Sequencing Considerations in the Third-Line Treatment of Metastatic Colorectal Cancer

ABSTRACT

Numerous advances in the standard of care for metastatic colorectal cancer (mCRC), including the approval of several new treatments indicated for treatment in the third line or later (3L+), have been made, yet data and appropriate guidance on the optimal sequencing and treatment strategies for these lines of therapy are lacking. Four treatments—regorafenib, trifluridine/tipiracil alone or with bevacizumab, and fruquintinib—are FDA-approved and recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for the treatment of mCRC in the 3L+. When considering sequencing of treatment options for patients in the 3L+, the goal of treatment is to improve survival, but also maintain quality of life, a goal that requires consideration of relative efficacy and cumulative toxicity such as persistent myelosuppression.

Am J Manag Care. 2024;30:S31-S35. https://doi.org/10.37765/ajmc.2024.89546

For author information and disclosures, see end of text.

Introduction

Colorectal cancer (CRC) remains a substantial global health concern, and the management of metastatic CRC (mCRC) continues to pose clinical challenges to providers and health systems. The primary goals of treatment for patients with metastatic disease are to prolong survival while preserving quality of life (QOL).^1,2

Identification of relevant, targetable biomarkers has led to improved outcomes for patients with mCRC.³ However, most patients with mCRC eventually experience disease progression, and they may require subsequent lines of treatment.⁴ Among unmet needs is the objective determination of optimal sequencing in the third or later lines (3L+) of therapy.⁵

As patients progress to later lines of therapies, treatment selection may be guided by prior therapy, toxicity, tumor molecular profile, patient age, performance status, comorbidities, and other factors.^5,6 Furthermore, with the goal of improving survival while maintaining QOL in mind, sequencing of all treatment options should be optimized to balance risk to benefit ratio.^2,4

This article explores sequencing considerations in the 3L treatment of mCRC, emphasizing the importance of tailoring therapeutic approaches to individual patients in an attempt to optimize both survival outcomes and QOL.

Therapy Sequencing of Approved Third-Line Agents

As outcomes for patients with mCRC have improved over past decades, more patients have become eligible for treatment in the 3L+.⁷ Thus, the ability to sequence these therapies in the most effective manner becomes important.

First-line (1L) and second-line (2L) therapies encompass regimens that combine chemotherapy with targeted biologics.⁵ For patients harboring microsatellite instability–high or mismatch repair–deficient tumors, or for those with POLE or POLD1 mutations, use of FDA-approved immunotherapies (eg, pembrolizumab, nivolumab with or without ipilimumab, and dostarlimab) may be considered if immunotherapy was not used during previous lines of therapy. The 2024 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer (version 1.2024) include checkpoint inhibitor therapy options: nivolumab ± ipilimumab, pembrolizumab, or dostarlimab-gxly. Nivolumab + ipilimumab combination is category 2B when intensive therapy is not recommended due to toxicity concerns.^5,8 In the 3L, there is limited evidence to rechallenge with previously used chemotherapy (eg, oxaliplatin, irinotecan) with data primarily available from single-arm studies with small sample sizes.⁹ Alternatively, providers may introduce new options—notably, regorafenib, trifluridine/tipiracil (FTD/TPI) alone or with bevacizumab, or fruquintinib.^5,8,10 Multiple 3L+ therapies are approved by the FDA, yet optimal sequencing of these agents remains challenging.⁵

Regorafenib was approved by the FDA in 2012 for the treatment of previously treated mCRC following chemotherapy-based treatments that include a fluoropyrimidine, oxaliplatin, irinotecan, and biologic therapies including anti-VEGF or anti-EGFR therapy, as indicated. It is a small-molecule, multikinase inhibitor that targets at least 20 kinases involved in tumor activity (eg, RET, RAF1, BRAF, and VEGFR).¹¹

