Abstract
PURPOSE
Metastatic colorectal cancer (mCRC) is a significant global health burden. This retrospective study compared the effectiveness of trifluridine/tipiracil (FTD/TPI), regorafenib, and chemotherapy rechallenge for third-line mCRC treatment.
MATERIALS AND METHODS
We reviewed the medical records of 132 patients with mCRC treated with regorafenib, FTD/TPI, or a rechallenge with the initial chemotherapy regimen in a third-line setting from four different institutions. The primary end point was progression-free survival (PFS). Secondary end points were objective response rate and overall survival (OS) across the three treatment approaches.
RESULTS
Twenty-nine patients received chemotherapy rechallenge, and 103 received FTD/TPI or regorafenib. Patients' characteristics were comparable, except for a lower number of left-sided primaries and KRAS wild-type tumors in the FTD/TPI-regorafenib group. The median PFS for the entire group was 3.0 months, and the median OS was 13.7 months. Chemotherapy rechallenge has resulted in a median PFS of 3.1 months and a median OS of 21.2 months, compared with 2.9 months (PFS) and 12.6 months (OS) for the FTD/TPI-regorafenib group. Multivariate analyses identified male sex and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 as independent prognostic factors for better PFS, whereas chemotherapy rechallenge, localized stage at diagnosis, and an ECOG PS of 0-1 were significant prognostic factors for better OS.
CONCLUSION
This study suggests that chemotherapy rechallenge may provide a survival benefit in the third-line treatment of mCRC. However, patient characteristics, such as sex and ECOG PS, should also be considered in treatment decisions. Further prospective studies are required to confirm our findings.
FTD/TPI, regorafenib, and chemotherapy rechallenge are third-line treatment options for metastatic colorectal cancer
INTRODUCTION
Metastatic colorectal cancer (mCRC) remains a significant global health burden, with over 1.9 million new cases and nearly 935,000 deaths reported worldwide in 2020.1 Although advances in systemic therapies and surgical techniques have improved patient outcomes, the management of mCRC in a third-line setting remains a challenge.2 The current standard of care in this setting includes the use of novel targeted agents, such as trifluridine/tipiracil (FTD/TPI) and regorafenib, both of which have demonstrated improved overall survival (OS) compared with placebo in phase III clinical trials.3,4
CONTEXT
Key Objective
The primary aim of this study was to confront the challenge of third-line treatment for metastatic colorectal cancer (mCRC) by directly comparing the effectiveness of existing standard-of-care options—trifluridine/tipiracil (FTD/TPI), regorafenib, and chemotherapy rechallenge.
Knowledge Generated
Analysis of data from 132 patients with mCRC revealed that those treated with chemotherapy rechallenge had a superior median progression-free survival (PFS) and overall survival (OS) of 3.1 and 21.2 months, respectively. By contrast, patients receiving FTD/TPI or regorafenib had a median PFS of 2.9 months and OS of 12.6 months. In addition, a localized initial cancer stage and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 were significant prognostic factors for better OS in patients who underwent chemotherapy rechallenge.
Relevance
The study's findings suggest a potential survival benefit of chemotherapy rechallenge for third-line mCRC treatment. It underscores the necessity of tailoring treatment decisions to individual patient factors, such as initial cancer stage and ECOG PS. The study advocates for further prospective research to confirm these preliminary findings and to potentially inform future treatment guidelines.
FTD/TPI is an oral combination of trifluridine (a nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor). This combination has been shown to increase the intracellular accumulation of trifluridine, leading to the inhibition of DNA synthesis and ultimately cell death.5 The RECOURSE trial demonstrated a significant improvement in OS with FTD/TPI compared with placebo in patients with mCRC who had progressed on standard therapies.3
Regorafenib, on the other hand, is an oral multikinase inhibitor that targets multiple signaling pathways implicated in tumor growth, angiogenesis, and metastasis.6 The CORRECT trial showed a significant improvement in OS with regorafenib compared with placebo in patients with mCRC who had progressed on standard therapies.4
Chemotherapy rechallenge, defined as the reintroduction of previously administered chemotherapeutic agents, is another therapeutic approach in the third-line setting of mCRC.7 This strategy is based on the hypothesis that tumor cells may regain or retain sensitivity to chemotherapy after treatment discontinuation, leading to a potential clinical benefit.
