of oxaliplatin was effective for elderly or vulnerable patients with mCRC.
Colorectal cancer is the third most common type of cancer in men and the second most common cancer in women (1). To date, standard first-line chemotherapy for metastatic CRC (mCRC) is the cytotoxic combination of fluoropyrimidine and either oxaliplatin or irinotecan, with or without a targeted agent, such as an angiogenesis inhibitor (bevacizumab) or anti-epidermal growth factor receptor antibody (cetuximab or panitumumab) if RAS is wild-type (2–5). Since these drugs have greatly improved outcomes of mCRC, it is crucial to select the optimal order and doses of the agents to be administered to improve the chances of effective long-term disease control with minimal adverse effects and maximal quality of life.
Elderly patients are not well represented in clinical trials, and those who are included are often a selection of fit elderly adults (6–8). Older age or frailty are risk factors for chemotherapy toxicities because of physiological changes, organ function, limited social support, and the presence of comorbidities (9). Therefore, specialized workup is required to avoid the toxicity of chemotherapy to this population.
The combination of capecitabine and oxaliplatin, known as XELOX or CAPEOX, has been shown to be non-inferior to FOLFOX, which is a combination of 5-fluorouracil/leucovorin and oxaliplatin, as first-line treatment of mCRC (10, 11). While the XELOX regimen, compared with the FOLFOX regimen, has some merits such as triweekly schedule and no requirement for an infusion pump, an oxaliplatin dose up to 130 mg/m2 may lead to increased toxicity compared with the use of 85 mg/m2 of the modified FOLFOX6 regimen (12). The dose intensity of oxaliplatin in XELOX with or without bevacizumab has been reported to be 80 to 90% (10, 13). Therefore, it seems that efficacy does not decline by starting oxaliplatin at 100 mg/m2, and adverse events are expected to be reduced.
This study was conducted to assess the efficacy and toxicity of the use of an initial dose of 100 mg/m2 of oxaliplatin in XELOX with bevacizumab to reduce adverse events.
Patients and Methods
Study design. This was a phase II, multicenter, open-label, single-arm, prospective, study conducted in 14 Japanese institutions. This study was carried out according to the ethical principles of the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects and was approved by the institutional review board of the participating institutions. All patients provided written informed consent. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000007662.
Patients. Patients with histologically confirmed CRC who had measurable unresectable and/or metastatic disease with an Eastern Cooperative Oncology Group performance status of 1 or 2 were eligible for this study. Other eligibility criteria included: No prior systemic chemotherapy for advanced colorectal cancer; ≥20 years of age; adequate baseline bone marrow function (leucocyte count ≥3,000/mm3, neutrophil count ≥1,500/mm3, hemoglobin ≥9.0 g/dl, and platelet count ≥100,000/mm3); adequate baseline hepatic function [serum total bilirubin <1.5 × upper limit of normal (ULN), and serum aspartate aminotransferase and alanine aminotransferase <2.5×ULN (or <2.5×ULN when liver metastases were present)]; adequate baseline renal function (serum creatinine <1.5×ULN); the ability to ingest substances orally; no brain metastasis; and a life expectancy of ≥90 days.
Major exclusion criteria were as follows: History of serious hypersensitivity for fluorouracil, levofolinate calcium, platinum, or bevacizumab; history of adverse events related to dihydropyrimidine dehydrogenase loss; two cancers within 5 years; major surgery within 4 weeks before enrollment; administration of antithrombotic drugs or anti-platelet drugs; uncontrollable serious comorbidities such as diarrhea, diabetes, hypertension, bleeding, peptic ulcer, or infection; symptoms of colorectal obstruction; history of gastrointestinal perforation within the last 1 year; renal failure that needed to be treated or proteinuria dipstick test of 2+ or higher by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (14).
Treatment. Patients received oxaliplatin (100 mg/m2) plus bevacizumab (7.5 mg/kg) intravenously on day 1 and capecitabine twice daily at a dose based on body surface area (2,000 mg/m2 per day) on days 1-14 of a 21-day cycle. This schedule was repeated until disease progression, development of unacceptable toxicity, or patient withdrawal of consent. Dose reductions or interruptions were allowed according to the study protocol. Subsequent dose escalations were not allowed. When the administration of oxaliplatin was discontinued due to oxaliplatin-induced toxicity, capecitabine plus bevacizumab was permitted. However, bevacizumab monotherapy, or administration of oxaliplatin without capecitabine were not allowed. Dose modifications were based on the most severe adverse events observed during the previous treatment cycle. In patients with febrile neutropenia, grade 3-4 of leucopenia, neutropenia, or thrombocytopenia, or grade 2-4 diarrhea, anorexia, nausea, or vomiting, or other grade 3-4 treatment-related toxicities, doses of oxaliplatin and capecitabine were reduced to 85 or 65 mg/m2 and 1,500 or 1,000 mg/m2, respectively from the next cycle. If severe grade 3-4 infusion reaction related to oxaliplatin occurred, the administration of oxaliplatin was discontinued. Oxaliplatin was suspended for grade 2 or 3 neuropathy until recovered to grade 1. When grade 2-3 neuropathy occurred again after rechallenge with oxaliplatin, oxaliplatin was discontinued. If patients had toxicities related to bevacizumab such as grade 3 or 4 proteinuria, or grade 3 or 4 hypertension, the administration of bevacizumab was suspended. No dose reduction of bevacizumab was set up for this study.
