Effect of preoperative chemotherapy on the histopathological classification of gastric cancer.

BACKGROUND: In the era of individualized gastric cancer (GC) treatment, accurate determination of histological subtype becomes increasingly relevant. As yet, it is unclear whether preoperative chemotherapy may affect the histological subtype. The aim of this study was to assess concordance in histological subtype between pretreatment biopsies and surgical resection specimens before and after the introduction of perioperative treatment. METHODS: Histological subtype was centrally determined in paired GC biopsies and surgical resection specimens of patients treated with either surgery alone (SA) in the Dutch D1/D2 study or with preoperative chemotherapy (CT) in the CRITICS trial. The histological subtype as determined in the resection specimen was considered the gold standard. Concordance rates and sensitivity and specificity of intestinal, diffuse, mixed, and "other" subtypes of GC were analyzed. RESULTS: In total, 105 and 515 pairs of GC biopsies and resection specimens of patients treated in the SA and CT cohorts, respectively, were included. Overall concordance in the histological subtype was 72% in the SA and 74% in the CT cohort and substantially higher in the diffuse subtype (83% and 86%) compared to the intestinal (70% and 74%), mixed (21% and 33%) and "other" subtypes (54% and 54%). In the SA cohort, sensitivities and specificities were 0.88 and 0.71 in the intestinal, 0.67 and 0.93 in the diffuse, 0.20 and 0.98 in the mixed, and 0.50 and 0.93 in the "other" subtypes, respectively. CONCLUSION: Our results suggest that accurate determination of histological subtype on gastric cancer biopsies is suboptimal but that the impact of preoperative chemotherapy on histological subtype is negligible.

Development of a UPLC-MS/MS Assay for the Quantitative Determination of Capecitabine, 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5'-fluorouracil (5-FU), and α-fluoro-ß-alanine (FBAL).

Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-ß-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples. Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-ß-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples.

Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial.

BACKGROUND: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial. PATIENTS AND METHODS: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival. RESULTS: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios. CONCLUSION: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).

A review of the bioanalytical methods for the quantitative determination of capecitabine and its metabolites in biological matrices.

The bioanalysis of the oral anticancer drug capecitabine and its metabolites has been investigated extensively over the past years. This paper reviews methods for the bioanalysis of capecitabine and its metabolites. The focus of this review will be on sample pre-treatment, chromatography and detection. Furthermore, the choice of standards and analytical problems encountered during analysis of capecitabine and its metabolites in biological matrices will be discussed. The major challenges in the bioanalysis of capecitabine and its metabolites are the simultaneous extraction and analysis due to the differences in polarity of the analytes. Furthermore we evaluate currently described methods for the quantification of capecitabine and its metabolites. Future wishes and perspectives are stated that could serve as an inspiration for further development of assays for the quantification of capecitabine and its metabolites.

Impact of upfront randomization for postoperative treatment on quality of surgery in the CRITICS gastric cancer trial.

BACKGROUND: Preoperative randomization for postoperative treatment might affect quality of surgery. In the CRITICS trial (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach), patients were randomized before treatment to receive chemotherapy prior to a D1 + gastrectomy (removal of lymph node station (LNS) 1-9 + 11), followed by either chemotherapy (CT) or chemoradiotherapy (CRT). In this analysis, the influence of upfront randomization on the quality of surgery was evaluated. METHODS: Quality of surgery was analyzed in both study arms using surgicopathological compliance (removal of ≥ 15 lymph nodes), surgical compliance (removal of the indicated LNS), and surgical contamination (removal of LNS that should be left in situ). Furthermore, the 'Maruyama Index of Unresected disease' (MI) was evaluated in both study arms, and validated with overall survival. RESULTS: Between 2007 and 2015, 788 patients with gastric cancer were included in the CRITICS study of which 636 patients were operated with curative intent. No difference was observed between the CT and CRT group regarding surgicopathological compliance (74.8% vs 70.9%, P = 0.324), surgical compliance (43.2% vs 39.2%, P = 0.381), and surgical contamination (59.4% vs 59.9%, P = 0.567). Median MI was 1 in both groups (range CT 0-88 and CRT 0-136, P = 0.700). A MI below 5 was associated with better overall survival (CT: P = 0.009 and CRT: P = 0.013). CONCLUSION: Surgical quality parameters were similar in both study arms in the CRITICS gastric cancer trial, indicating that upfront randomization for postoperative treatment had no impact on the quality of surgery. A Maruyama Index below five was associated with better overall survival.