Regorafenib therapy was associated with low rates of grade 3 and 4 hematologic adverse events (AEs) in clinical trials.¹¹ In the ReDOS trial, the dose escalation strategy was associated with a lower rate of nonhematologic toxicities of grade 3 or higher when compared with the standard dose, with toxicities still notable as early as cycle 1 (hand-foot skin reaction [HFSR], 7.4%; fatigue, 5.6%; hypertension, 3.7%).¹² Additionally, regorafenib was discontinued in 20% of patients receiving the dose-escalation strategy due to AEs. Patients given regorafenib who had progression-free survival (PFS) for longer than 4 months were more likely to have had an ECOG performance status of 0, a longer time since diagnosis of metastatic disease, and no liver metastases.¹³ NCCN Guidelines® and the European Society for Medical Oncology (ESMO) recommend a treatment sequence that may include regorafenib in the 3L setting. This recommendation involves regorafenib use following the completion of 2 prior lines of standard chemotherapy-based regimens.^8,14

FTD/TPI is approved for use alone or in combination with bevacizumab in adult patients with mCRC who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biologic therapy; and, if RAS wild-type, an anti-EGFR therapy. It consists of trifluridine (a thymidine-based nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor). FTD/TPI becomes incorporated into cancer cell DNA and subsequently inhibits cellular proliferation.¹⁵

In the pivotal RECOURSE trial (NCT01607957), hematologic AEs including neutropenia, anemia, and febrile neutropenia (FN) were among the most common AEs leading to dose reduction.¹⁵ Additionally, 3.6% of patients discontinued FTD/TPI due to AEs.In the SUNLIGHT pivotal trial (NCT04737187), use of FTD/TPI plus bevacizumab produced significant improvement in both PFS and overall survival (OS) over FTD/TPI monotherapy.¹⁶ Notably, this significant improvement was seen regardless of prior bevacizumab use, although PFS and OS were numerically longer in those who did not receive bevacizumab in prior lines of therapy than in those who did.¹⁶

This draws attention to the possible need to consider a patient’s prior use of bevacizumab when deciding whether to use FTD/TPI plus bevacizumab in the 3L. Additionally, neutropenia and anemia were the most common laboratory anomalies or AEs observed among patients treated with either FTD/TPI monotherapy or FTD/TPI plus bevacizumab in this trial.¹⁵ The myelosuppression noted in results of both the RECOURSE and SUNLIGHT trials highlights the importance of regularly monitoring patients for hematologic toxicities and adjusting treatment through dose reductions and treatment delays when these toxicities occur.¹⁵ Both the NCCN Guidelines® and ESMO recommend both FTD/TPI and FTD/TPI plus bevacizumab as treatment options for those who have progressed through standard therapies; however, they suggest a preference for FTD/TPI plus bevacizumab combination therapy over monotherapy.^8,17

Fruquintinib was approved in the US in November 2023 for patients with mCRC who were previously treated with a fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy; and, if RAS wild-type and it is medically appropriate, an anti-EGFR therapy.¹⁰ This small-molecule VEGFR inhibitor slows tumor growth by inhibiting VEGF-induced phosphorylation. Patients given fruquintinib in the FRESCO-2 clinical trial (NCT04322539) did not experience higher rates of hematologic AEs when compared with those given placebo, although AEs causing treatment discontinuationwere noted in 20% of trial participants given fruquintinib. This drug has been added to the NCCN Guidelines recommendations for the treatment of 3L+ mCRC.⁸

The NCCN Guidelines offer no specific guidance regarding ideal sequencing between these recommended therapeutics.⁸ The decision about how to best sequence patients in 3L+ therapy with regorafenib, FTD/TPI monotherapy, FTD/TPI plus bevacizumab, or fruquintinib requires a case-by-case evaluation.^8,18

A US-based retrospective cohort study compared sequential treatment with regorafenib followed by FTD/TPI with or without bevacizumab (R-T) in 393 patients, compared with FTD/TPI with or without bevacizumab followed by regorafenib (T-R) in 435 patients.¹⁹ Median OS was numerically longer for R-T than for T-R, but this finding was not statistically significant (OS, 13.1 vs 11.5 months, respectively; HR, 0.94; 95% CI, 0.74-1.19). Additionally, time to treatment discontinuation did not differ between the R-T and T-R groups (8.7 vs 8.1 months; HR, 0.91; 95% CI, 0.73-1.14).

