Economic Evaluation of Monoclonal Antibodies in Metastatic Colorectal Cancer: A Systematic Review.

INTRODUCTION: Colorectal cancer (CRC) is one of the major causes of mortality and morbidity worldwide. The median overall survival (OS) of patients with metastatic CRC (mCRC) has doubled over the last 20 years partly due to the introduction of advanced biologic therapies. However, these treatment modalities bear significant costs on healthcare systems globally, and may jeopardize their fiscal sustainability. The aim of this systematic review was to critically appraise the economic evaluations of monoclonal antibodies in mCRC. METHODOLOGY: A literature search was performed in the electronic databases of: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, EMBASE, EMBASE Alert, PUBMED, NHS Economic Evaluation and Health Technology Assessment Database for full articles published from 1 January 2013 to 31 December 2020. RESULTS: Twenty economic analyses were identified in the literature that fulfilled the inclusion criteria and evaluated the cost-effectiveness of (a) bevacizumab as first-line treatment for mCRC and as maintenance treatment, (b) cetuximab as first-line treatment, (c) panitumumab versus bevacizumab and cetuximab versus bevacizumab as first-line treatment, (d) aflibercept and ramucirumab as second-line treatment, (e) cetuximab and panitumumab as third-line treatment, (f) cetuximab versus panitumumab as later lines of treatment, and (g) RAS testing prior to anti-epidermal growth factor receptor (EGFR) treatment. CONCLUSIONS: Bevacizumab in combination with chemotherapy is cost-effective as neither first-line treatment nor maintenance treatment. Sequential treatment with bevacizumab in first-line and second-line treatment was also not cost-effective. Testing for KRAS and extended RAS mutations is cost-effective and should be performed prior to anti-EGFR treatment. In the RAS wild-type subgroup of mCRCs the use of anti-EGFR (panitumumab or cetuximab) in first-line treatment leads to a more favorable cost-effectiveness profile than the corresponding anti-VEGF (bevacizumab). Cetuximab is not cost-effective as a first-line treatment. Anti-EGFR administration is not a cost-effective strategy in third-line treatment, even for RAS wild-type mCRCs, compared to best supportive care. Aflibercept was superior to ramucirumab and costed less, but neither were cost-effective compared to standard care.

Endoscopy and MR enteroclysis: equivalent tools in predicting clinical recurrence in patients with Crohn's disease after ileocolic resection.

BACKGROUND: Ileocolonoscopy poses the gold standard in the evaluation of postoperative recurrence of Crohn's disease (CD) at the site of ileocolonic anastomosis. Magnetic resonance enteroclysis (MRE) on the other hand is a promising technique for small bowel imaging. The aim was to compare MRE and ileocolonoscopy for predicting clinical recurrence in CD patients who have undergone ileocolonic resection. METHODS: We included 29 patients in the study. The median time since index operation was 35 months and between ileocolonoscopy and MRE was 3 days. Patients were followed up for a maximum of 2 years unless clinical recurrence occurred earlier. Endoscopic findings were evaluated on a 5-grade scale (i0-i4), whereas MRE findings on the neoterminal ileum and anastomosis were assessed according to a previously validated 4-grade scale MR score (MR0-MR3). RESULTS: By classifying patients into subgroups of endoscopic severity of postoperative recurrence using as a threshold an endoscopic score of i3, we found that 10% of patients in the i0 to i2 group had a clinical recurrence during the 2-year follow-up period as compared to 52.6% of subjects with i3 to i4 (P = 0.043). The corresponding clinical exacerbation rates in the subgroups based on MRE severity assessment were 12.5% for MR0 to MR1 and 50% for MR2 to MR3 (P = 0.09). CONCLUSIONS: Our data suggest that colonoscopy and MR enteroclysis are of similar value to predict the risk of clinical recurrence in postoperative patients with Crohn's disease.

Azathioprine is superior to budesonide in achieving and maintaining mucosal healing and histologic remission in steroid-dependent Crohn's disease.