Despite the availability of these treatment options, there is limited evidence directly comparing the efficacy of FTD/TPI, regorafenib, and chemotherapy rechallenge in the third-line treatment of mCRC. Hence, we aimed to evaluate the efficacy of a chemotherapy rechallenge versus either regorafenib or FTD/TPI in a pure third-line setting in patients with mCRC. This article presents the results of a retrospective study that evaluated the comparative effectiveness of FTD/TPI, regorafenib, and chemotherapy rechallenge in patients with mCRC.
MATERIALS AND METHODS
The medical records of patients with mCRC treated at four different institutions between February 2014 and April 2020 were retrospectively reviewed. Eligible patients received oxaliplatin or irinotecan-based frontline chemotherapy. They should have also received an alternate second-line regimen (for oxaliplatin, they should have received an irinotecan-containing regimen; for irinotecan, they should have received an oxaliplatin-containing regimen). All eligible patients received third-line therapy consisting of regorafenib, FTD/TPI, or rechallenge with the same first-line regimen. Oral and intravenous fluoropyrimidines were used interchangeably. Patients who received the first-line irinotecan-containing regimen were allowed to receive a single-agent irinotecan as the third line. Patients who received targeted therapy (bevacizumab or antiepidermal growth factor receptor [EGFR] therapy) with any of the chemotherapy lines were also eligible.
Data related to cancer, patient, and treatment characteristics were collected.
The primary end point of the study was to compare the progression-free survival (PFS) of patients who received FTD/TPI or regorafenib versus rechallenge with chemotherapy. The secondary end points were response rate (RR) and OS. RRs were assessed using imaging reports and on the basis of the response evaluation criteria for solid tumors (version 1.1).8
Statistical Analysis
Patient characteristics were summarized using frequencies and percentages for categorical variables and medians and ranges for continuous variables.
PFS was calculated as the time from the start of third-line therapy to either progression or death. OS was calculated as the time from the start of third-line therapy to the date of death or last follow-up. Additional survival was calculated as the time from the start of first-line therapy to death or the last follow-up.
Univariate and multivariate analyses were performed to evaluate disease-related, patient-related, and treatment-related factors for both PFS and OS. The probabilities of PFS and OS were calculated using the Kaplan-Meier estimator, with the variance estimated using Greenwood's formula. Multivariate analysis was performed using Cox proportional hazards regression, considering the (type of third-line) as the main effect. The assumption of proportional hazards for each factor in the Cox proportional hazards model was tested. Stepwise variable selection was used to identify significant risk factors associated with the outcomes. Factors that were significantly associated with the outcome variable at the 5% level were retained in the final model. The interactions between the main effects and significant covariates were tested. Statistical analyses were performed using IBM SPSS Statistics 24 (Armonk, NY).
Institutional Review Board Statement
This study was conducted in accordance with the principles of the Declaration of Helsinki.9 Approval was granted by the Research Ethics Committee under number RAC 2231130.
Informed Consent Statement
Since the study involved retrospective data, we were exempted from obtaining informed consent from the patients.
RESULTS
A total of 132 patients were eligible for inclusion, of which 29 received a chemotherapy rechallenge and 103 received either FTD/TPI or regorafenib. Table 1 shows the patient characteristics for the entire group and for the groups that received either chemotherapy rechallenge versus FTD/TPI or regorafenib. It is apparent that no significant difference exists between the two treatment groups except for the left side of the primary tumor, which was 86.2% in the chemotherapy rechallenge group versus 73.8% in the FTD/TPI-regorafenib group. In addition, 55.2% of the chemotherapy rechallenge group had wild-type KRAS, whereas only 30.1% of the FTD/TPI-regorafenib group had wild-type KRAS.
TABLE 1.