There is a paucity of data surrounding sequencing as it relates to fruquintinib. Data are limited to 2 China-based studies, both of which support that regorafenib followed by fruquintinib may be associated with longer OS than the reverse.^20,21 However, further confirmatory prospective trials are needed.

Impact of Hematologic Toxicities on Treatment Sequencing

Neutropenia, a reduced absolute neutrophil count commonly associated with myelosuppressive chemotherapy, remains a significant burden on both patients being treated for cancers and for health care systems. FN, a severe form of neutropenia, is considered an oncologic emergency; it occurs in 7.8 per 1000 patients with cancer in the US.²² These chemotherapy-related neutropenic and FN events impose a substantial impact on patients in terms of mortality and hospitalizations and on health care systems in terms of costs.

As patients and physicians navigate the progression of mCRC, the burden of these AEs becomes more pronounced. Myelosuppression creates challenges to administering additional chemotherapy (eg, FTD/TPI alone or with bevacizumab) immediately after previous use of intensive lines of therapy that also have caused bone marrow toxicity.²³ Exposure to multiple lines of chemotherapy can lead to residual bone marrow injury (ie, hematologic toxicities including neutropenia, anemia, and/or thrombocytopenia) and cumulative neurotoxicity that can affect QOL and overall patient outcomes.^24,25 In a survey of patients with prior exposure to chemotherapy, a moderate to major overall impact on QOL due to myelosuppression and related AEs was reported by 88% of respondents.

Maintaining QOL has emerged as a valued treatment goal as revealed in a survey of over 600 physicians—34% cited QOL as their foremost objective for mCRC patients in the 3L setting.²⁶ It is also important to explore strategies that mitigate the additive bone marrow suppression associated with chemotherapeutic regimens.²³ Incorporating therapies with alternative mechanisms of action may achieve this objective and ensure that all potentially active agents remain available to patients.

Both regorafenib and fruquintinib are associated with low rates of hematologic toxicity, as previously discussed.^10,11 It is important to note that both of these therapies are associated with other nonhematologic toxicities, such as HFSR and fatigue, that will also have an impact on QOL.^10,12,27,28Close patient monitoring is still needed to manage these nonhematologic toxicities, minimize impact to QOL, and maximize clinical benefit of treatment.⁵ Dose optimization and/or modifications of either regorafenib or fruquintinib may be necessary to address treatment-related toxicities while preserving patient QOL. Such modifications are key to ensuring that the benefits of treatment are realized without compromising the patient’s overall well-being.⁵

Economic Considerations

The economic landscape of mCRC treatment extends beyond the costs of therapies themselves; it encompasses a spectrum of expenses associated with the AE profiles of treatments, including hematologic toxicities (eg, neutropenia), which is a major cost driver for patients with mCRC.²⁹ These considerations are crucial when evaluating the overall economic impact of different therapeutic options for mCRC.²² Cancer-related neutropenia, which includes neutropenia related to chemotherapy, can impose a significant economic burden on health care systems and patients. Overall cost includes direct costs such as expenses associated with hospitalizations and indirect costs from loss of productivity.

A study published in 2017 examined 2012 data from the National Inpatient Sample and the Kids’ Inpatient Database of the Healthcare Costs and Utilization Project (HCUP) from the Agency for Healthcare Research and Quality as they relate to chemotherapy-induced neutropenia.³⁰ International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes were used to identify cancer-related neutropenia hospitalizations. For analysis, inpatient stays with a diagnosis of primary or secondary cancer and of neutropenia or fever with undetermined cause were selected. Costs (2012 US$) were calculated by converting hospital charges to costs using HCUP cost-to-charge ratios as designated by the Centers for Medicare & Medicaid Services.