BACKGROUND: The effects of azathioprine (AZA) and budesonide (BUD) on mucosal healing and histologic remission of Crohn's disease (CD) are insufficiently studied. In this prospective study we evaluated the comparative effects of AZA and BUD on endoscopic and histologic activity in patients with steroid-dependent Crohn's ileocolitis or proximal colitis who had achieved clinical remission on conventional steroids. METHODS: Patients were randomized to AZA (2.0-2.5 mg/kg a day) or BUD (6-9 mg a day) for 1 year. The study protocol included clinical examination, laboratory tests, calculation of the Crohn's Disease Activity Index (CDAI), completion of the Inflammatory Bowel Disease Questionnaire (IBDQ), at baseline and then every 2 months for 1 year. Ileocolonoscopy with regional biopsies was performed at baseline and then at the end of the study to assess mucosal healing and the histologic activity of CD. RESULTS: Thirty-eight patients were randomized to AZA and 39 to BUD. At the end of the study 32 and 25 patients in the AZA and BUD groups, respectively, were in clinical remission (P = 0.07). The Crohn's Disease Endoscopic Index of Severity (CDEIS) score fell significantly only in the AZA group (P < 0.0001). Complete or near complete healing was achieved in 83% of AZA-treated patients compared with only 24% of BUD-treated patients (P < 0.0001). Histologic activity as assessed by an average histology score (AHS) fell significantly only in the AZA group (P < 0.001 versus baseline) and was significantly lower than in the BUD group at the end of the study (P < 0.001). Eight patients in the AZA group were withdrawn for adverse events (n = 6) or relapse of disease compared with 14 patients in the BUD group who were withdrawn for relapse of disease. CONCLUSIONS: In patients with steroid-dependent inflammatory Crohn's ileocolitis or proximal colitis who achieve clinical remission with conventional steroids, a 1-year treatment with AZA was superior to BUD in achieving and maintaining mucosal healing and histologic remission.

A pilot study comparing hydrocortisone premedication to concomitant azathioprine treatment in preventing loss of response to infliximab.

OBJECTIVES: Antibodies to infliximab may lead to loss of response to infliximab (IFX) in Crohn's disease. Azathioprine (AZA) coadministration prevents the formation, whereas hydrocortisone (HC) premedication reduces the levels of antibodies to IFX. This pilot study aims at assessing the efficacy of these strategies to prevent loss of response to IFX. METHODS: Eligible patients had active steroid-dependent luminal Crohn's disease and received IFX (5 mg/kg at weeks 0, 2, and 6 for induction and then scheduled q8 week for remission maintenance). Patients were stratified in a 1 : 1 ratio to oral AZA (2-2.5 mg/kg/day, stratum A) or HC premedication (250 mg intravenously, stratum B). Stratum A included only patients naive to AZA; stratum B included both AZA naive and intolerant patients. Steroids were tapered within 6-8 weeks. Patients were followed up with monthly clinical assessments, laboratory tests, Crohn's Disease Activity Index calculations, adverse-events check up, and adherence to treatment. RESULTS: Overall, 23 patients received IFX/HC and 23 IFX/AZA. There were no differences at baseline in any patient-related or disease-related parameters. Seventeen (74%) patients on IFX/AZA completed the study; six patients were withdrawn for primary nonresponse (one patient), lost response to IFX (two patients), or AZA-related adverse events. Eighteen (78%) patients on IFX/HC completed the study; five patients were withdrawn for primary nonresponse (one patient), loss of response (two patients), or infusion reactions to IFX. No significant differences emerged between strata in clinical remission rates or lost response to IFX. CONCLUSION: This prospective 2-year pilot study has not confirmed superiority of any available strategy to maintain the efficacy of IFX.

How adherent to treatment with azathioprine are patients with Crohn's disease in long-term remission?

BACKGROUND: Patients with longstanding quiescent Crohn's disease on azathioprine usually maintain an excellent quality of life but are also concerned about long-term safety. This may affect adherence to treatment. The aim of the present study was to assess the adherence to azathioprine in a cohort of patients with Crohn's disease in long-term remission. METHODS: Thirty patients with Crohn's disease in remission on azathioprine for > or =48 months were enrolled in the study. All were asked to record the number of azathioprine tablets they consumed daily. Notes were kept every other month for 6 months. Adherence was defined as consumption of > or =80% of medication. RESULTS: Most patients (18/28, 74.3%) were not adherent to treatment. The mean (+/-SD) daily dose of azathioprine in adherent and nonadherent patients was 145 +/- 45 mg and 102 +/- 20 mg, respectively. However, there were no significant differences between the 2 groups in the mean IBDQ score and mean Crohn's Disease Activity Index (CDAI) score, both throughout the entire study and at each time point of the study. Male gender, single status, and consumption of >5 concomitant medications were associated with nonadherence. CONCLUSIONS: Most patients with Crohn's disease in longstanding remission had low self-reported adherence to azathioprine. Both male gender and single status were associated with nonadherence to azathioprine, whereas disease factors were not related to self-reported adherence. Patients considered nonadherent to treatment maintained disease remission and a quality of life similar to patients who were adherent to treatment.

