Abstract
Background/Aim: Metastatic colorectal cancer (mCRC) is mainly a disease of the elderly. The aim of this retrospective study was to investigate the efficacy and safety of oxaliplatin-based regimens as first-line chemotherapy in elderly patients with mCRC. Patients and Methods: We recruited mCRC patients aged ≥75 years who were treated with oxaliplatin-based chemotherapy as first-line therapy from October 2011 to November 2020. Primary outcome was median progression-free survival (PFS) and incidence of adverse events, while secondary outcomes included overall survival (OS), relative dose intensity (RDI) and tumor response rate. Results: The study enrolled 41 patients with mCRC aged ≥75 years. Median PFS and OS were 9.3 months and 38.9 months, respectively. Median rate of starting dose per standard dose and median RDI of L-OHP were 94.6% [interquartile range (IQR)=80.0-100] and 52.4% (IQR=30.2-71.1), respectively. The most common adverse events of grade ≥3 were neutropenia (21.4%), high blood pressure (16.7%), and anorexia (14.3%). Conclusion: Although the RDI of L-OHP drug was low, the PFS, OS, and incidence of adverse events were similar to previous reports of oxaliplatin-based regimens not limited to the elderly. Oxaliplatin-based regimens as first-line chemotherapy may be safely and effectively adapted to patients aged ≥75 years with mCRC by continuing chemotherapy with implementation of a reduction and discontinuation of anticancer drugs depending on adverse events.
Colorectal cancer (CRC) is mainly a disease of the elderly (1). The median age at diagnosis of CRC is about 66 years, and 29.4% of patients are diagnosed at 75 years or older (1). Expansion of the worldwide population and elevation of life expectancy have increased the number of elderly individuals, and in clinical practice, increased numbers of elderly patients with CRC undergo surgery and/or receive chemotherapy (2). Elderly patients are more likely than younger patients to present with age-related decline in organ function and comorbidities at diagnosis (3). Risks associated with old age should therefore be taken into account when treatment options are considered in these patients. However, most clinical trials of CRC have not included patients aged ≥75, because they are usually designed for patients without comorbidities (4).
Oxaliplatin (L-OHP), a third-generation platinum analog, is effective against metastatic CRC (mCRC) when used in combination with fluoropyrimidines and monoclonal antibodies raised against vascular endothelial growth factor (VEGF) (5-8) or epidermal growth factor receptors (EGFR) (9, 10). However, few reports have described the efficacy and safety of L-OHP-based regimens in elderly patients with mCRC (11-13). First, Fukuichi et al. reported a retrospective study of patients with unresectable stage IV CRC who received L-OHP-based chemotherapy as first-line chemotherapy in which the response rate, progression-free survival (PFS), overall survival (OS), and frequency of grade 3-4 toxicity were not significantly different between patients aged <75 and ≥75 years old (11). Importantly, however, the sample size of the elderly group was small (n=18). Second, Goldberg et al. reported a pooled analysis of the safety and efficacy of L-OHP in 614 patients with CRC aged ≥70 years who received the FOLFOX4 [5-fluorouracil (5-FU) + leucovorin (l-LV) + L-OHP] regimen in adjuvant, first-line, and second-line settings in 2006 (12). This study could not evaluate the efficacy of chemotherapy because the subjects included not only first-line but also adjuvant and second-line treatment. Finally, Seymour et al. reported a randomized trial designed for elderly and frail patients with previously untreated advanced CRC who were considered unfit for full-dose chemotherapy (13). The study subjects were limited to the elderly and frail patients who needed a reduced dosage, and started at 80% of standard cytotoxic drug doses. Accordingly, it remains uncertain whether oxaliplatin-based regimens as first-line chemotherapy are suitable for elderly patients with mCRC.
The aim of this retrospective study was to investigate the efficacy and safety of oxaliplatin-based regimens as first-line chemotherapy in elderly patients with mCRC.
Patients and Methods
Study design and participants. We conducted a single-center, retrospective study at Gifu University Hospital. Study participants included patients with mCRC aged 75 years or over who started L-OHP-based chemotherapy as first-line between October 2011 and November 2020. Patients who withdrew from this study were excluded.
Primary outcome was PFS and the incidence of adverse events, while secondary outcomes included OS and RDI. Data were extracted from the electronic medical and pharmaceutical records of the central database in our hospital and retrospectively analyzed.