Characteristics of 132 Patients With Metastatic Colorectal Cancer Treated With Third-Line Therapy
| Variable | Whole Group | XELOX/FOLFOX - XELIRI/FOLFIRI | FTD/TPI - Regorafenib |
|---|---|---|---|
| No. of patients | 132 | 29 | 103 |
| Age, years, median (IQR) | 55 (46-63) | 59 (52-63.5) | 54 (45-62) |
| <65, No. (%) | 105 (79.5) | 23 (79.3) | 82 (79.6) |
| ≥65, No. (%) | 27 (20.5) | 6 (20.4) | 21 (20.4) |
| Sex, No. (%) | |||
| Male | 72 (54.5) | 18 (62.1) | 54 (52.4) |
| Female | 60 (45.5) | 11 (37.9) | 49 (47.6) |
| ECOG performance status, No. (%) | |||
| 0 | 5 (3.8) | 2 (6.9) | 3 (2.9) |
| 1 | 71 (53.8) | 15 (51.7) | 55 (53.4) |
| 2 | 49 (37.1) | 12 (41.4) | 37 (35.9) |
| 3 | 6 (4.5) | 0 (0) | 6 (5.8) |
| Stage at diagnosis, No. (%) | |||
| Stage I | 1 (0.8) | 0 (0) | 1 (1) |
| Stage II | 3 (2.3) | 0 (0) | 3 (2.9) |
| Stage III | 30 (22.7) | 6 (20.7) | 24 (23.3) |
| Stage IV | 98 (74.2) | 23(79.3) | 75 (72.8) |
| Primary side, No. (%) | |||
| Left-sided | 101 (76.6) | 25 (86.2) | 76 (73.8) |
| Right-sided | 31 (23.5) | 4 (13.8) | 27 (26.2) |
| Mucinous histology, No. (%) | |||
| Yes | 14 (11.4) | 2 (6.9) | 13 (12.6) |
| No | 117 (88.6) | 27 (93.1) | 90 (87.4) |
| Liver metastases, No. (%) | |||
| Yes | 88 (66.7) | 19 (65.5) | 69 (67) |
| No | 44 (33.3) | 10 (34.5) | 34 (33) |
| KRAS status, No. (%) | |||
| Wild-type | 47 (35.6) | 16 (55.2) | 31(30.1) |
| Mutated | 66 (50) | 10 (34.5) | 56 (54.4) |
| Unknown | 19 (14.4) | 3 (10.3) | 16 (15.5) |
| Duration of first-line therapy, months, median (range) | 8 (2-45) | ||
| ≤6, No. (%) | 50 (37.9) | 12 (41.4) | 38 (38.8) |
| >6, No. (%) | 77 (58.3) | 17 (58.6) | 60 (61.2) |
| Time from stage IV to third line, months, median (IQR) | 30.1 (18.7-42.5) | 25.5 (15.7-42) | 30.4 (19-43.7) |
| Previous bevacizumab, No. (%) | 81 (61) | 17 (58) | 64 (62) |
| Previous anti-EGFR, No. (%) | 53 (40) | 13 (45) | 40 (39) |
| Third-line therapy, No. (%) | 53 (40) | ||
| Regorafenib | 62 (47) | — | 62 (60.2) |
| FTD/TPI | 41 (31.1) | — | 41 (39.8) |
| XELIRI/FOLFIRI | 11 (8.3) | 11(37.9) | — |
| XELOX/FOLFOX | 18 (13.6) | 18 (62.1) | — |
| Biologic agents in third line, No. (%) | |||
| Anti-EGFR | 8 (6.1) | 8 (27.6) | 0 (0) |
| Bevacizumab | 13 (9.8) | 12 (41.4) | 1 (1) |
| None | 111 (84.1) | 9 (31) | 102 (99) |
Abbreviations: ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal group factor receptor; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; FOLFOX, 5-fluorouracil, leucovorin and oxaliplatin; FTD/TPI, trifluridine/tipiracil; XELIRI, capecitabine and irinotecan; XELOX, capecitabine and oxaliplatin.
Of the whole group, nine patients achieved partial response (PR) and 30 had stable disease (SD), for a disease control rate of 29%. Eighty patients had progressive disease as the best response. The corresponding PR and SD for the rechallenge group were six (20%) and four (14%), and for the FTD/TPI-regorafenib group, they were three (3%) and 25 (24%), respectively.
