Are All Anti-Angiogenic Drugs the Same in the Treatment of Second-Line Metastatic Colorectal Cancer? Expert Opinion on Clinical Practice.
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ABSTRACT:
SUBMITTER: Lai E
PROVIDER: S-EPMC8141840 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: There are no clinical studies comparing the efficacy of bevacizumab vs.aflibercept in association with folfiri in RAS mutated (RAS-M) metastatic colorectal cancer patients (mCRC) pretreated with folfox and bevacizumab. Patients and Methods: Consecutive RAS-M unresectable mCRC patients progressing to first-line folfox/bevacizumab were treated with 12 cycles of folfiri/bevacizumab (arm A) or folfiri/aflibercept (arm B) at Oncologist discretion. Differences in overall survival between the two schedules were analyzed. Responses and toxicities were described with RECIST and NCI-CTC v4.0, respectively. Results: Seventy-four patients were treated from January 2014 to January 2018; 31 with arm A, 43 with arm B. Among clinical factors there was a predominance of more extended disease (>2 metastatic sites) in arm B (26/43 [60.5%] vs. 10/31 [32.2%] arm A; p = 0.0414). Fifty-nine patients were evaluable for response: arm A, 5 PR (Partial Response), 15 SD (Stable Disease), 8 PD (Progressive Disease); arm B, 5 PR, 16 SD, 10 PD. There were no grade 4 toxic events. Duration of first-line chemotherapy was significantly shorter in patients treated in arm B (12 pts <6 months, 16 pts ≥6, and <12, 15 pts ≥12) vs. arm A (1 pts <6 months, 14 pts ≥6, and <12, 16 pts ≥12) (p = 0.0210); these patients were excluded from survival analysis to avoid prognostic interferences. No maintenance treatment with aflibercept was done in arm B while in arm A bevacizumab with or without fluorouracil and folinic acid were allowed. Median OS were 8.9 months in arm A vs. 12.1 months in arm B (+3.2 months; p = 0.9331, HR: 1.02; 95% CI: 0.57-1.84). Six-months survivals were 65% in arm A and 80% in arm B. Conclusions: Folfiri/bevacizumab and folfiri/aflibercept are equally effective second-line therapies in RAS-M mCRC patients. Although not significant, folfiri/aflibercept was associated with a lower risk of death particularly during the 6-months induction phase.
| S-EPMC6700318 | biostudies-literature
Project description:BackgroundExposing patients with metastatic colorectal cancer (mcrc) to all three active chemotherapeutic agents (oxaliplatin, irinotecan, fluorouracil) has improved survival. The benefit of second-line chemotherapy after a first-line triplet is not clearly defined. We evaluated the efficacy of second-line chemotherapy in patients who had received first-line triplet therapy.MethodsThe medical records of patients treated on a prospective trial of first-line triplet therapy were reviewed for second-line treatment. Univariate and multivariate analyses were performed to establish factors of prognostic significance.ResultsOf the 53 patients who received first-line triplet therapy, 28 (53%) received second-line chemotherapy [13 men; 8 with a colon primary; mutant KRAS in 10, wild-type in 15, and unknown status in 3; Eastern Cooperative Oncology Group performance status (ps) of 1 in 16 patients, ps 2 in 3, ps 3 in 2, and unknown in 7; involved organs: liver in 17 patients, lung in 16, and peritoneum in 8]. Second-line chemotherapy consisted of xelox or folfox in 13 patients, xeliri or folfiri in 12, and single-agent irinotecan in 3. Concurrent bevacizumab was given in 16 patients (57%), and cetuximab, in 2 (7%). Median survival was 28.0 months [95% confidence interval (ci): 22.8 months to 33.2 months] for patients receiving second-line therapy and 23.0 months (95% ci: 13.2 months to 32.8 months) for those not receiving it. Best response was partial in 6 patients (21%), stable disease in 11 (39%), and progressive disease in 11 (39%). Median progression-free survival was 4.8 months (95% ci: 2.4 months to 9.6 months), and overall survival was 15 months (95% ci: 9.6 months to 20.4 months).ConclusionsSecond-line chemotherapy after first-line triplet therapy in mcrc is feasible and suggests efficacy comparable to that reported for second-line therapy after a doublet, regardless of the agent used.
| S-EPMC6380651 | biostudies-literature
Project description: Not available
| S-EPMC11234808 | biostudies-literature
Project description:The optimal chemotherapeutic regimen for use beyond the second line for patients with metastatic colorectal cancer (mCRC) remains unclear.We systematically searched the Cochrane Database of Systematic Reviews, EMBASE and Medline for records published between January 2002 and May 2017, and cancer congress databases for records published between January 2014 and June 2017. Eligible studies evaluated the efficacy, safety and patient-reported outcomes of monotherapies or combination therapies at any dose and number of treatment cycles for use beyond the second line in patients with mCRC. Studies were assessed for design and quality, and a qualitative data synthesis was conducted to understand the impact of treatment on overall survival and other relevant cancer-related outcomes.The search yielded 938 references of which 68 were included for qualitative synthesis. There was limited evidence to support rechallenge with chemotherapy, targeted therapy or both. Compared with placebo, an overall survival benefit for trifluridine/tipiracil (also known as TAS-102) or regorafenib has been shown for patients previously treated with conventional chemotherapy and targeted therapy. There was no evidence to suggest a difference in efficacy between these treatments. Patient choice and quality of life at this stage of treatment should also be considered when choosing an appropriate therapy.These findings support the introduction of an approved agent such as trifluridine/tipiracil or regorafenib beyond the second line before any rechallenge in patients with mCRC who have failed second-line treatment.