Chemotherapy. Patients were treated with either a modified FOLFOX6 regimen every 2 weeks, or a capecitabine (CAP) plus L-OHP (CapeOX) regimen or S-1 plus L-OHP (SOX) regimen every 3 weeks. Modified FOLFOX6 consisted of 2 h continuous infusion of L-OHP at 85 mg/m2, 2 h bolus injection of L-leucovorin (l-LV) at 200 mg/m2, and 10 min bolus injection of 5-fluorouracil (5-FU) at 400 mg/m2 followed by continuous infusion of 5-FU for 46 h at 2,400 mg/m2. CapeOX consisted of 2 h bolus injection of L-OHP at 130 mg/m2 and oral administration of CAP at 1,000 mg/m2 twice a day from day 1 to day 15, followed by a rest for 7 days. SOX consisted of 2 h bolus injection of L-OHP at 130 mg/m2 and oral treatment with S-1 at 40 mg/m2 twice a day from day 1 to day 15, followed by a rest for 7 days.
Assessment of adverse events. Adverse events associated with L-OHP-based chemotherapy included hematological toxicities such as decreased white blood cells (WBC), neutropenia, thrombocytopenia, and anemia; and non-hematological toxicities including nausea, vomiting, anorexia, fatigue, peripheral neuropathy, constipation, diarrhea, oral mucositis, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), rash acneiform, dysgeusia, paronychia, proteinuria, hypertension, increased blood bilirubin, increased creatinine, increased aspartate aminotransferase, hypomagnesemia and febrile neutropenia. Symptoms of these adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (14). The incidence of adverse events was used as the primary indicator of the safety of chemotherapy.
Efficacy of chemotherapy. PFS was used as the primary indicator of the efficacy of chemotherapy. PFS was defined as the time from the start of treatment to the first of either disease progression, relapse or death from any cause, and OS as the time from the start of treatment to death.
Tumor response rates were assessed as indicators of the efficacy of chemotherapy. The tumor response was evaluated on computed tomography (CT) scans as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) using the response evaluation criteria in solid tumors (RECIST) guideline version 1.1 (15). Response rate was defined as the CR plus PR rate.
Statistical analysis. Data were analyzed using IBM SPSS version 22 (IBM Japan Ltd., Tokyo, Japan) and R software version 3.5.1 (16). Values of p<0.05 were considered significant. Patient characteristics were summarized as median with 25th and 75th percentiles for continuous variables and frequencies and percentages for categorical variables. A Kaplan-Meier estimate and log-rank test were used to assess OS and PFS.
Ethics statement. This study was conducted in accordance with the guidelines for human studies adopted by the ethics committee of Gifu University Graduate School of Medicine and as notified by the Japanese government (Institutional review board approval No. 2021-037). In view of the retrospective nature of the study, the need for informed consent from the patients was not mandated.
Results
Patient demographics. As shown in Table I, a total of 41 patients aged ≥75 years (27 men and 14 women) with mCRC receiving L-OHP-based chemotherapy as a first-line therapy were studied. Median age and body mass index (BMI) were 79 years (range=77-81 years) and 22.4 [inter quartile rage (IQR)= 19.7-23.8]. The rate of hypertensive patients was 56.1% (n=26), and median systolic pressure was 127 mmHg (IQR=117-134). Although median creatinine clearance was 59.1 ml/min (IQR=47.6-663.3), which was decreased from mild to moderate, others were in the normal range.
Patient characteristics.
The rate of patients treated with either modified FOLFOX6 + bevacizumab (B-mab), modified FOLFOX6 + panitumumab (P-mab), modified FOLFOX6 + cetuximab (C-mab), CapeOX + B-mab, and SOX + B-mab were 31.7% (n=13), 17.1% (n=7), 9.8% (n=4), 29.3% (n=12) and 12.2% (n=5), respectively.
Efficacy of treatment in elderly patients with mCRC receiving oxaliplatin-based chemotherapy as first-line therapy. The median PFS and OS were 9.3 months [95% confidence interval (CI)=7.4-12.7] and 38.9 months (95%CI=18.5-52.3), respectively (Figure 1A and B). The disease control rate of CR, PR, SD and PD and the response rate (CR + PR) were 2.4% (n=1), 34.1% (n=14), 29.3% (n=12), 31.7% (n=13) and 36.6% (n=15), respectively (Table II). The median number of courses of chemotherapy was 9 (IQR= 6-15) (Table II).
Cumulative progression-free survival (A) and overall survival (B) in patients with metastatic colorectal cancer aged ≥75 years after first-line oxaliplatin-based chemotherapy.
Response to chemotherapy and number of courses of chemotherapy.