Assessment. Tumor assessments by computed tomographic scans covering the chest, abdomen, and pelvis were performed every 9 weeks until disease progression. Responses were evaluated by investigators according to the Response Evaluation Criteria for Solid Tumors (RECIST) criteria version 1.1 (15). Physical examination and laboratory data were assessed at screening, baseline, and every 3 weeks. Assessment of all toxicities was graded according to CTCAE version 4.0 (14).
Statistical analysis. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), 1-year survival rate, disease control rate (DCR), dose intensity, and adverse events. ORR was defined as the proportion of patients with a complete or partial response according to the RECIST criteria version 1.1. The DCR was defined as the proportion of complete or partial response, and stable disease. PFS was defined as the time from the date of enrollment to the date of disease progression or death from any cause. OS was defined as the time from the date of enrollment to the date of death from any cause, and the 1-year survival rate was defined as the proportion of patients who were alive at 1 year after enrollment.
The required sample size was estimated based on an expected ORR of 53% and a threshold ORR of 37% based on previously published studies of XELOX plus bevacizumab (13, 16). It was estimated that a total sample size of at least 52 patients was required to allow a one-sided significance level of 10% and a power of 80% considering the patients excluded from the full analysis set (FAS). ORR, DCR, PFS, and OS were analyzed in the FAS, which included all enrolled patients who met the inclusion criteria and who received study treatment. The safety analysis set included all patients who received study treatment. We used the Kaplan–Meier method to estimate survival curves and Greenwood’s formula to calculate the 95% confidence interval (CI) for survival rates. Statistical analyses were conducted with R, version 3.0.1.
Results
Patient characteristics. Between April 2012 and March 2016, a total of 56 patients were enrolled from 14 institutions in Japan. One patient was ineligible due to a short duration from surgery to entry. Two patients withdrew before study treatment was administered. Efficacy and safety analyses were therefore conducted in FAS of the remaining 53 patients. The characteristics of the 53 eligible patients are listed in Table I. The median age was 71 years (range=44-85 year), and 22 patients (41.5%) were above 75 years old. The PS of the majority of the 48 patients (90.6%) was 1. The others had PS 2, and there was no patient whose PS was 0. Comorbidities were present in 28 out of the 53 patients. The most frequent comorbidity was hypertension (n=16 patients), followed by diabetes (n=5).
Patient characteristics.
Treatment. At the time of analysis, the median follow-up duration was 19.1 months. During the follow-up, 47 patients (88.7%) discontinued study treatment, and six continued. Disease progression was the most common reason for treatment discontinuation [26 patients (49.1%)], followed by an unrelated adverse event (AE) [13 (24.5%)], patient refusal [3 (5.7%)], and conversion surgery because of prominent response [five patients (9.4%)].
Efficacy. A complete response was observed in three patients (5.7%), partial response in 24 (45.3%), stable disease in 22 (43.4%), and progressive disease in one (1.9%); it was not possible to evaluate the response in two patients (3.8%). Therefore, the ORR was 50.9% (95% CI=36.8-64.9), and the primary endpoint was met. The DCR was extremely favorable at 94.3%. A waterfall plot of the best overall response for each patient is shown in Figure 1. The median PFS was 11.4 (95% CI=8.4-12.7) months (Figure 2A). The median OS was 26.5 (95% CI=19.1-33.3) months, and the 1-year OS rate was 82.4% (95% CI=68.9-90.4) (Figure 2B). ORR, PFS, and OS for the subgroup of RAS status, and for the subgroup of sidedness of primary tumor site are reported in Table II.
Waterfall plot of the best overall response for each patient. The best calculated responses based on measurable lesions of the 50 evaluable patients. Three patients who discontinued the treatment before diagnostic imaging assessment were not included. CR: Complete response; PR: partial response; SD: stable disease; PD: progressive disease.
Progression-free survival (PFS) (A) and overall survival (B) for all eligible patients.
Tumor response by Response Evaluation Criteria for Solid Tumors criteria version 1.1 (15), and median survival according to mutation status and sidedness of primary tumor.
Safety. All AEs that occurred in patients are shown in Table III. Among the hematological AEs, the proportions of grade 3-4 leucopenia and neutropenia were 15.1% and 9.4%, respectively. The most frequent common non-hematological AE was neuropathy (any grade 56.6%; grade 3-4 9.4%). There was no treatment-related death.
Adverse events according to the Common Terminology Criteria for Adverse Events v. 4.0 (14).