Investigators identified more than 91,000 cancer-related hospitalizations for neutropenia among adults and almost 17,000 more among children, accounting for 5.2% of all cancer-related hospitalizations among adults and 22.7% among children.³⁰ Hospitalizations for cancer-related neutropenia in adults were longer (by 2.7 days) and more costly (by $5685) than for conditions not related to neutropenia. The estimated mean hospital costs per stay were $14,278 for adult patients with cancer of the rectum or anus and $15,431 for adult patients with colon cancer, totaling over $70 million for hospitalizations related to neutropenia in adult patients with CRC in 2012. Neutropenia-related hospitalizations in cancer patients accounted for 5.2% of all cancer-related hospitalizations and for 8.3% of all cancer-related hospitalization costs. These results highlight the disproportionate burden to health systems and costs associated with the potentially life-threatening occurrence of cancer-related neutropenia.

A 2022 expert review examined studies published between 2015 and 2020 that reported on the burden of chemotherapy-induced FN in terms of hospitalization, mortality, and cost.²² Among adults with solid tumors hospitalized for neutropenia or FN, mortality ranged between 2.6% and 7.0%. Risk factors for mortality included older age, admission to intensive care, and presence of comorbidities or other diagnoses such as infection, sepsis, or pneumonia.

A retrospective, open-cohort study of medical and pharmacy claims from the first quarter of 2009 to the second quarter of 2014 identified 4158 patients with a diagnosis of mCRC and more than 1 claim (prescription or administration) of more than 1 recommended mCRC treatment.²⁹ Of these, 2261 patients (54.4%) had a 2L treatment, and 1115 (26.8%) had a 3L treatment. On average (SD), each patient had 2.1 (1.4) episodes of mCRC treatment, with each treatment episode lasting a mean (SD) of 166 (144) days.²⁹ The occurrence of AEs was high and was associated with substantial economic burden. During the 1L treatment episode, 90% of patients experienced 1 or more AE, and AE rates remained high in the 2L and 3L (85% and 86%, respectively).

Reported monthly total costs were significantly higher for patients who experienced 1 or more AEs in the cardiovascular, central nervous system, endocrine or metabolic, hematologic, and respiratory categories compared with those who did not experience AEs in that same category. Hematologic AEs were the costliest, followed by those affecting respiratory, endocrine or metabolic, and central nervous systems.²⁹ Specifically, after adjustment of the model for differences in patient baseline characteristics, the adjusted monthly total costs for patients with hematologic AEs were $19,115 and for those with AEs that were not hematologic were $17,209—a significant difference of $2289 (P < .05). In addition, patients with hematologic AEs during treatment episodes often had other types of AEs, resulting in higher health care costs than noted among patients with nonhematologic AEs.

To date, there is no US-based cost-effectiveness study of real-world data that incorporates all of the aforementioned 3L therapies, particularly one that includes fruquintinib. However, in a 2022 study, Cho et al used a Markov model to evaluate the relative cost-effectiveness of 4 treatment options for mCRC based on an assessment of benefits, toxicities, and cost of care.³¹ The treatment regimens evaluated were regorafenib standard dosing (RSD) of 160 mg once daily orally; regorafenib initiated at 80 mg once daily and escalated weekly in 40-mg increments up to 160 mg once daily, as tolerated (ReDOS); FTD/TPI; and FTD/TPI plus bevacizumab. Relative cost effectiveness was evaluated using quality-adjusted life-years (QALYs). This evaluation included a comparison of costs for AEs across each therapy regimen based on data reported in the pivotal trials for each regimen.

Costs associated with AE management were lowest with the RSD and ReDOS regimens ($5715 and $9008, respectively).³¹ AE-related costs for managing the FTD/TPI and FTD/TPI plus bevacizumab regimens were more than twice as high as were those associated with RSD ($15,160 and $17,179).

Costs of AE management have not been incorporated as factors in provider and health-system assessments of treatment regimens for advanced, incurable cancers. It is also acknowledged that additional cost-effectiveness data are needed to better understand how fruquintinib fits into this landscape. Still, the results of studies discussed here provided cost information that can be associated with AE management and put particular emphasis on costs related to myelosuppression and other toxicities. Incorporating cost of AE management into the development of treatment pathways should be considered.