The median follow-up time for the whole group was 17 months (95% CI, 15 to 19), and for the chemotherapy rechallenge, it was 19.8 months (95% CI, 17 to 22.6) versus 16.3 months (95% CI, 12.3 to 20.5) for the FTD/TPI-regorafenib group. The PFS and OS for the whole group were 3.0 months (95% CI, 2.67 to 3.49) and 13.7 months (95% CI, 10.3 to 17.1), respectively. The PFS for the chemotherapy rechallenge group versus the FTD/TPI-regorafenib was 3.1 months (95% CI, 2.6 to 3.7) and 2.9 months (95% CI, 2.3 to 3.5; P = .357; Fig 1), and the OS was 21.2 months (95% CI, 17.3 to 25.1) and 12.6 months (95% CI, 9.3 to 15.1; P = .006), respectively (Fig 2). The PFS for patients on FTD/TPI versus regorafenib was 3.5 months (95% CI, 3.2 to 3.9) versus 2.6 months (95% CI, 2.2 to 2.9), whereas the OS was 15.8 months (95% CI, 10.5 to 21.1) versus 10.6 months (95% CI, 6.6 to 14.6).
FIG 1.
Kaplan-Meier plot for PFS of patients receiving chemotherapy rechallenge versus FTD/TPI-regorafenib group. FTD/TPI, trifluridine/tipiracil; PFS, progression-free survival.
FIG 2.
Kaplan-Meier plot for overall survival of patients receiving chemotherapy rechallenge versus FTD/TPI-regorafenib group. FTD/TPI, trifluridine/tipiracil; OS, overall survival.
Median survival calculated from the start of first-line chemotherapy for the whole group was 41.6 months (95% CI, 37.1 to 46.1) and for the chemotherapy rechallenge versus the FTD/TPI group was 45.5 months (95% CI, 27.4 to 63.6) and 41.6 months (95% CI, 34.7 to 48.4) respectively, P = .386.
Univariate and multivariate analyses were performed on the different factors that might affect PFS and OS after third-line therapy. Table 2 shows the results of univariate analysis with male sex, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, and the absence of mucinous histology with statistically better PFS, whereas an ECOG PS of 0-1, localized stage at diagnosis, and chemotherapy rechallenge had statistically better OS.
TABLE 2.
Univariate Analysis of Factors Affecting OS and PFS in the Third-Line Setting of Metastatic CRC
| Characteristic | Median OS (95% CI) | P | Median PFS (95% CI) | P |
|---|---|---|---|---|
| Age, years | .723 | .178 | ||
| <65 | 13.7 (9.3 to 18.1) | 3.1 (2.7 to 3.6) | ||
| ≥65 | 16.8 (10.7 to 23.0) | 3 (2.1 to 3.8) | ||
| Sex | .837 | .01 | ||
| Male | 16.4 (10.7 to 22.1) | 3.3 (2.9 to 3.7) | ||
| Female | 12.6 (9.9 to 15.3) | 2.8 (2.2 to 3.4) | ||
| ECOG PS | .005 | <.001 | ||
| 0-1 | 16.5 (10.6 to 22.3) | 3.5 (2.8 to 4.2) | ||
| >1 | 10.6 (5.5 to 15.8) | 2.4 (1.9 to 3.0) | ||
| Stage at diagnosis | .033 | .69 | ||
| Localized | 18.8 (15.2 to 22.3) | 3.2 (1.8 to 4.6) | ||
| Metastatic | 11.6 (8.4 to 14.8) | 3.1 (2.7 to 3.5) | ||
| Primary location | .957 | .08 | ||
| Left colon | 15.8 (12.0 to 19.5) | 3.3 (2.8 to 3.7) | ||
| Right colon | 12.7 (8.1 to 17.3) | 2.6 (2.2 to 3.0) | ||
| Mucinous histology | .901 | .037 | ||
| Yes | 10.3 (6.0 to 14.6) | 2.6 (2.1 to 3.0) | ||
| No | 15.8 (12.1 to 19.4) | 3.2 (2.8 to 3.6) | ||
| Site of metastases | ||||
| Peritoneum | .623 | .374 | ||
| Yes | 12.6 (7.1 to 18.1) | 2.5 (1.9 to 3.1) | ||
| No | 16.4 (11.2 to 21.5) | 3.2 (2.8 to 3.6) | ||
| Lymph nodes | .085 | .237 | ||
| Yes | 12.9 (11.3 to 14.5) | 3.2 (2.5 to 4.0) | ||
| No | 19 (10.3 to 27.8) | 2.9 (2.6 to 3.2) | ||
| Liver | .152 | .336 | ||