The median rate of the starting dose per standard dose of L-OHP, 5-FU (i.v), 5-FU (d.i.v), CAP and S-1 was 94.9% (IQR=80.0-100), 97.2% (IQR=80.0-100), 97.6% (IQR=83.2-99.7), 91.7% (IQR=80.0-100) and 91.7% (IQR=80.0-100), and median relative dose intensity (RDI) was 53.9% (IQR=30.3-73.6), 51.8% (IQR=28.1-75.1), 68.7% (IQR=55.2-80.0), 65.2% (IQR=59.7-82.1) and 81.7% (IQR=72.9-86.9), respectively (Table III).
Relative dose intensity of each anticancer drug.
Reasons for discontinuation or dose reduction of anticancer drugs in treatment of chemotherapy. As shown in Table IV, the most common adverse events were peripheral neuropathy (85.7%, n=36), followed by anemia (78.6%, n=33) and anorexia (71.4%, n=30). The most common adverse events of grade ≥3 were neutropenia (21.4%, n=9), high blood pressure (16.7%, n=7) and anorexia (14.3%, n=6).
All grades and grade 3 or 4 adverse events.
Table V shows the reasons for discontinuation or dose reduction of anticancer drugs in treatment of chemotherapy. The most common reasons for discontinuation were hematological toxicities (n=26), followed by anorexia (n=12), fatigue (n=10), peripheral neuropathy (n=5), oral mucositis (n=5), pain (n=3), and palmar-plantar erythrodysesthesia syndrome (hand foot syndrome) (n=3). The most common reasons for dose reduction of anticancer drugs were peripheral neuropathy (n=15), followed by hematological toxicities (n=11), fatigue (n=9) and anorexia (n=6).
Reasons for discontinuation or reduction of chemotherapy.
Discussion
In this study, we determined that L-OHP-based regimens may be safely and effectively adapted as first-line chemotherapy in patients aged ≥75 years with mCRC by continuing chemotherapy and implementing reduction or discontinuation depending on adverse events.
A total of 63.4% (26/41) of our subjects met the start criteria of WBC (3,000-12,000/μl), hemoglobin (≥9.0 g/dl), platelet (≥10×104/μl), neutrophil (≥1,500/μl) creatinine clearance (Ccr) (≥50 ml/min), total bilirubin (T-Bil) (≤2.0 mg/dl), aspartate aminotransferase (AST) (≤100 IU/l) and alanine aminotransferase (ALT) (≤100 IU/l), which were stipulated by studies of oxaliplatin-based regimens not limited to elderly, including WJOG4407G (17), SOFT (18), NO16966 (19), OPUS (9) and PRIME (10). In our cohort, Ccr was below 50 ml/min in 13 patients; AST, ALT, and T-Bil were under their respective criteria in one patient each; and neutrophils were under the criterion in one patient. As a result, the median rate of starting dose per the standard dose of each cancer drug was high, ranging from 91.7% to 99.9%.
The incidence of grade ≥3 hematological adverse events in this study, including neutropenia, thrombopenia and anemia, showed almost no difference to that of previous studies of L-OHP-based regimens not limited to elderly patients (Table VI). In contrast, the incidence of all grades of anemia in this study was higher than that in these previous studies. The reason is considered to be to the low hemoglobin at the start of treatment, attributable to the subjects’ age of ≥75 years. Moreover, the ratio of febrile neutropenia (5%) per grade ≥3 neutropenia (21%) was higher than that in previous studies not limited to elderly (Table VI). Attention should therefore be given to the development of febrile neutropenia in elderly patients with neutropenia.
Comparison of efficacy and safety between the present study and previous studies of oxaliplatin-based regimens.
Further, the incidence of all grades and grade ≥3 neuropathy induced by L-OHP showed almost no difference to previous studies of L-OHP-based regimens not limited to elderly (Table VI), nor did the incidence of all grade and grade ≥3 other non-hematological adverse events.
The median RDI of each cancer drug in the overall period was lower than those in the SOFT (L-OHP: 75.5%; S-1: 79.9%; B-mab: 88.5%) (18) and PRIME studies [L-OHP: 77% (KRAS wild-type), 80% (KRAS mutant); 5-FU (i.v): 77% (KRAS wild-type), 80% (KRAS mutant); 5-FU (d.i.v): 78% (KRAS wild-type), 81% (KRAS mutant); P-mab: 81% (KRAS wild-type), 83% (KRAS mutant)] (10). Common reasons for discontinuation or dose reduction of anticancer drugs in this study were hematological toxicities, anorexia, fatigue, neuropathy, and oral mucositis. Nevertheless, the rate of adverse events of grade ≥3 in this study was closely similar to those of the SOFT and PRIME studies (Table VI). Moreover, despite the elderly age of our subjects, OS was longer than that in these other studies, and PFS showed almost no difference with them (Table VI). These findings therefore suggest that treatment can be continued in elderly patients with suitable control of adverse events by reduction or discontinuation of anticancer drugs based on the criteria mentioned above, and that this may result in improved efficacy of treatment, even if RDI is reduced.