Managed Care Considerations

While 3L+ treatment options continue to expand, there is a lack of comparative trials. This lack of evidence-based guidance regarding the most effective sequencing for mCRC therapies adds to the complexity of treatment decision-making that would be most appropriate for individual patients.¹⁸ To address this knowledge gap, there is a pressing need for data that can further elucidate the intricacies of treatment sequencing. Such studies are essential to guide informed decision-making for health care providers and managed care organizations.

Formal pathways or guidelines lack direct guidance on optimal treatment sequencing in mCRC; instead, they provide a variety of treatment sequencing strategies. In the absence of standardized guidance, health care plans and systems can derive relevant data based on real-world comparative effectiveness evaluations.⁸ This flexibility enables health care entities to adapt to the unique needs of their patient populations and ensure that treatment decisions are evidence-based and patient-centered.

The future development of real-world and head-to-head data will play a pivotal role in informing appropriate utilization management strategies. As patients reach later lines of treatment, these strategies will be instrumental in optimizing the selection and sequencing of therapies. Managed care organizations will need to be proactive in leveraging emerging data to tailor treatment approaches effectively while managing costs and ensuring that patients receive the most suitable care based on their clinical status and history.

Conclusions

With an expanding landscape of treatment options, the need for well-informed sequencing strategies in 3L+ treatments is becoming increasingly crucial for patients with mCRC. Four FDA-approved 3L+ treatment options currently exist in the United States including regorafenib, FTD/TPI alone or with bevacizumab, and fruquintinib.^10,15 With these new approvals, no singular treatment sequence is recommended above others by the NCCN Guidelines.⁸ The future development of well-designed comparative studies between approved treatment sequences may aid in clinical decision-making and help address the unanswered questions surrounding sequencing.

Striking a balance between the patient’s QOL and the effectiveness of treatment is also crucial. Addressing the risk of toxicities including neuropathy and myelosuppression is crucial to improve overall outcomes.^22,24

In light of these challenges and opportunities, the treatment landscape for 3L+ mCRC is evolving. As new therapies continue to emerge and more data become available, the medical community can strive towards a more personalized, effective, and patient-centered treatment strategy. Achieving a balance between cost effectiveness, toxicity, efficacy, and QOL remains the ultimate goal for optimizing patient outcomes in this complex therapeutic landscape of mCRC.

Authorship Affiliation: Department of Medical Oncology, Access Hope, City of Hope (AB), Duarte, CA; Department of Hematology and Medical Oncology, Mayo Clinic (TB-S), Phoenix, AZ.

Source of Funding: This supplement was supported by Bayer US, LLC.

Author Disclosures: Dr Barzi reports paid consultancies or advisory boards for Bayer US, LLC. Dr Barzi also reports travel support for attending the European Society for Medical Oncology 2023 conference. Dr Bekaii-Saab reports the following personal conflicts of interest: serving as a consultant to Abbvie, Inc; Aptitude Health; AstraZeneca; BeiGene, Inc; Blueprint Medicines Corporation; Boehringer Ingelheim Pharmaceuticals, Inc; Celularity Inc; Daiichi Sankyo Company Limited; Deciphera Pharmaceuticals, Inc; Exact Sciences Corporation, Exelixis, Inc; Foundation Medicine, Inc; GSK plc; Illumina, Inc; Janssen Pharmaceuticals, Inc; Kanaph Therapeutics Inc; Lisata Therapeutics, Inc; MJH Life Sciences; Natera, Inc; Sanofi; Swedish Orphan Biovitrum AB; Stemline Therapeutics, Inc; Treos Bio Limited; Xilio Therapeutics; and Zai Lab; serving as a scientific advisory board member for Artiva Biotherapeutics, Inc; AstraZeneca; Eisai Co, Ltd; Exelixis, Inc; FibroGen, Inc; Immuneering Corporation; Imugene Limited; Kintor Pharmaceutical Limited; Merck & Co, Inc; Pancreatic Cancer Action Network; Replimune Group Inc; Sun Pharmaceutical Industries Ltd; Valley Health System; Xilis; and 1Globe Health; and receiving royalties from UpToDate. He also reports an additional personal conflict of interest: inventions/patents 18/183,488: Human PD1 peptide vaccines and uses thereof, 19/055,687: Methods and compositions for the treatment of cancer cachexia. He reports the following institutional conflicts of interest: receiving research funding from Agios Pharmaceuticals, Inc; Arcus Biosciences, Inc; Arys Medical; Atreca, Inc; Bayer US, LLC; Boston Biomedical, Inc; Bristol Myers Squibb Company; Celgene Corporation; Clovis Oncology, Inc; Eisai Co, Ltd; Genentech, Inc; Incyte; Ipsen Pharma; Lilly; Merus; Mirati Therapeutics, Inc; Novartis AG; Pfizer Inc; and Seagen Inc, and serving as a consultant to Arcus Biosciences, Inc; Bayer US, LLC; Eisai Co, Ltd; Genentech, Inc; Incyte; Ipsen Pharma; Les Laboratoires Servier; Merck & Co, Inc; Merck KGaA; Merus; Pfizer Inc; and Seagen Inc.