| Yes | 12.8 (7.3 to 18.3) | 2.9 (2.6 to 3.3) | ||
| No | 16.4 (10.6 to 22.2) | 3.5 (2.9 to 4.0) | ||
| Lung | .656 | .907 | ||
| Yes | 15.8 (11.2 to 20.3) | 2.9 (2.3 to 3.5) | ||
| No | 12.7 (6.5 to 19.0) | 3.2 (2.7 to 3.8) | ||
| RAS gene | .068 | .87 | ||
| Mutated | 11.2 (6.0 to 16.4) | 2.8 (2.1 to 3.5) | ||
| Wild | 19 (12.6 to 25.4) | 3.5 (3.3 to 3.6) | ||
| Third-line therapy | .006 | .357 | ||
| Chemotherapy | 21.2 (17.3 to 25.1) | 3.1 (2.6 to 3.7) | ||
| FTD/TPI-rego | 12.6 (9.3 to 15.1) | 2.9 (2.3 to 3.5) | ||
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FTD/TPI, trifluridine/tipiracil; OS, overall survival; PFS, progression-free survival; rego, regorafenib.
Multivariate analysis indicated that male sex and an ECOG PS of 0-1 were independent positive prognostic factors for PFS. In terms of OS, independent positive prognostic factors were identified as receiving chemotherapy rechallenge as the third line, with an ECOG PS of 0-1 and localized disease (Table 3).
TABLE 3.
Multivariate Analysis of Factors Affecting OS and PFS in the Third-Line Setting of Metastatic CRC
| Covariate | OS | PFS | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Type of third line | ||||
| Chemotherapy rechallenge | 1 | .001 | 1 | .23 |
| FTD/TPI-regorafenib | 2.89 (1.57 to 5.3) | 1.29 (0.84 to 2) | ||
| ECOG PS | ||||
| 0-1 | 1 | <.001 | 1 | <.001 |
| >1 | 2.4 (1.49 to 3.97) | 2.18 (1.47 to 3.2) | ||
| Sex | — | — | ||
| Male | — | — | 1 | .04 |
| Female | — | — | 1.48 (1.02 to 2.16) | |
| Disease stage | — | — | ||
| Localized | 1 | .007 | — | — |
| Metastatic | 2.17 (1.23 to 3.82) | — | — | |
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FTD/TPI, trifluridine/tipiracil; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
DISCUSSION
Patients with mCRC in whom two lines of therapy failed had limited options. Before the approval of regorafenib and FTD/TPI, a chemotherapy rechallenge was commonly used. Several retrospective and phase II trials have been published, with or without anti-EGFR.10-14 RR to chemotherapy rechallenge with or without anti-EGFR therapy ranged from 3% to 54% with the PFS and OS ranging from 2.5 to 6.5 months and 8 to 18 months, respectively. Unfortunately, no randomized trials have compared chemotherapy reintroduction with the best supportive care. In many of the above studies, liquid biopsies used for the selection of the continuous wild-type RAS gene confirmed a better efficacy when the chemotherapy rechallenge was coupled with anti-EGFR therapy.
In two randomized trials, regorafenib was compared with best supportive care in patients with mCRC who failed at least two lines of therapy, including fluoropyrimidine, oxaliplatin, and irinotecan, and showed statistically improved PFS and OS.4,15 FTD/TPI was compared with best supportive care in two randomized studies in patients with mCRC who failed at least two lines of therapy (similar to regorafenib studies) and showed improved PFS and OS.3,16 The above studies have resulted in the above two agents being approved by the Food and Drug Administration and the European Medicinal Agency, and are the preferred choice in the third-line setting in many management guidelines by different societies.17,18 No randomized trials have compared regorafenib or FTD/TPI with chemotherapy rechallenges.