AVEX is a randomized, open-label, phase 3 trial of CAP with or without B-mab in patients aged ≥70 years with previously untreated, unresectable mCRC who were not deemed to be candidates for L-OHP-based or irinotecan-based chemotherapy regimens (20). Because L-OHP was not administered, the incidence of neutropenia and febrile neutropenia was lower than that in the present study (Table VI). Additionally, there is no need to consider a decrease in QOL due to the neuropathy induced by L-OHP. However, although PFS in AVEX showed almost no difference with our present study, OS was shorter than that in our study. We previously reported that a dose reduction in L-OHP based on renal function is not needed in patients with mCRC (21, 22). Thus, L-OHP-based regimens may be recommended in elderly patients with mCRC, if neuropathy due to L-OHP is tolerated, because administration of L-OHP may contribute to the prolongation of OS.
There are several limitations to the present study. First, it was conducted under a retrospective, single-arm design, and potentially relevant confounding factors may therefore have been missed. Second, we could not evaluate the comprehensive geriatric assessment such as cancer specific geriatric assessment (23, 24). Third, although the sample size was larger than that in a similar previous report (11), it was still small. Additionally, data were obtained from a single institution. It is important to note the non-generalizability of the present results, given that it is impossible to avoid the selection bias occurring in single-institution studies. A larger randomized control study is needed to confirm these results.
Conclusion
Our study revealed that L-OHP-based regimens as first-line chemotherapy may be safely and effectively adapted to patients aged ≥75 years with mCRC by continuing chemotherapy while implementing a reduction or discontinuation of anticancer drugs depending on adverse events.
Footnotes
Authors’ Contributions
S.Y. and H.F. conceived the study concepts. S.Y., H.F. K. Murayama, and K. Matsuura performed the statistical analysis. H.I., D.W., R.K., K.U., and A.S. provided technical support. H.I., S.K., A.M., K.U., and R.K. contributed to the interpretation of data and assisted in the preparation of the manuscript. S.Y., H.F., K. Murayama, and A.S. drafted the initial manuscript. S.K., A.M., N.M., and K. Matsuura conducted critical revision of the manuscript. All Authors reviewed the manuscript.
Conflicts of Interest
H Fujii has received honoraria for lectures from Ono Pharm., Chugai Pharm., and Taiho Pharm. H Iihara has received honoraria for lectures from Taiho Pharm., Chugai Pharma., Yakult Honsha., Astellas Pharma., Eli Lilly and Company., Daiichi Sankyo., AstraZeneca plc, Nippon Kayaku, Ono Pharm., and Nippon Boehringer Ingelheim. A Makiyama has received honoraria for lectures from Eli Lilly and Company, Taiho Pharm., and Takeda Pharma. N Matsuhashi has received honoraria for lectures from Asahi Kasei Pharma, Chugai Pharm., Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, Kaken Pharm., Sanofi, Taiho Pharm., Takeda Pharm., and Yakult Honsha.; grants or research funds made to institution from Abbott, Asahi Kasei Pharma, Chugai Pharm., Covidien Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, EP CRSU, EPS Corporation, FUJIFILM, Johnson & Johnson, Kaken Pharm., Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharm., Otsuka Pharm., Sanofi, ShiftZero K.K., Taiho Pharm., Takeda Pharm., TERUMO, Tsumura, and Yakult Honsha. A Suzuki has received honoraria for lectures from Toa Eiyo, Asahi Kasei Pharma, Daiichi Sankyo, Pfizer Eisai, Nippon Shinyaku, Celltrion Healthcare Japan, Otsuka Pharm., Sandoz, Daiichi Sankyo, Nipro, Taiho Pharm., Asahi Kasei Pharma, Nippon Chemiphar, Japan Blood Products Organization, Takeda Pharm., and Nippon Boehringer Ingelheim.; and grants made to institution from Nippon Kayaku, Asahi Kasei Pharma, Chugai Pharm., Taiho Pharm., Daiichi Sankyo, Japan Blood Products Organization, Mochida Pharm., Sun Pharma. The other Authors have no conflicts of interest in relation to this study.
- Received August 8, 2023.
- Revision received September 4, 2023.
- Accepted September 6, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