Authorship Information: Concept and design (TB-S); analysis and interpretation of data (TB-S) drafting of the manuscript (TB-S, AB); critical revision of the manuscript for important intellectual content (TB-S, AB); supervision (AB).

Address Correspondence To: Tanios Bekaii-Saab, MD. Mayo Clinic, 5881 East Mayo Boulevard, Phoenix, AZ, 85054. Email: bekaii-saab.tanios@mayo.edu

REFERENCES

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
2. Riedesser JE, Ebert MP, Betge J. Precision medicine for metastatic colorectal cancer in clinical practice. Ther Adv Med Oncol. 2022;14:17588359211072703. doi:10.1177/17588359211072703
3. Malki A, ElRuz RA, Gupta I, Allouch A, Vranic S, Al Moustafa AE. Molecular mechanisms of colon cancer progression and metastasis: recent insights and advancements. Int J Mol Sci. 2020;22(1):130. doi:10.3390/ijms22010130
4. Grothey A, Marshall JL, Bekaii-Saab T. Sequencing beyond the second-line setting in metastatic colorectal cancer. Clin Adv Hematol Oncol. 2019;17(1; suppl 7)1-19.
5. Bekaii-Saab T, Kim R, Kim TW, et al. Third- or later-line therapy for metastatic colorectal cancer: reviewing best practice. Clin Colorectal Cancer. 2019;18(1):e117-e129. doi:10.1016/j.clcc.2018.11.002
6. Modest DP, Pant S, Sartore-Bianchi A. Treatment sequencing in metastatic colorectal cancer. Eur J Cancer. 2019;109:70-83. doi:10.1016/j.ejca.2018.12.019
7. Loupakis F, Antonuzzo L, Bachet JB, et al. Practical considerations in the use of regorafenib in metastatic colorectal cancer. Ther Adv Med Oncol. 2020;12:1758835920956862. doi:10.1177/1758835920956862
8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer. V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed January 30, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.
9. Arnold D, Prager GW, Quintela A, et al. Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review. Ann Oncol. 2018;29(4):835-856. doi:10.1093/annonc/mdy038
10. Fruzaqla. Prescribing information. Takeda Pharmaceuticals; 2023. Accessed February 14, 2024. https://www.fruzaqla.com/sites/default/files/resources/fruzaqla-prescribing-information.pdf
11. Stivarga. Prescribing information. Bayer HealthCare Pharmaceuticals; 2020. Accessed February 14, 2024. https://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf
12. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4
13. Van Cutsem E, Martinelli E, Cascinu S, et al. Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study. Oncologist. 2019;24(2):185-192. doi:10.1634/theoncologist.2018-0072
14. Cervantes A, Adam R, Rosello S, et al; ESMO Guidelines Committee. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022:34(1):10-32. doi:10.1016/j.annonc.2022.10.003
15. Lonsurf. Prescribing information. Taiho Oncology; 2023. Accessed February 14, 2024.
    https://taihocorp-media-release.s3.us-west-2.amazonaws.com/documents/prescribing-information.pdf
16. Prager GW, Taieb J, Fakih M, et al; SUNLIGHT Investigators. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657-1667. doi:10.1056/NEJMoa2214963
17. Cervantes A, Martinelli E; ESMO Guidelines Committee. Updated treatment recommendation for third-line treatment in advanced colorectal cancer from the ESMO Metastatic Colorectal Cancer Living Guideline. Ann Oncol. 2023;35(2):241-243. doi:10.1016/j.annonc.2023.10.129