Our study was the fourth retrospective study to evaluate the efficacy of chemotherapy rechallenge with either TFP/TPI or regorafenib. In a study by Kostek et al,19 104 patients with mCRC who failed two lines of therapy were retrospectively evaluated according to the type of third-line therapy received. Patients who progressed to first-line therapy within 3 months were excluded from the study. Seventy-three patients received regorafenib, and 31 patients received chemotherapy rechallenge. The median PFS for the rechallenge group versus the regorafenib group was 9.16 months (95% CI, 7.15 to 11.18) versus 3.41 months (95% CI, 3.01 to 3.82), respectively (hazard ratio [HR], 0.22 [95% CI, 0.11 to 0.43]; P < .001). The OS for the rechallenge group versus the regorafenib group was 12.0 months (95% CI, 8.1 to 15.9) versus 6.6 months (95% CI, 6.0 to 7.3), respectively (HR, 0.29 [95% CI, 0.16 to 0.54]; P < .001). Calgeri et al20 reported the second study (the PROSERpINa study) as a poster presentation at the American Society of Medical Oncology in 2019. In their report, 341 patients with mCRC progressing after at least two lines of therapy were analyzed for survival. Of these, 133 underwent chemotherapy rechallenge/reintroduction, and 208 received either FTD/TPI or regorafenib. The median OS was 18.5 months (95% CI, 14.3 to 22.7) for the chemotherapy rechallenge/reintroduction, 6 months (95% CI, 5.6 to 9.5) for regorafenib, and 7.6 months (95% CI, 5.6 to 9.5) for FTD/TPI (log-rank P < .0001). The authors performed a propensity score analysis adjusted for ECOG PS, number of metastatic sites, and treatment line. With 115 patients in each group, the median OS for the chemotherapy rechallenge/reintroduction group versus the FTD/TPI-regorafenib group was 15.8 versus 7.1 months with an adjusted HR of 1.96 (95% CI, 1.44 to 2.66) and P < .0001. Similarly, the PFS for the propensity score groups was 5.5 versus 3.9 months, respectively (HR, 1.45 [95% CI, 1.11 to 1.91]; P = .006). The RR also improved with chemotherapy rechallenge/reintroduction at 29% versus 1.5% for the FTD/TPI group (chi-square P < .00001).
The most recent study addressing third-line chemotherapy rechallenge versus regorafenib was reported by Tasci et al.21 In their study, 128 patients who received a rechallenge were compared with 266 patients who received regorafenib. The study showed a PFS of 5.82 months versus 4 months for the rechallenge and regorafenib group, respectively (HR, 1.45; P = .167). The disease control rate was 77% in the rechallenge group and 49.5% in the regorafenib group (P < .001). Similarly, OS was significantly higher for the rechallenge versus regorafenib group (11.99 months v 8.8 months; HR, 1.51; P ≤ .001).21
The results of our study support the findings of these three studies. There was no improvement in PFS for the rechallenge group compared with the FTD/TPI-regorafenib group (3.1 v 2.9 months, respectively; P = .357), whereas there was a significant difference in OS in favor of the chemotherapy rechallenge group (21.2 v 12.6 months; P = .006). This is likely related to a greater depth of response to chemotherapy rechallenge than to FTD/TPI or regorafenib. This is supported by a higher RR for the rechallenge group (20%) than for the FTD/TPI-regorafenib group (3%). This phenomenon has been observed in other studies, such as the FIRE-3 trial, where a greater depth of response was confirmed in the anti-EGFR arm compared with the bevacizumab arm, with a similar PFS in both arms.22 Other possible factors could be the type of practice for post–third-line therapy, where many patients postchemotherapy rechallenge receive either FTD/TPI or regorafenib, whereas a minority of patients receive chemotherapy rechallenge after either FTD/TPI or regorafenib. These data (post–third-line therapy) are not available to us as they were not part of the design of the study.