| S-EPMC5913602 | biostudies-other
Project description:Colorectal cancer (CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various anti-angiogenic agents in patients with metastatic CRC (mCRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in mCRC patients. Despite the discovery of several promising anti-angiogenic agents, mCRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.
| S-EPMC4501927 | biostudies-literature
Project description:Regardless of line of therapy, treatment goals in chronic phase chronic myeloid leukemia (CML) are: avoid progression to accelerated phase or blast crisis CML such that patients achieve a life expectancy comparable with that of the general population; avoid adverse events (AEs); and restore and maintain quality of life. The most important prognostic factor for achieving these goals is response to tyrosine kinase inhibitors (TKIs) at key milestones. For patients failing a TKI, a treatment change is mandatory to limit the risk of progression and death. There is currently no precise guideline for patients that fail a second-generation TKI, and there is a paucity of data to guide clinical decision making in this setting. There is, therefore, an unmet need for practical and actionable guidance on how to manage patients who fail a second-generation TKI. Although the term 'failure' includes patients failing for resistance or intolerance, the focus of this paper is failure of a second-generation TKI because of resistance. CML patients who fail their first second-generation TKI for true resistance need a more potent therapy. In these patients, the key issues to consider are the relative appropriateness of early allogeneic hematopoietic stem cell transplantation or the use of a further TKI. Selection of the next line of treatment after second-generation TKI resistance should be individualized and must be based on patient-specific factors including cytogenetics, mutation profile, comorbidities, age, previous history of AEs with prior TKI therapy, and risk profile for AEs on specific TKIs. This expert opinion paper is not in conflict with existing recommendations, but instead represents an evolution of previous notions, based on new data, insights, and clinical experience. We review the treatment options for patients resistant to second-generation TKI therapy and provide our clinical opinions and guidance on key considerations for treatment decision making.
| S-EPMC7266739 | biostudies-literature
Project description:The aim of this study was to compare the efficacy, safety and survival rate of a treatment regimen comprising capecitabine plus irinotecan (XELIRI) to those of a standard regimen comprising leucovorin, fluorouracil and irinotecan (FOLFIRI), to determine the correlation among the inherited genetic variations in UGT1A1, UGT1A7 and UGT1A9. A total of 84 consecutive patients with histologically confirmed metastatic colorectal cancer (mCRC) were included in the study. All patients were treated with FOLFIRI or XELIRI. The median progression-free survival time was 4.4 months for FOLFIRI and 5.7 months for XELIRI (hazard ratio=1.35; 95% confidence interval, 0.83-2.21; P=0.22). When compared with FOLFIRI (6.34%), XELIRI was associated with lower rates of severe toxicity (3.29) (P=0.026) and similar disease control rates (69.57% for FOLFIRI and 61.11% for XELIRI; P=0.49). In total, 17 single nucleotide polymorphisms were identified, five of which revealed an association with grade 3/4 neutropenia, including UGT1A7*4; however, UGT1A1*28 and UGT1A1*6, which have been previously reported, were not significant. Additionally, H2 haplotypes, which include UGT1A9*22, and H5 and H7 haplotypes, which include UGT1A7*2, UGT1A7*3 and UGT1A7*4, were associated with a higher risk of severe neutropenia. In conclusion, XELIRI is an effective treatment regimen with acceptable response rates and tolerability for mCRC patients as a second-line treatment. Furthermore, inherited genetic variations in UGT1A1, UGT1A7 and UGT1A9 are associated with grade 3/4 neutropenia.
| S-EPMC4156196 | biostudies-literature
Project description:PurposeEtirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC).MethodsPatients were randomized to EP 145 mg/m2 or irinotecan 350 mg/m2 Q21d until disease progression/unacceptable toxicity. The primary endpoint was progression-free survival (PFS) with response determined by central radiologic review (RECIST version 1.1).ResultsThe study was terminated before completing accrual due to evolving standards of care. Eighty-three patients were randomized. Median PFS was longer with EP versus irinotecan (4.0 versus 2.8 months, respectively; HR 0.65; 95% CI 0.40-1.04; P = 0.07). Six-month PFS rates were 32.8 and 15.4%, respectively. Median OS was 9.6 and 8.4 months in EP and irinotecan arms, respectively (HR 0.91; 95% CI 0.56-1.49). ORRs were 10 and 5%, respectively (P = 0.676); median DOR was significantly longer in EP arm (7.9 versus 1.4 months; P = 0.018). The most common grade-3/4 adverse events for EP and irinotecan were diarrhea (21 vs 20%), neutropenia (10 vs 22%), abdominal pain (14 vs 5%), nausea (14 vs 2%), and vomiting (12 vs 7%), respectively.ConclusionEP is active and safe for second-line treatment of KRAS-mutant, irinotecan-naïve mCRC.
| S-EPMC6863159 | biostudies-literature
Project description:BackgroundThe ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab.MethodsThe subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis.ResultsSixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0-1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46-1.34], p = 0.373, adjusted HR: 0.87 [0.41-1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38-1.12], p = 0.125, adjusted HR 0.53 [0.27-1.07], p = 0.078).ConclusionIn mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents.
| S-EPMC8555183 | biostudies-literature
Project description:Background:Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired. Methods:We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported. Results:The overall effect of B across the two lines resulted in a HR?=?0.80 (95% CI 0.68-0.95, p?=?0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR?=?0.90, 95% CI 0.72-1.12, p?=?0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR?=?0.64, 95% CI 0.49-0.84, p?=?0.0011) versus CT alone. Conclusion:Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies.
| S-EPMC7378711 | biostudies-literature