Outcomes after prophylactic gastrectomy for hereditary diffuse gastric cancer.

BACKGROUND: Patients with hereditary diffuse gastric cancer and a CDH1 mutation have a 60-80 per cent lifetime risk of developing diffuse gastric cancer. Total prophylactic gastrectomy eliminates this risk, but is associated with considerable morbidity. The effectiveness (removal of all gastric mucosa) and outcomes of this procedure were evaluated retrospectively. METHODS: All consecutive individuals undergoing a prophylactic gastrectomy for a CDH1 mutation or gastric signet ring cell foci at the authors' institute between 2005 and 2017 were included. RESULTS: In 25 of 26 patients, intraoperative frozen-section examination (proximal resection margin) was used to verify complete removal of gastric mucosa. All definitive resection margins were free of gastric mucosa, but only after the proximal margin had been reresected in nine patients. In the first year after surgery, five of the 26 patients underwent a relaparotomy for adhesiolysis (2 patients) or jejunostomy-related complications (3 patients). Six patients were readmitted to the hospital within 1 year for nutritional and/or psychosocial support (4 patients) or surgical reintervention (2 patients). Mean weight loss after 1 year was 15 (95 per cent c.i. 12 to 18) per cent. For the 25 patients with a follow-up at 1 year or more, functional complaints were reported more frequently at 1 year than at 3 months after the operation: bile reflux (15 versus 11 patients respectively) and dumping (11 versus 7 patients). The majority of patients who worked or studied before surgery (15 of 19) had returned fully to these activities within 1 year. CONCLUSION: The considerable morbidity and functional consequences of gastrectomy should be considered when counselling individuals with an inherited predisposition to diffuse gastric cancer. Intraoperative frozen-section examination is recommended to remove all risk-bearing gastric mucosa.

Association between hospital volume and quality of gastric cancer surgery in the CRITICS trial.

BACKGROUND: Studies investigating the association between hospital volume and quality of gastric cancer surgery are lacking. In the present study, the effect of hospital volume on quality of gastric cancer surgery was evaluated by analysing data from the CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. METHODS: Patients who underwent gastrectomy with curative intent in the Netherlands were selected from the CRITICS trial database. Annual hospital volume of participating centres was derived from the Netherlands Cancer Registry. Hospital volume was categorized into very low (1-10 gastrectomies per year per institution), low (11-20), medium (21-30) and high (31 or more), and linked to the CRITICS database. Quality of surgery was analysed by surgicopathological compliance (removal of at least 15 lymph nodes), surgical compliance (removal of indicated lymph node stations) and the Maruyama Index. Postoperative morbidity and mortality were also compared between hospital categories. RESULTS: Between 2007 and 2015, 788 patients were included in the CRITICS study, of whom 494 were analysed. Surgicopathological compliance was higher (86·7 versus 50·4 per cent; P < 0·001), surgical compliance was greater (52·9 versus 19·8 per cent; P < 0·001) and median Maruyama Index was lower (0 versus 6; P = 0·006) in high-volume hospitals compared with very low-volume hospitals. There was no statistically significant difference in postoperative complications or mortality between the hospital volume categories. CONCLUSION: Surgery performed in high-volume hospitals was associated with better surgical quality than surgery carried out in lower-volume hospitals.

DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update.

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.

Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies.

The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3 R/3 R genotype was formally associated with inferior ORR (odds ratio (OR) 0.3, P=0.0025), whereas ENOSF1 rs2612091 G/G was nominally associated with OS after adjustment for TYMS 3 R/3 R (hazard ratio (HR) 1.5, P=0.041). In a subgroup analysis of patients with locally advanced disease (n=33), ENOSF1 rs2612091 was strongly associated with OS (HR 6.5, P=0.001). CYP3A4*22/CYP3A5*3 genotype was nominally associated with grade 3/4 toxicity in patients receiving docetaxel-containing chemotherapy (P=0.0175). This is the first study suggesting that ENOSF1 rs2612091 is prognostic or predictive of OS in gastric cancer. This finding requires prospective validation.

