The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: Systematic review and economic evaluation (review of NICE Guidance No. 33)

School of Health and Related Research, University of Sheffield, UK.
Health technology assessment (Winchester, England) (Impact Factor: 5.03). 06/2008; 12(15):iii-ix, xi-162. DOI: 10.3310/hta12150
Source: PubMed


To evaluate three technologies for the management of advanced colorectal cancer: (1) first-line irinotecan combination [with 5-fluorouracil (5-FU)] or second-line monotherapy; (2) first- or second-line oxaliplatin combination (again, with 5-FU); and (3) raltitrexed, where 5-FU is inappropriate. To examine the role of irinotecan and oxaliplatin in reducing the extent of incurable disease before curative surgery (downstaging).
Ten electronic bibliographic databases covering the period up to August 2004.
Searches identified existing studies of the effectiveness and economics of the technologies and any studies that evaluated any of the indications outlined above were included. Data were extracted and assessed generic components of methodological quality. Survival outcomes were meta-analysed.
Seventeen trials were found, of varying methodological quality. Compared with 5-FU, first-line irinotecan improved overall survival (OS) by 2-4 months (p=0.0007), progression-free survival (PFS) by 2-3 months (p<0.00001) and response rates (p<0.001). It offered a different toxicity profile and no quality of life (QoL) advantage. However, second-line irinotecan compared with 5-FU improved OS by 2 months (p=0.035) and PFS by 1 month (p=0.03), and provided a better partial response rate, but with more toxicities and no QoL advantage. Compared with second-line best supportive care, irinotecan improved OS by 2 months (p=0.0001), had a different toxicity profile and maintained baseline QoL longer, but with no overall difference. The addition of oxaliplatin to second-line 5-FU is associated with a borderline significant improvement in overall survival (p<0.07); a significantly higher response rate (<0.0001); and more serious toxicities. There is no evidence for a significant difference in QoL. Schedules with treatment breaks may not reduce clinical effectiveness but reduce toxicity. The addition of oxaliplatin to second-line 5-FU also saw no improvement in OS (p<0.07), better PFS (by 2.1 months, p=0.0001), an 8.9% higher response rate (p<0.0001), more toxicities and no QoL advantage. There was no significant difference in OS or PFS between first-line irinotecan and oxaliplatin combinations except when 5-FU was delivered by bolus injection, when oxaliplatin provided better OS (p=0.032) and response rates (p=0.032), but not PFS (p=0.169). The regimens had different toxicity profiles and neither conferred a QoL advantage. When compared to 5-FU, raltitrexed is associated with no significant difference in overall or progression-free survival; no significant difference in response rates; more vomiting and nausea, but less diarrhoea and mucositis; no significant difference in, or worse QoL. Raltitrexed treatment was cut short in two out of four included trials due to excess toxic deaths. 5-FU followed by irinotecan was inferior to any other sequence. First-line irinotecan/5-FU combination improved OS and PFS, although further unplanned therapy exaggerated the OS effect size. Staged combination therapy (combination oxaliplatin followed by combination irinotecan or vice versa) provided the best OS and PFS, although there was no head-to-head comparison against other treatment plans. In the only trial to use three active chemotherapies in any staged combination, median OS was over 20 months. In another study, the longest median OS from a treatment plan using two active agents was 16.2 months. Where irinotecan or oxaliplatin were used with 5-FU to downstage people with unresectable liver metastases, studies consistently showed response rates of around 50%. Resection rates ranged from 9 to 35% with irinotecan and from 7 to 51% with oxaliplatin. In the one study that compared the regimens, oxaliplatin enabled more resections (p=0.02). Five-year OS rates of 5-26% and disease-free survival rates of 3-11% were reported in studies using oxaliplatin. Alone or in combination, 5-FU was more effective and less toxic when delivered by continuous infusion. Existing economic models were weak because of the use of unplanned second-line therapies in their trial data: the survival benefits in patients on such trials cannot be uniquely attributed to the allocated therapy. Consequently, the economic analyses are either limited to the use of PES (at best, a surrogate outcome) or are subject to confounding. Weaknesses in cost components, the absence of direct in-trial utility estimates and the limited use of sensitivity analysis were identified. Improvements to the methodologies used in existing economic studies are presented. Using data from two trials that planned treatment sequences, an independent economic evaluation of six plans compared with first-line 5-FU followed on progression by second-line irinotecan monotherapy (NHS standard treatment) is presented. 5-FU followed on progression by irinotecan combination cost 13,174 pounds per life-year gained (LYG) and 10,338 pounds per quality-adjusted life-year (QALY) gained. Irinotecan combination followed on progression by additional second-line therapies was estimated to cost 12,418 pounds per LYG and 13,630 pounds per QALY gained. 5-FU followed on progression by oxaliplatin combination was estimated to cost 23,786 pounds per LYG and 31,556 pounds per QALY gained. Oxaliplatin combination followed on progression by additional second-line therapies was estimated to cost 43,531 pounds per LYG and 67,662 pounds per QALY gained. Evaluations presented in this paragraph should be interpreted with caution owing to missing information on the costs of salvage therapies in the trial from which data were drawn. Irinotecan combination followed on progression by oxaliplatin combination cost 12,761 pounds per LYG and 16,663 pounds per QALY gained. Oxaliplatin combination followed on progression by irinotecan combination cost 16,776 pounds per LYG and 21,845 pounds per QALY gained. The evaluation suggests that these two sequences have a cost-effectiveness profile that is favourable in comparison to other therapies currently funded by the NHS. However, the differences in OS observed between the two trials from which data were taken may be a result of heterogeneous patient populations, unbalanced protocol-driven intensity biases or other differences between underlying health service delivery systems.
Treatment with three active therapies appears most clinically effective and cost-effective. NHS routine data could be used to validate downstaging findings and a meta-analysis using individual patient-level data is suggested to validate the optimal treatment sequence.