Our multivariate analysis confirmed no significant difference in PFS between chemotherapy rechallenge and treatment with FTD/TPI or regorafenib in the third-line setting. However, it showed the superiority of chemotherapy rechallenge in terms of OS. In addition, it confirms that PS is an independent prognostic factor in the third-line setting, a finding that has been confirmed in other studies. In addition, the male sex fared better for unknown reasons.
Our study has several limitations. Being a retrospective study, it is inherently limited by potential biases in the selection of patients and treatments and in the recording and interpretation of data. These biases may affect the generalizability of the results. In addition, the sample size was small, particularly for the chemotherapy rechallenge group. This limits the statistical power of the study and might have influenced the reliability and validity of the results. The heterogeneity of treatments comparing the chemotherapy rechallenge group with a group receiving either FTD/TPI or regorafenib potentially confounded the results as it might not accurately represent the efficacy of each individual treatment. Furthermore, the differences in RAS status between the two groups can influence the response to treatment, which could have added another confounding factor to the results.
The lack of adverse effect data is another limitation of the study as it does not report on adverse events or quality-of-life measures, which are important considerations in the holistic assessment of treatment efficacy. Finally, our study compared chemotherapy rechallenge with FTD/TPI or regorafenib in the third-line setting. The recent SUNLIGHT trial has shown superior efficacy of the combination of FTD/TPI and bevacizumab to FTD/TPI alone, with improved PFS and OS.23 Unfortunately, the above combination was not a standard of care at the dates our data were collected, and a re-evaluation needs to be performed to compare the combination of FTD/TPI and bevacizumab with chemotherapy rechallenge.
In conclusion, overall, this study provides valuable insights into the efficacy of different treatment options in the third-line setting for patients with mCRC. The results suggest that chemotherapy rechallenge may be a viable option for some patients, with better OS than treatment with regorafenib or FTD/TPI. This conclusion needs to be taken with caution given the retrospective and nonrandomized nature of the study. Further research is needed to confirm these findings and identify the most appropriate treatment strategies for individual patients.
DATA SHARING STATEMENT
All data and documents needed will be provided upon request through e-mail: bazarbashi@gmail.com.
AUTHOR CONTRIBUTIONS
Conception and design: Shouki Bazarbashi, Nashwa Abdel-Aziz, Mervat Mahrous, Sherif Elsamany, Mohammed Alghamdi
Administrative support: Mervat Mahrous, Mohammed Alghamdi
Provision of study materials or patients: Shouki Bazarbashi, Mohamed Aseafan, Nashwa Abdel-Aziz, Mervat Mahrous, Mohammed Alghamdi
Collection and assembly of data: Shouki Bazarbashi, Radwan Alkhatib, Mohamed Aseafan, Yasmin Tuleimat, Nashwa Abdel-Aziz, Mervat Mahrous, Sherif Elsamany, Mohammed Alghamdi
Data analysis and interpretation: Shouki Bazarbashi, Radwan Alkhatib, Mohamed Aseafan, Yasmin Tuleimat, Nashwa Abdel-Aziz, Tusneem Elhassan, Mohammed Alghamdi
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/go/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Shouki Bazarbashi
Honoraria: Roche, Bayer, Pfizer, Bristol Myers Squibb, Merck Sharp & Dohme, Lilly, Merck Serono, BeiGene, Hikma, AstraZeneca, Ipsen
Consulting or Advisory Role: Pfizer, Bristol Myers Squibb, Astellas Pharma, Roche, Merck Sharp & Dohme, Hikma, Merck KGaA, Bayer, Taiba, Ipsen, AstraZeneca
Research Funding: Lilly, Merck KGaA (Inst), Astellas Pharma (Inst), Kite/Gilead (Inst)
Travel, Accommodations, Expenses: Janssen, Merck, Servier, AstraZeneca, Hikma Pharmaceuticals, Ipsen
Sherif Elsamany
Honoraria: Amgen, Merck Serono, Servier
Consulting or Advisory Role: MSD
Research Funding: Amgen
Travel, Accommodations, Expenses: Hikma Pharmaceuticals
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data and documents needed will be provided upon request through e-mail: bazarbashi@gmail.com.