Biobanking of fresh-frozen endoscopic biopsy specimens from esophageal adenocarcinoma.

The process of preparing endoscopic esophageal adenocarcinoma samples for next-generation DNA/RNA sequencing is poorly described. Therefore, we assessed the feasibility and pitfalls of preparing esophageal adenocarcinoma endoscopic biopsies toward DNA/RNA samples suitable for next-generation sequencing. In this prospective study, four tumor biopsy samples were collected from consecutive esophageal cancer patients during esophagogastroduodenoscopy and fresh-frozen in liquid nitrogen. DNA and RNA were isolated from samples with a tumor percentage of at least 50%. For next-generation sequencing, double-stranded DNA (dsDNA) is required and high-quality RNA preferred. The quantity dsDNA and RNA quantity and quality were assessed with the Nanodrop 2000 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) and Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). Biopsy samples of 69 consecutive patients with esophageal adenocarcinoma were included. In five patients (7%), the tumor percentage was less than 50% in all four biopsies. Using a protocol allowing simultaneous DNA and RNA isolation, the median dsDNA yield was 2.4 µg (range 0.1-12.0 µg) and the median RNA yield was 0.5 µg (range 0.01-2.05 µg). The median RNA integrity number of samples that were fresh-frozen within 30 minutes after sampling was 6.7 (range 4.2-8.9) compared with 2.5 (1.8-4.5) for samples that were fresh-frozen after 2 hours. The results from this study show that obtaining dsDNA and RNA for next-generation sequencing from endoscopic esophageal adenocarcinoma samples is feasible. Tumor percentage and dsDNA/RNA yield and quality emphasize the need for sampling multiple biopsies and minimizing the delay before fresh-freezing.

HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53.

BACKGROUND: Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy. METHODS: Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2-11 of TP53 in tumour tissue were sequenced. RESULTS: DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV-) tumours (13%), 10 (9%) were p16-negative (HPV-/p16-) and 4 (4%) overexpressed p16 (HPV-/p16+). Patients with HPV-/p16- disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%, P<0.001) and HPV-/p16+ tumours (75%, P=0.078). Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219). Disruptive mutations in TP53 were found in 80% of HPV-/p16- tumours vs 6% of HPV+/p16+ tumours (P<0.001). In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS. CONCLUSIONS: HPV- tumours are frequently TP53 mutated. HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.

Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option.

BACKGROUND: Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for patients with rectal cancer receiving chemoradiotherapy. Its place in the treatment of locally advanced anal carcinoma (AC), however, remains undetermined. We investigated whether capecitabine is as effective as 5-FU in the treatment of patients with locally advanced AC. METHODS: One hundred and five patients with squamous cell AC stage T2-4 (T2>4 cm), N0-1, M0 or T1-4, N2-3, M0, were included in this retrospective study. Forty-seven patients were treated with continuous 5-FU (750 mg m(-2)) on days 1-5 and 29-33, mitomycin C (MMC, 10 mg m(-2)) on day 1, and radiotherapy; 58 patients were treated with capecitabine (825 mg m(-2) b.i.d. on weekdays), MMC (10 mg m(-2)) on day 1, and radiotherapy. The primary end points of the study were: clinical complete response rate, locoregional control (LRC) and overall survival (OS). Secondary end points were: colostomy-free survival (CFS), toxicity and associations of genetic polymorphisms (GSTT1, GSTM1, GSTP1 and TYMS) with outcome and toxicity. RESULTS: Clinical complete response was achieved in 41/46 patients (89.1%) with 5-FU and in 52/58 patients (89.7%) with capecitabine. Three-year LRC was 76% and 79% (P=0.690, log-rank test), 3-year OS was 78% and 86% (P=0.364, log-rank test) and CFS was 65% and 79% (P=0.115, log-rank test) for 5-FU and capecitabine, respectively. GSTT1 and TYMS genotypes were associated with severe (grade 3-4) toxicity. CONCLUSIONS: Capecitabine combined with MMC and radiotherapy was equally effective as 5-FU-based chemoradiotherapy. This study shows that capecitabine can be used as an acceptable alternative to 5-FU for the treatment of AC.

