Monique E. van Leerdam

Crizotinib-induced fatal fulminant liver failure

Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis.

Infradiaphragmatic irradiation and high procarbazine doses increase colorectal cancer risk in Hodgkin lymphoma survivors

Background:Hodgkin lymphoma (HL) survivors are at increased risk of second malignancies, but few studies have assessed colorectal cancer (CRC) risk after HL treatment. We assessed long-term, subsite-specific CRC risk associated with specific radiation fields and chemotherapy regimens.Methods:In a Dutch cohort of 3121 5-year HL survivors treated between 1965 and 1995, subsite-specific CRC incidence was compared with general population rates. Treatment effects were quantified by Cox regression analyses.Results:After a median follow-up of 22.9 years, 55 patients developed CRC. The standardized incidence ratios (SIR) was 2.4-fold increased (95% confidence interval (95%CI) 1.8–3.2), leading to 5.7 excess cases per 10 000 patient-years. Risk was still increased 30 years after HL treatment (SIR: 2.8; 95%CI: 1.6–4.6). The highest (SIR: 6.5, 95%CI: 3.3–11.3) was seen for transverse colon cancer (15.0 (95%CI: 4.3–40.8) after inverted-Y irradiation). A prescribed cumulative procarbazine dose >4.2 g m−2 was associated with a 3.3-fold higher CRC risk (95%CI: 1.8–6.1) compared to treatment without procarbazine. Patients receiving >4.2 g m−2 procarbazine and infradiaphragmatic radiotherapy had a hazard ratio of 6.8 (95%CI: 3.0–15.6) compared with patients receiving neither treatment, which is significantly higher than an additive joint effect (Padditivity=0.004).Conclusions:Colorectal cancer surveillance should be considered for HL survivors who received Infradiaphragmatic radiotherapy and a high cumulative procarbazine dose.

Do men and women need to be screened differently with fecal immunochemical testing? A cost-effectiveness analysis

Background: Several studies suggest that test characteristics for the fecal immunochemical test (FIT) differ by gender, triggering a debate on whether men and women should be screened differently. We used the microsimulation model MISCAN-Colon to evaluate whether screening stratified by gender is cost-effective. Methods: We estimated gender-specific FIT characteristics based on first-round positivity and detection rates observed in a FIT screening pilot (CORERO-1). Subsequently, we used the model to estimate harms, benefits, and costs of 480 gender-specific FIT screening strategies and compared them with uniform screening. Results: Biennial FIT screening from ages 50 to 75 was less effective in women than men [35.7 vs. 49.0 quality-adjusted life years (QALY) gained, respectively] at higher costs (€42,161 vs. −€5,471, respectively). However, the incremental QALYs gained and costs of annual screening compared with biennial screening were more similar for both genders (8.7 QALYs gained and €26,394 for women vs. 6.7 QALYs gained and €20,863 for men). Considering all evaluated screening strategies, optimal gender-based screening yielded at most 7% more QALYs gained than optimal uniform screening and even resulted in equal costs and QALYs gained from a willingness-to-pay threshold of €1,300. Conclusions: FIT screening is less effective in women, but the incremental cost-effectiveness is similar in men and women. Consequently, screening stratified by gender is not more cost-effective than uniform FIT screening. Impact: Our conclusions support the current policy of uniform FIT screening. Cancer Epidemiol Biomarkers Prev; 26(8); 1328–36. ©2017 AACR.

Chemoprevention in Patients with Peutz‐Jeghers Syndrome: Lessons Learned

Abstract Lessons Learned. Motivating patients to enroll in chemopreventive studies is challenging. Chemoprevention with toxic drugs is not feasible. Background. LKB1 mutations are the underlying genetic abnormality causing Peutz‐Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods. Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high‐risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results. Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49‐year‐old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52‐year‐old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized. Conclusion. Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

Stage distribution of screen-detected colorectal cancers in the Netherlands

We read with interest the results of the pilot study in England, which was performed to establish the acceptability and diagnostic performance of screening with the faecal immunochemical test (FIT) over the guaiac faecal occult blood test (gFOBT).1 When comparing gFOBT to FIT, the uptake increased from 59.4% to 66.4%, positivity rate increased from 1.7% to 7.8% (at a cut-off level of 20 µg Hb/g faeces) and colorectal cancer (CRC) detection doubled. Moreover, this report showed that also with FIT cut-off levels above 20 µg Hb/g faeces, improved clinical outcomes can be achieved over gFOBT. However, for a screening programme to be effective, it is a prerequisite to detect cancers in an early stage. Thus far, information on stage distribution of screen-detected CRCs in a population-based FIT screening programme is lacking. In our study, we collected data on all CRCs detected in patients aged 60–75 years in the Netherlands in 2015 through the Netherlands Cancer Registry. In total, 9437 CRCs were diagnosed in 9301 patients: 3579 (38.5%) patients were diagnosed after a positive FIT in the CRC screening programme (screen-detected), 4506 (48.4%) patients were diagnosed due …

Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

Objective Hodgkins lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics. Design 54 t-CRCs diagnosed in a Hodgkins lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111). Results KRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome. Conclusions We have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.

4702 National survey of management in peptic ulcer hemorrhage.

Aim:Evaluation of management in patients with peptic ulcer hemorrhage (PUH) in the Netherlands. Methods: A questionnaire was sent to gastroenterologists and internists, performing endoscopy, in every hospital in the Netherlands (N=123). Endoscopic therapy, acid suppressant therapy, endoscopic re-intervention and management of Helicobacter pylori were evaluated. Results: 90/123 (73%) questionnaires were returned. Endoscopic hemostatic therapy is given in ulcers classified as Forrest Ia/ Ib/ IIa/ IIb by respectively 89%/ 93%/ 83% and 47% of responders. Gastroenterologists perform more often endoscopic therapy in Forrest Ib (p=0.03), IIa (p=0.002) and IIb (p=0.001) ulcers compared to internists. As first modality , endoscopic injection therapy is used by 93%. Adrenaline combined with polidocanol is used in 60%, adrenaline alone in 14%, polidocanol alone in 6%, adrenaline and histoacryl/ thrombine/ fibrine/ alchohol in 7%, 4%, 1% and 1% respectively. 68% of responders add a sclerosant to adrenaline injections. Acid suppressant therapy is given by 97% of responders; 71% preferred proton pump inhibitors, 26% H2-receptorantagonists, both mainly given intravenously (80% and 92% respectively). In case of suspected rebleeding 71% perform endoscopic re-intervention (89% of gastroenterologists vs. 60% of internists, p=0.005), whereas the others refer the patient directly for surgery. Detection of H. pylori is performed by almost all responders. Eradication is confirmed by only 64% (80% of gastroenterologists vs. 50% of internists, p=0.004). Conclusions: There are important differences in management of PUH between gastroenterologists and internists in the Netherlands. Despite consensus conferences and results of randomised trials, a significant percentages of patients with PUH are still not adequately treated endoscopically, nor is H. pylori eradication confirmed in all patients.