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    • "Irinotecan, a topoisomerase I inhibitor, is mostly used in the treatment of patients with advanced colorectal cancer, either in combination with one or more agents, such as fluorouracil, oxaliplatin, bevacizumab and cetuximab, or as monotherapy. Irinotecan is usually associated with a high prevalence of grades 3–4 gastrointestinal toxicities, such as mucositis and diarrhoea (Keefe et al., 2007; Hind et al., 2008; Peterson et al., 2011). A number of strategies have been assessed in the management of chemotherapy-related intestinal mucositis, including treatment with sulfasalazine, amifostine , sucralfate, octreotide, hyperbaric oxygen, misoprostol and probiotics (Peterson et al., 2011; Gibson et al., 2013). "
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    ABSTRACT: Intestinal mucositis is a common toxicity that occurs during irinotecan-based cancer chemotherapy regimens. We have shown that mucositis courses with cytokine activation followed by nitric oxide synthesis. Recently, some studies have provided evidence of up-regulated interleukin-18 (IL-18) production in patients suffering from inflammatory bowel disease. Therefore, we investigated the role of IL-18 in the pathogenesis of irinotecan-induced intestinal mucositis. Wild type (wt), IL-18 or caspase-1 knockout mice (n=6) received either saline or irinotecan (60 mg kg(-1) /4 days, i.p.) or the IL-18 binding protein (IL-18bp, 10 mg kg(-1) ) prior to irinotecan. On day 5, diarrhea was monitored, and following euthanasia, proximal intestinal strips were obtained for histopathology, in vitro gut contractility, myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activity, and detection of IL-18 expression. Irinotecan induced severe diarrhea accompanied by intestinal injury (mainly villi shortening and increased crypt depth). Additionally, increased MPO and iNOS activity, iNOS immunostaining and IL-18 expression were observed in irinotecan-injected wt mice versus saline group (P<0.05). Moreover, IL-18 seems to derive from macrophages. In vitro, intestinal smooth muscle strips were hyperresponsive to acetylcholine after irinotecan treatment. Increases in MPO and iNOS activity, intestinal contractility and diarrhea were prevented in caspase-1(-/-) and IL-18(-/-) mice, and in IL-18bp-treated wt mice. Furthermore, the genetic deletion of IL-18 improved survival in irinotecan-treated mice and prevented iNOS immunoexpression and IL-18 production. Targeting interleukin-18 function may be a promising therapeutic approach to blunting the development of intestinal mucositis during irinotecan treatment regimens.
    Full-text · Article · Jan 2014 · British Journal of Pharmacology
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    • "months and mean survival of 24–27 months have been reported (Tournigand et al, 2004; Hind et al, 2008). Current real-world treatment patterns show that about half of patients progress and go on to receive second-line combination therapy (typically involving cross-over between FOLFIRI and FOLFOX) (Hess et al, 2010; Rosé et al, 2012), with similar patterns for use of additional biologic therapy in this setting. "
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    ABSTRACT: Background: Mean survival in cancer trials can be estimated with statistical techniques to extrapolate study survival curves. This methodology was applied to data from the VELOUR trial, where use of the novel biologic aflibercept (ziv-aflibercept in the United States) in combination with fluorouracil+leucovorin+irinotecan (FOLFIRI), had significantly increased median overall survival (OS) by 1.44 months, vs placebo plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) resistant to, or that had progressed following, an oxaliplatin-containing regimen. Methods: Parametric survival analyses were used to identify distributions with the best fit to the empirical VELOUR data. Mean OS for the two treatment groups (and pre-defined subgroups) was calculated from the fitted curves over a 15-year survival period. Results: Overall, the log-logistic distribution was the best-fitting for both treatment arms and, with it, the estimated difference in mean OS over 15 years between aflibercept+FOLFIRI and placebo+FOLFIRI was 4.7 months. In addition, the survival advantage with aflibercept was at least 3 months for the ITT population, whichever distribution was used to extrapolate survival. Conclusion: Extrapolation of survival curves suggests the mean OS difference for aflibercept in the VELOUR trial is at least 3 months in the ITT population and selected subgroups.
    Full-text · Article · Sep 2013 · British Journal of Cancer
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    • "Irinotecan has demonstrated usefulness for various types of cancer, including colon and lung cancers, and its applications have been widening. Irinotecan suppresses the action of topoisomerase 1, which is involved in DNA replication, thereby demonstrating a strong antitumor effect; however, it can cause severe adverse effects including leukopenia and diarrhea [16, 17, 75–94]. "
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    Full-text · Article · Jun 2013 · Evidence-based Complementary and Alternative Medicine
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