Annemieke Cats

The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer

OBJECTIVES:Approximately 10–15% of all pancreatic cancers (PCs) may be hereditary in origin. We investigated the use of endoscopic ultrasonography (EUS) for the screening of individuals at high risk for developing PC. In this paper the results of first-time screening with EUS are presented.METHODS:Those eligible for screening in this study were first-degree family members of affected individuals from familial pancreatic cancer (FPC) families, mutation carriers of PC-prone hereditary syndromes, individuals with Peutz–Jeghers syndrome, and mutation carriers of other PC-prone hereditary syndromes with clustering (≥2 cases per family) of PC. All individuals were asymptomatic and had not undergone EUS before.RESULTS:Forty-four individuals (M/F 18/26), aged 32–75 years underwent screening with EUS. Thirteen were from families with familial atypical multiple-mole melanoma (FAMMM), 21 with FPC, 3 individuals were diagnosed with hereditary pancreatitis, 2 were Peutz–Jeghers patients, 3 were BRCA1 and 2 were BRCA2 mutation carriers with familial clustering of PC, and 1 individual had a p53 mutation. Three (6.8%) patients had an asymptomatic mass lesion (12, 27, and 50 mm) in the body (n=2) or tail of the pancreas. All lesions were completely resected. Pathology showed moderately differentiated adenocarcinomas with N1 disease in the two patients with the largest lesions. EUS showed branch-type intraductal papillary mucinous neoplasia (IPMN) in seven individuals.CONCLUSIONS:Screening of individuals at a high risk for PC with EUS is feasible and safe. The incidence of clinically relevant findings at first screening is high with asymptomatic cancer in 7% and premalignant IPMN-like lesions in 16% in our series. Whether screening improves survival remains to be determined, as does the optimal screening interval with EUS.

Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group

BACKGROUND The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the studys primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56-0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. INTERPRETATION Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. FUNDING Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.

Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study

Background and aims Patients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance protocol for these patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance. Methods Databases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC). Results In 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5–26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4–16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence. Conclusions HPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a ‘serrated pathway’ to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered.

One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome

BACKGROUND & AIMS Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program. METHODS The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy. RESULTS After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without. CONCLUSIONS With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended.

A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity

BACKGROUND Targeting the vascular endothelial growth factor or the epidermal growth factor receptor (EGFR) has shown efficacy in advanced colorectal cancer (ACC), but no data are available on the combination of these strategies with chemotherapy in the first-line treatment. The CAIRO2 study evaluates the effect of adding cetuximab, a chimeric mAb against EGFR, to capecitabine, oxaliplatin and bevacizumab in the first-line treatment of ACC. PATIENTS AND METHODS In all, 755 patients were randomly assigned between treatment with capecitabine, oxaliplatin and bevacizumab with or without cetuximab. The primary end point is progression-free survival. We here present the toxicity results in the first 400 patients that entered the study. RESULTS The incidence of overall grade 3-4 toxicity was significantly higher in arm B compared with arm A (81% versus 72%, P = 0.03). This difference is fully attributed to cetuximab-related skin toxicity. The addition of cetuximab did not result in an increase of gastrointestinal toxicity or treatment-related mortality. CONCLUSIONS The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab in the first-line treatment of ACC appears to be safe and feasible. No excessive or unexpected toxicity in the cetuximab-containing treatment arm was observed.

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patients perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS)

BackgroundRadical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively.Methods/designIn this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate.ConclusionResults of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer.Trial registrationclinicaltrials.gov NCT00407186

Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents

BACKGROUND Early predictive markers for response are needed for advanced colorectal cancer (ACC) patients. We assessed the value of circulating tumour cells (CTC) in ACC patients treated with chemotherapy plus targeted agents (CAIRO2 phase III trial) and compared the results with computed tomography (CT) imaging. MATERIALS AND METHODS CTC were determined at baseline and at different time points during treatment. Patients were stratified into low (less than three CTC per 7.5 ml of blood) or high CTC (three or more CTC per 7.5 ml of blood). RESULTS A total of 467 patients were assessable for CTC analysis. Among them, 129 patients (29%) with high baseline CTC had a significantly decreased progression-free survival [PFS; hazard ratio (HR) 1.5] and overall survival (OS; HR 2.2) compared with 322 patients with low baseline CTC. This difference remained statistically significant during treatment. The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1-2 weeks after the start of treatment 20.0% and 95.1%, respectively. The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone. CONCLUSIONS The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.

Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer

PURPOSE The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. PATIENTS AND METHODS Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. RESULTS With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. CONCLUSION After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.

Relationship between Single Nucleotide Polymorphisms and Haplotypes in DPYD and Toxicity and Efficacy of Capecitabine in Advanced Colorectal Cancer

Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine. Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab ± cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival. Results: A total of 29 SNPs were detected in the case–cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14+1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14+1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14+1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) = 0.57 (0.35–0.95)]. Conclusions: DPYD IVS14+1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine. Clin Cancer Res; 17(10); 3455–68. ©2011 AACR.