The long-term efficacy of azathioprine does not wane after four years of continuous treatment in patients with steroid-dependent luminal Crohn's disease.

BACKGROUND: The long-term effectiveness of azathioprine, in Crohn's disease (CD) patients remains a matter of debate. This study aims at assessing the effectiveness and safety of azathioprine in patients treated continuously for less or more than 4 years. METHODS: Patients with steroid-dependent Crohn's disease in remission on azathioprine (2-2.5 mg/kg) for between 2 and 8 years were assigned into two groups. Patients in Group A were being treated continuously for 2 to 4 years whereas patients in Group B for 4 to 8 years. Patients were followed every month for 1 year with physical examination and laboratory tests. Compliance with treatment was also assessed every month. Every 3 months the Crohn's Disease Activity Index (CDAI) was calculated and the quality of life (QOL) Inflammatory Bowel Disease Questionnaire (IBDQ) was completed. Colonoscopy with calculation of the Crohn's Disease Endoscopic Index of Severity (CDEIS) was performed at baseline and at the end of the study. The primary end point was relapse after 1 year. Secondary end points were safety of treatment, QOL, and endoscopic healing. RESULTS: Fifty-eight patients were included in Group A and 42 in Group B. The relapse rates per protocol were 19.6% and 11.9%, respectively (p: not significant). There were no significant differences overall and at each time point of the study between the two treatment groups regarding compliance with and safety of treatment, CDAI, IBDQ, and CDEIS scores. Multifactorial analysis did not identify any factor influencing the remission of disease in any patient group. CONCLUSIONS: Long-term treatment with azathioprine of steroid-dependent Crohn's disease is efficacious and safe.

High-level microsatellite instability is not involved in gallbladder carcinogenesis.

The molecular alterations involved in the pathogenesis of gallbladder cancer are not yet well defined. Our aim was to determine the microsatellite status of gallbladder carcinomas and its possible correlation with alterations in K-ras and p53 genes as well as the clinicopathological characteristics of these tumors. A group of 37 gallbladder carcinomas was analyzed for alterations in a proposed panel of mononucleotide and dinucleotide markers of microsatellite instability. Somatic frameshift mutations at repeated sequences in the coding regions of TGF-betaRII, Bax, hMSH3, hMSH6 were also examined. The findings were correlated with the presence of K-ras and p53 alterations, and tumors' clinicopathological features. Microsatellite instability and/or LOH was observed in 9 gallbladder carcinomas. Cases showing microsatellite instability displayed alterations only in dinucleotide markers and were classified as MSI-L carcinomas. A subset of gallbladder carcinomas is characterized by low-level instability, based on the analysis of the above mentioned panel of markers. The pathway of microsatellite instability seems to play a minor role in the pathogenesis of gallbladder cancer.

Evaluation of BAT-26 as an indicator of microsatellite instability in gallbladder carcinomas.

BACKGROUND/AIMS: The genetic pathways of gallbladder cancer are not yet well defined, since the contribution of genetic abnormalities, clarified in other organs, remains questionable. Our aim was to evaluate the role of microsatellite instability in this organs carcinogenesis. METHODOLOGY: We investigated a group of 20 gallbladder carcinomas from Greek patients with regard to alterations in length of the BAT-26 mononucleotide marker--as an indicator of microsatellite instability. The findings were correlated with the presence of p53 and ras mutations, alterations of the bax and TGF-beta RII genes and tumors' clinicopathological features. Polymerase chain reaction and electrophoretic analysis in a non-denaturating 25% polyacrylamide gel was performed for the detection of BAT-26 size variations. RESULTS: None of our specimens showed microsatellite instability at the BAT-26 marker. CONCLUSIONS: BAT-26, an indicator of high-level microsatellite instability, may not be sufficient, when used alone, for determining the microsatellite instability status of gallbladder carcinomas, since these may be characterized by low-level instability. Bax and TGF-beta RII genes may not also be targets of instability in this type of tumors.