18. Byrne M, Saif MW. Selecting treatment options in refractory metastatic colorectal cancer. Onco Targets Ther. 2019;12:2271-2278. doi:10.2147/OTT.S194605
19. Bekaii-Saab T, Ahn D, Yuan C, et al. Sequential treatment with regorafenib (REG) and trifluridine/tipiracil (TAS) +/- bevacizumab (Bev) in refractory metastatic colorectal cancer (mCRC) in community clinical practice in the USA. Ann Oncol. 2023;34(S2):S442. doi:10.1016/j.annonc.2023.09.1807
20. Zhang Q, Chen M, Wang Z, et al. Efficacy and safety comparison of regorafenib and fruquintinib in metastatic colorectal cancer-an observational cohort study in the real world. Clin Colorectal Cancer. 2022;21(3):e152-e161. doi:10.1016/j.clcc.2022.01.007
21. Deng YY, Zhang XY, Zhu PF, et al. Comparison of the efficacy and safety of fruquintinib and regorafenib in the treatment of metastatic colorectal cancer: a real-world study. Front Oncol. 2023;13:1097911. doi:10.3389/fonc.2023.1097911
22. Boccia R, Glaspy J, Crawford J, Aapro M. Chemotherapy-induced neutropenia and febrile neutropenia in the US: a beast of burden that needs to be tamed? Oncologist. 2022;27(8):625-636. doi:10.1093/oncolo/oyac074
23. Grothey A, Ciardiello F, Marshall JL. How to incorporate a chemo-free interval into the management of metastatic colorectal cancer. Clin Adv Hematol Oncol. 2020;18(10; suppl 16):1-24.
24. Epstein RS, Aapro MS, Basu Roy UK, et al. Patient burden and real-world management of chemotherapy-induced myelosuppression: results from an online survey of patients with solid tumors. Adv Ther. 2020;37(8):3606-3618. doi:10.1007/s12325-020-01419-6
25. Stubblefield MD, Burstein HJ, Burton AW, et al. NCCN task force report: management of neuropathy in cancer. J Natl Compr Canc Netw. 2009;7(suppl 5):S1-S26. doi:10.6004/jnccn.2009.007
26. Prager G, Köhne CH, O‘Connor JM, et al. The Screening and Consensus Based on Practices and Evidence (SCOPE) program-results of a survey on daily practice patterns for patients with mCRC. Curr Oncol. 2021;28(3):2097-2106. doi:10.3390/curroncol28030194
27. Anderson RT, Keating KN, Doll HA, Camacho F. The hand-foot skin reaction and quality of life questionnaire: an assessment tool for oncology. Oncologist. 2015;20(7):831-838. doi:10.1634/theoncologist.2014-0219
28. Gupta D, Lis CG, Grutsch JF. The relationship between cancer-related fatigue and patient satisfaction with quality of life in cancer. J Pain Symptom Manage. 2007;34(1):40-47. doi:10.1016/j.jpainsymman.2006.10.012
29. Latremouille-Viau D, Chang J, Guerin A, et al. The economic burden of common adverse events associated with metastatic colorectal cancer treatment in the United States. J Med Econ. 2016;20(1):54-62. doi:10.1080/13696998.2016.1225577
30. Tai E, Guy GP, Dunbar A, Richardson LC. Cost of cancer-related neutropenia or fever hospitalizations, United States, 2012. J Oncol Pract. 2017;13(6):e552-e561. doi:10.1200/JOP.2016.019588
31. Cho SK, Bekaii-Saab T, Kavati A, Babajanyan S, Hocum B, Barzi A. Value-based analysis of therapies in refractory metastatic colorectal cancer in US. Clin Colorectal Cancer. 2022;21(4):277-284. doi:10.1016/j.clcc.2022.09.003