Abstract
Background/Aim: The study aimed to determine the effectiveness of cetuximab and panitumumab on the survival of patients with metastatic colorectal cancer or those who had undergone conversion surgery and to identify their prognostic factors. Patients and Methods: This retrospective cohort study used data from patients with metastatic colorectal cancer who received cetuximab or panitumumab as first-line targeted agent-based therapy. Overall survival and conversion surgery rates were evaluated, and the prognostic factors were determined. Results: A total of 1,749 and 318 patients received cetuximab or panitumumab with chemotherapy, respectively. Overall survival and conversion surgery rates were similar between the cetuximab [hazard ratio (HR)=0.96] and panitumumab groups (HR=1.00). The prognostic factors associated with metastasectomy significantly lowered mortality among patients with metastatic colorectal cancer (HR=0.61). Older age (≥70 years), tumor stage 4B and 4C, right-sided tumors, mucinous adenocarcinoma, primary tumor resection, and the number of positive lymph nodes were associated with higher mortality and lower conversion surgery rates. Conclusion: Though panitumumab- and cetuximab-based therapies showed no differences, several factors, such as age over 70 years old, tumor stage 4B and 4C, undifferentiated carcinoma, mucinous carcinoma, right-sided tumor, number of positive lymph nodes, obstruction, and primary tumor resection increased the mortality risk of patients. This study underscores the importance of metastasectomy in current treatment guidelines and future clinical trials.
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally (1). During the first diagnosis, the liver and lungs are the sites of distant metastases in about 20-25% of CRC patients (2). In recent decades, metastatic CRC (mCRC)-caused mortality rate has declined because of improvements in early detection and comprehensive treatment plans, particularly with the use of a combination of chemotherapy and targeted monoclonal antibodies (mAbs). Among the mAbs against epidermal growth factor receptor (EGFR), panitumumab, a human immunoglobulin G2 (IgG2), and cetuximab, a chimeric IgG1 antibody, were approved as therapies for mCRC. Chemotherapy with 5-fluorouracil (5-FU)/leucovorin (LV)/oxaliplatin (FOLFOX) or FOLFIRI (5-FU/LV/irinotecan) combined with targeted mAbs is the most common therapeutic regimen for patients with mCRC (3, 4). However, the National Comprehensive Cancer Network (NCCN) guidelines (version 4, 2021) suggest intensive systemic chemotherapy with a targeted agent (such as panitumumab or cetuximab) as the first-line therapy for patients with mCRC (5-8).
In an indirect network meta-analysis by Wu et al., the ranking of treatment efficacy showed that panitumumab is the most effective agent for improving overall survival (OS) of patients with mCRC, among a few first-line targeted agents, based on the surface under the cumulative ranking curve; in contrast, cetuximab is the most effective for improving the objective response rate (ORR) (4). Furthermore, a post hoc analysis by Taniguchi et al. reported that panitumumab was a better second-line targeted therapeutic agent than cetuximab for improving OS and progression-free survival (PFS) in patients with mCRC (9). Patients’ survival rate increased when their unresectable mCRC was converted to a resectable disease, following first-line targeted therapy, which is referred to as achieving conversion surgery (7, 8, 10, 11). However, to our knowledge, no previous study has investigated which anti-EGFR-targeted agent (cetuximab vs. panitumumab) can achieve a higher successful conversion surgery rate. The comparative effectiveness of cetuximab or panitumumab combined with chemotherapy as first-line targeted therapy for mCRC remains unclear. Further, studies reporting the differences in survival outcomes and conversion surgery rates between patients with mCRC treated with cetuximab or panitumumab can facilitate precise clinical decisions.
In Taiwan, cetuximab or panitumumab, combined with chemotherapy, as the first-line systemic therapy for patients with Kirsten rat sarcoma virus (KRAS) wild type mCRC, have been reimbursed by the National Health Insurance (NHI) since December 1, 2012, and April 1, 2016, respectively (12). Using the data from the large nationwide population datasets, the Taiwan Cancer Registry (TCR) and the NHI Database (NHID), the study aimed to 1) assess the effectiveness of cetuximab and panitumumab on the survival outcomes of patients with mCRC or those who had undergone conversion surgery, and 2) identify the prognostic factors impacting OS and achieving conversion surgery in patients with mCRC treated with first-line therapy (cetuximab or panitumumab) combined with chemotherapy.
Patients and Methods
Data sources. NHID, a nationwide single-payer insurance program in Taiwan implemented in 1995, covers more than 99.99% of its population (13, 14). NHID stores data in different datasets, including registries of beneficiaries, ambulatory care claims, inpatient claims, and prescriptions dispensed at pharmacies and medical facilities and by board-certified specialists; thus, it contains patient information on cancer diagnosis, clinical visits, admission, medication records, surgical records, and comorbidities, and the claims data are representative of the country. This database was used to collect complete records of the prescriptions of targeted agents, such as cetuximab and panitumumab, as well as the patients’ surgical status. The claims in the NHID were thoroughly examined to determine the time of initiation and discontinuation of targeted therapy and chemotherapy for mCRC.