Discussion
The eligibility criteria of this trial were limited to PS 1 to 2, and the median age was higher than other previous Japanese first-line chemotherapy trials for patients with mCRC (13). This study demonstrated that XELOX therapy with a reduced dose of oxaliplatin was a safe and effective treatment for vulnerable or elderly patients with mCRC. With the use of reduced starting drug doses adopted for this population, combination chemotherapy including oxaliplatin seems preferable to single-agent fluoropyrimidines.
The subgroup of frail or elderly patients has a high risk of severe AEs from chemotherapy compared with fit or younger patients due to a decline in organ function or multiple comorbidities (6). Therefore, this population is regarded as not being able to tolerate intensive chemotherapy. In an off-trial situation, physicians tend to use reduced-doses or single-agent schedules for patients that the treating oncologist considered standard full-dose regimens to be unsuitable (17–20). They are concerned about the AEs of standard-dose treatments, patients’ wishes to avoid toxic effects, and an assumption to improve quality of life. Several randomized clinical trials have demonstrated superior response rates and PFS times with doublet therapy compared with single-agent fluoropyrimidine therapy (21–23). The efficacies of our trial were comparable to those of historical data of XELOX with bevacizumab for mCRC (13, 16).
Increasing the dose in chemotherapy is assumed to increase both the efficacy and toxicity of chemotherapy. The recommended dose and the maximum tolerated dose (MTD) of anticancer agents is traditionally determined by prespecified rules based on actual observations of target events (e.g., dose-limiting toxicity) in a phase I trial (24). However, reducing the dose of chemotherapy may actually reduce the efficacy. Furthermore, the MTD is usually determined for fit patients with a good performance status, and the administration of MTD can lead to overdose for the elderly or frail patients.
In the phase I trial to set the dose of XELOX therapy, the dose of oxaliplatin was fixed at 130 mg/m2 as determined from another phase I study of oxaliplatin (12), and different doses of capecitabine (500, 825, 1,000 or 1,250 mg/m2 twice daily, days 1-14) were assessed (25). Most principal dose-limiting toxicities determined during the first treatment cycle were diarrhea or neutropenia. The dose intensity of oxaliplatin in XELOX at an initial dose of 130 mg/m2 of oxaliplatin with or without bevacizumab was about 90% even in the previous clinical trials for fit patients (10, 13). Matsui et al. reported a favorable response rate of 51% and a median PFS of 11.3 months with lower adverse events in biweekly XELOX plus bevacizumab at a dose of 85 mg/m2 of oxaliplatin (26). Therefore, the reduction in the initial dose of oxaliplatin to 100 mg/m2 might have reasonably reduced the AEs of initial chemotherapy.
From the analysis of large number cohort or meta-analysis, mCRC of the right-colon were associated with poorer outcomes, and the impact of sidedness of the primary tumor on bevacizumab efficacy are controversial (27–30). Although subgroup analyses of RAS status and primary tumor site did not differ significantly, no conclusions can be drawn due to the small sample size. In addition, because this was a single-arm study, therefore it is not possible to distinguish whether any of these factors are predictive markers for bevacizumab or have any prognostic value. KRAS or RAS wild-type were clearly less frequent among patients with right-sided tumors in our study (data not shown). These deviations resulting in similar prognostic values in relation to sidedness might explain the conflict of data from previous reports (31–34).
Our trial has some limitations. Firstly, it had a small sample size and was a single-arm trial, which might have caused selection bias. Secondly, the eligibility criteria were not strictly limited to elderly or vulnerable patients. Finally, comprehensive assessment before treatment was not performed.
In conclusion, the dose-reduction strategy for oxaliplatin was effective for elderly or vulnerable patients with mCRC.
Acknowledgements
The Authors would like to thank all the patients, family members, and staff from all the hospitals that participated in this study. The Authors also thank members of the datacenter of SCCRE, especially for Y Takeda, Ph.D. for her generous support.
Footnotes
Authors’ Contributions
DS, TS, and TM designed the concept and the protocol of the work, AK, NM, TO, DS, JH, KN, MI, TK, MT, YK, HT, KM, MU, TS, and TM collected the data. MU and TM directed the project. AK, DS and TS analyzed and interpreted the data. AK wrote the article with support from DS and NM. MM, YD and HE supervised this project. All Authors provided critical feedback and contributed to the final article.
Conflicts of Interest
Dr. Sakai reports grants and personal fees from Chugai Pharma, grants from Yakult Honsha, grants from Ono Pharmaceutical, grants and non-financial support from Daiichi Sankyo, grants from Lilly Japan, outside the submitted work. Dr. Satoh reports grants, personal fees and others from Ono Pharmaceutical, grants, personal fees and others from Chugai Pharmaceutical, grants, personal fees and others from Yakult Honsha, grants and personal fees from Elli Lilly, grants from MSD, grants and other from Bristol Myers, grants from Astellas, grants and personal fees from Daiichi-Sankyo, grants and others from Taiho Pharmaceutical, personal fees from Takara-Bio, grants and others from Sanofi-Aventis, grants from Giliad Sciences, grants from Palexell, outside the submitted work. All other authors declare no conflicts of interest.
- Received January 26, 2022.
- Revision received February 17, 2022.
- Accepted February 21, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.