The TCR database, organized and funded by the Ministry of Health and Welfare, Taiwan, was implemented in 1979 and has an excellent coverage rate (97%); it includes a self-check procedure using standardized logic algorithms at the TCR central office to identify and correct potential errors before data submission (15). This database was used to identify the patient’s cause of death to obtain mortality data and was traced until December 31, 2020. These databases were linked to individual personal identification numbers (PINs) to establish patient-level information on demographic characteristics and research outcomes, and the data were anonymized. The study protocol was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital (KSVGH21-CT1-25) and the requirement for participants’ consent was waived owing to the retrospective study design and anonymization of patient data. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Study population. This is a retrospective cohort study of newly diagnosed patients with mCRC from January 1, 2013, to December 31, 2019. The study used the International Classification of Diseases for Oncology (ICD-O) codes (third edition): C180-C189, C199, and C209, to identify patients who underwent treatment with cetuximab or panitumumab as first-line targeted therapy in the TCR database. The index date was defined as the date on which the patient received the first cycle of cetuximab or panitumumab. The study enrolled patients who underwent at least six cycles of targeted therapy, with an interval shorter than 60 days between consecutive cycles. The study excluded patients if they were 1) younger than 20 years, 2) underwent targeted therapy within a year before the diagnosis date, 3) underwent first-line therapy for less than six cycles, or had a follow-up duration shorter than 3 months, or 4) received targeted therapy with intervals longer than 60 days between consecutive cycles. Based on these criteria, the biweekly systemic therapy of at least six cycles within three months is the standard treatment for patients with advanced colon cancer. Since the patients might not be able to receive systemic therapy, consistently, every two weeks in a real-world situation, the study chose to enroll patients with an interval shorter than 60 days between consecutive cycles.
Study variables and outcomes. Variables analyzed included the year of diagnosis, year of targeted therapy, age, sex, tumor differentiation grade, primary tumor location, tumor stage (4A, 4B, and 4C), tumor size, lymph node status, carcinoembryonic antigen (CEA), Kirsten rat sarcoma virus (KRAS) status, bowel obstruction, bowel perforation, radiotherapy, surgical procedures before the index date, targeted agent (TA) cycles, Charlson comorbidity index (CCI) score (16, 17), and co-medication one year before the index date. In addition, mucinous (codes M-8470 and M-8480-8481) and signet ring cell (code M-8490) histologic types were included in the analyses. Histological definitions for adenocarcinoma included the following ICD-O codes: M-8140, M-8210-8211, M-8255, M-8260-8261, M-8263, M-8323, M-8470, M-8480-8481, and M-8490. Primary tumor location and sidedness [right-sided (cecum, ascending colon, hepatic flexure, or transverse colon) vs left-sided (splenic flexure, descending colon, sigmoid colon, rectosigmoid junction, or rectum)] were also analyzed for the groups. According to the American Joint Committee on Cancer CRC staging system (seventh edition), stage 4A refers to distant metastasis to one organ, and stage 4B and 4C refer to metastasis to two or more organs. The primary outcomes reported were OS and conversion surgery rates, which were evaluated from the index date to the end of 2020, death, or censorship. Conversion surgery was defined as surgical treatment with the goal of resection in patients with initially unresectable mCRC in response to systemic therapy. The secondary outcomes included the identification of prognostic factors affecting OS or conversion surgery.
Statistical analyses. Descriptive statistics were used to express the demographic and tumor characteristics of the patients. A standardized mean difference exceeding 0.1 was used to identify differences in baseline covariates between the patient groups treated with cetuximab or panitumumab (18, 19). OS was calculated using the Kaplan–Meier method and compared using the log-rank test for unadjusted survival differences between the groups. The cumulative incidence of conversion surgery rates was also compared. However, the adjusted survival hazard ratio (HR) for comparison between the two groups was estimated using multivariate analysis by fitting a Cox proportional hazards model and expressed as HRs and their corresponding 95% confidence intervals (CIs). Owing to the differences in the reimbursement dates in NHID, where the costs of cetuximab and panitumumab were reimbursed for patients with mCRC on December 1, 2012, and April 1, 2016, respectively, a sensitivity analysis was performed to compare the cetuximab group to the panitumumab group after an index date in 2016 to examine the robustness of our findings. Prognostic factors for OS and conversion surgery were estimated by fitting a Cox proportional hazard model. The model included the following covariates measured during follow-up: year of diagnosis, index year, age, sex, income, tumor differentiation grade, stage, tumor size, lymph node status, radiotherapy, surgical procedures before the index date, CCI score, CEA status, bowel obstruction, and a bowel perforation. Subgroup analyses for OS and conversion surgery were performed by examining the interaction terms of treatment status (cetuximab vs panitumumab) and clinical and tumor characteristics as covariates in the models. All statistical analyses were performed using the SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA), and two-tailed p-values <0.05 were considered significant.
Results
Cohort characteristics. A total of 2,067 patients with mCRC who received targeted therapy combined with chemotherapy as the first-line regimen enrolled between January 1, 2013, and December 31, 2019, were included in the study after applying the exclusion criteria (Figure 1). Of these, 1,749 and 318 patients were included in the cetuximab and panitumumab therapy groups, respectively. Patient characteristics are summarized in Table I.
Flow chart of cohort selection. mCRC, Metastatic colorectal cancer.
Baseline characteristics of patients with mCRC before targeted therapy.
Overall survival and conversion surgery. Among the enrolled patients, 1,289 (62.36%) died during follow-up: 1,157/1,749 (66.2%) in the cetuximab group and 132/318 (41.5%) in the panitumumab group. The median OS of the panitumumab group (median OS=29.5 months, 95% CI=26.0-35.1) was similar to that of the cetuximab group (median OS=26.2 months, 95% CI=24.9-27.3), with a crude HR of 0.91 (95% CI=0.76-1.09) and adjusted HR of 0.96 (95% CI=0.72-1.28). In contrast, the rate of conversion surgery showed no significant difference between the groups [crude HR=1.28 (95% CI=1.00-1.64), adjusted HR=1.03 (95% CI=0.73-1.37)] (shown in Table II, Figure 2). Among the patients with mCRC with an index date after 2016, the crude and adjusted HRs of OS for the cetuximab and panitumumab groups were 0.99 (95% CI=0.72-1.37) and 0.87 (95% CI=0.64-1.18), respectively. The crude and adjusted HRs of conversion surgery rates for the cetuximab and panitumumab groups were 1.23 (95% CI=0.95-1.60) and 1.04 (95% CI=0.75-1.44), respectively, among patients with mCRC (shown in Table III). No significant interactions were observed in the subgroup analyses of the primary outcomes (Figure 3).
Prognostic factor analysis for OS and conversion surgery rates.
Kaplan-Meier survival curves for patients with metastatic colorectal cancer (mCRC). (A) Overall survival (OS); (B) Cumulative incidence curves for conversion surgery.
Prognostic factor analysis for OS and conversion surgery rates after 2016.
Subgroup analyses of (A) overall survival (OS) and (B) conversion surgery associated with the use of panitumumab versus cetuximab.
Prognostic factor analyses for OS and conversion surgery rates. Univariable analysis showed that age ≥70 years, tumor stage 4B and 4C, poorly differentiated and undifferentiated tumor anaplasticity, tumor size >5 cm, signet ring cell and mucinous carcinoma, right-sided tumor, number of positive lymph nodes, bowel obstruction, and bowel perforation were significantly associated with a poor OS outcome. Resections of the primary tumors, the liver, and the lungs before the index date, age <50 years, index years, and TA cycle number were significantly associated with better OS. Additionally, the multivariable analysis demonstrated that age >70 years, tumor stage 4B and 4C, undifferentiation anaplasia, mucinous carcinoma, right-sided tumor, number of positive lymph nodes, CEA, obstruction, and primary tumor resection before the index date were independently predicting prognostic factors for poor OS, and liver metastasectomy before the index date and the number of cycles of targeted therapy was independent prognostic factors for better OS. Univariate analysis for conversion surgery showed that age ≥70 years, tumor stage 4B and 4C, primary tumor resection before the index date, mucinous carcinoma, right-sided tumor, number of positive lymph nodes, CCI score, and TA cycle number had significantly lowered the possibility for conversion surgery. Similarly, multivariate analyses also revealed that age ≥70 years, tumor size >5 cm, mucinous type, right-sided tumor, tumor stage 4B and 4C, primary tumor resection before the index date, number of positive lymph nodes, and TA cycle number independently decreased the possibility of conversion surgery (Table II).
Discussion
The present study demonstrated that the survival benefit and conversion surgery outcomes were similar in patients with mCRC who were treated with panitumumab or cetuximab plus chemotherapy as the first-line targeted therapy. These efficacy findings were consistent with those of previous studies, which implies comparable efficacies induced by panitumumab and cetuximab plus chemotherapy in patients with refractory mCRC (20-23). Moreover, our findings were similar to those of an indirect network meta-analysis by Wu et al. (4), wherein a head-to-head comparison of survival outcomes is reported using the first-line targeted therapies, panitumumab, and cetuximab, plus chemotherapy, in patients with KRAS wild-type mCRC. Interestingly, the ASPECCT study reported that panitumumab yielded better survival outcomes than cetuximab in a subgroup analysis of patients previously treated with bevacizumab (9, 21). This might be because of a difference in the antitumor activity of panitumumab and cetuximab in patients with mCRC who received prior bevacizumab. A possible mechanism for the differing efficacies of panitumumab and cetuximab might be owing to their varying affinities for EGFR binding. Panitumumab has been reported to have a one- to two-log higher affinity than cetuximab but has a binding epitope that is similar to that of cetuximab (24). Several studies have demonstrated that cetuximab adequately blocks the binding of low-affinity ligands to EGFR but cannot block the activation of the EGFR pathway by high-affinity ligands (25). In contrast, panitumumab effectively inhibits both low- and high-affinity ligand-driven ERK signaling (26). Clinical data indicate that the efficacy of cetuximab may be reduced in patients with mCRC who have previously received bevacizumab (27). Thus, panitumumab plus chemotherapy could be an alternative to cetuximab plus chemotherapy in patients with mCRC.
Prognostic factors, such as age >70 years, tumor stage 4B and 4C, undifferentiation and anaplastic differentiation, tumor sidedness, presence of mucinous adenocarcinoma, number of positive lymph nodes and primary tumor resection, reduced the survival and conversion surgery benefits in patients with mCRC, identified using multivariate analysis. The survival outcomes associated with different prognostic factors in the present study are similar to those reported in previous studies (9, 28-33). These prognostic factors are associated with higher mortality because patients with these disease statuses were less likely to receive conversion surgery. However, a previous study has reported evidence of survival benefits in patients with mCRC who underwent conversion surgery (10). The present study confirmed the OS benefits of patients with mCRC who underwent liver metastasectomy using multivariate analysis.
The subgroup analyses in our study for OS and conversion surgery outcomes showed no significant interactions or differences. Similar to our findings, Sakai et al. and Yamaguchi et al. also reported no significant difference in the survival outcomes induced by panitumumab and cetuximab among patients with refractory mCRC (20, 22). To the best of our knowledge, the present study is the first to specifically focus on patients with mCRC to estimate the OS and conversion surgery outcomes of first-line therapy with panitumumab vs. cetuximab combined with chemotherapy. Thus, we extended the current evidence to demonstrate that the conversion surgery outcome of first-line therapy with panitumumab or cetuximab was associated with a comparable OS outcome among patients with mCRC.
The strengths of this study include the comprehensive enrollment of patients with mCRC from a nationwide claims database; the ability to capture complete information on comorbidities, treatments, procedures, and medications reimbursed by the NHI; and confirmed cancer diagnosis via linkage to the TCR. Furthermore, the sample size of the present study was larger than that of previous studies. These factors improved the validity of our analysis and allowed us to compare the effectiveness of the two targeted biologics-based therapeutic regimens.
Study limitations. First, differences in information on the different reimbursement dates in the NHID (panitumumab and cetuximab were reimbursed for patients with mCRC on April 1, 2016, and December 1, 2012, respectively) could have introduced a historical bias. To overcome this limitation, sensitivity analysis was performed to compare the groups on the index date after 2016 to examine the study’s robustness. Second, owing to the lack of data on disease severity, the number of metastatic organs, and the extent of metastatic disease for analysis, we employed the covariate, tumor stages 4A, 4B, and 4C, to adjust for the confounding effect. Finally, there was no information in the databases on the patients’ performance status, nutritional condition, length of life expectancy, and hematologic, hepatic, and renal function. Instead, the study adjusted for age, comorbidities, and co-medication for covariates between the two groups.
Conclusion
This study’s findings suggest that panitumumab in combination with chemotherapy as first-line therapy provides an OS benefit and a conversion surgery rate similar to those with cetuximab in patients with mCRC. Some prognostic factors caused patients with mCRC to achieve a lower conversion surgery rate, which also increased mortality risk. This underscores the importance of metastasectomy in current treatment guidelines and future clinical trials.
Acknowledgements
The Authors thank Health Data Science Center, National Cheng Kung University Hospital, for providing administrative and technical support and Ms. Hsiao-Ling Chiu of the Cancer Center, Kaohsiung Veterans General Hospital, for her advisory comments on interpreting the results. This research was funded by Kaohsiung Veterans General Hospital [grant number KSVGH111-070].
Footnotes
Authors’ Contributions
Conceptualization, Y.C.S., C.C.W., C.C.S., and Y.H.C.; methodology, validation, formal analysis, investigation, resources, data curation, Y.C.S., C.C.W., M.C.H., C.W.H., Y.C.C., and Y.C.W.; writing – original draft preparation, Y.C.S., and C.C.W.; writing – review and editing, C.C.S. and C.C.W.; supervision, Y.C.S. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received July 29, 2023.
- Revision received September 19, 2023.
- Accepted September 26, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