Differences in outcomes of oesophageal and gastric cancer surgery across Europe.

BACKGROUND: In several European countries, centralization of oesophagogastric cancer surgery has been realized and clinical audits initiated. The present study was designed to evaluate differences in resection rates, outcomes and annual hospital volumes between these countries, and to analyse the relationship between hospital volume and outcomes. METHODS: National data were obtained from cancer registries or clinical audits in the Netherlands, Sweden, Denmark and England. Differences in outcomes were analysed between countries and between hospital volume categories, adjusting for available case-mix factors. RESULTS: Between 2004 and 2009, 10 854 oesophagectomies and 9010 gastrectomies were registered. Resection rates in England were 18·2 and 21·6 per cent for oesophageal and gastric cancer respectively, compared with 28·5-29·9 and 41·4-41·9 per cent in the Netherlands and Denmark (P < 0·001). The adjusted 30-day mortality rate after oesophagectomy was lowest in Sweden (1·9 per cent). After gastrectomy, the adjusted 30-day mortality rate was significantly higher in the Netherlands (6·9 per cent) than in Sweden (3·5 per cent; P = 0·017) and Denmark (4·3 per cent; P = 0·029). Increasing hospital volume was associated with a lower 30-day mortality rate after oesophagectomy (odds ratio 0·55 (95 per cent confidence interval 0·42 to 0·72) for at least 41 versus 1-10 procedures per year) and gastrectomy (odds ratio 0·64 (0·41 to 0·99) for at least 21 versus 1-10 procedures per year). CONCLUSION: Hospitals performing larger numbers of oesophagogastric cancer resections had a lower 30-day mortality rate. Differences in outcomes between several European countries could not be explained by differences in hospital volumes. To understand these differences in outcomes and resection rates, with reliable case-mix adjustments, a uniform European upper gastrointestinal cancer audit with recording of standardized data is warranted.

Influence of hospital type on outcomes after oesophageal and gastric cancer surgery.

BACKGROUND: Outcomes after oesophagectomy and gastrectomy vary considerably between hospitals. Possible explanations include differences in case mix, hospital volume and hospital type. The present study examined the distribution of oesophagectomies and gastrectomies between hospital types in the Netherlands, and the relationship between hospital type and outcome. METHODS: Data were obtained from the nationwide Netherlands Cancer Registry. Hospitals were categorized as university hospitals (UH), non-university teaching hospitals (NUTH) and non-university non-teaching hospitals (NUNTH). Hospital type-outcome relationships were analysed by Cox regression, adjusting for case mix, hospital volume, year of diagnosis and use of multimodal therapies. RESULTS: Between 1989 and 2009, 10 025 oesophagectomies and 14 221 gastrectomies for cancer were performed in the Netherlands. The percentage of oesophagectomies and gastrectomies performed in UH increased from 17·6 and 6·4 per cent respectively in 1989 to 44·1 and 12·9 per cent in 2009. After oesophagectomy, the 3-month mortality rate was 2·5 per cent in UH, 4·4 per cent in NUTH and 4·1 per cent in NUNTH (P = 0·006 for UH versus NUTH). After gastrectomy, the 3-month mortality rate was 4·9 per cent in UH, 8·9 per cent in NUTH and 8·7 per cent in NUNTH (P < 0·001 for UH versus NUTH). Three-year survival was also higher in UH than in NUTH and NUNTH. CONCLUSION: Oesophagogastric resections performed in UH were associated with better outcomes but, owing to variation in outcomes within hospital types, centres of excellence cannot be designated solely on hospital type. Detailed information on case mix and outcomes is needed to identify centres of excellence.

Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer.

BACKGROUND: Capecitabine is an attractive radiosensitizer. In this study acute toxicity and surgical complications were evaluated in patients with locally advanced rectal cancer following total mesorectal excision (TME) after preoperative chemoradiotherapy (CRT) with capecitabine. METHODS: Between 2004 and 2008, consecutive patients with clinical tumour category (cT) 3-4 (with a threatened circumferential resection margin or cT3 within 5 cm of the anal verge) or clinical node category 2 rectal cancer were treated with preoperative CRT (25 × 2 Gy, capecitabine 825 mg/m(2) twice daily, days 1-33). TME followed 6 weeks later. Toxicity was scored according to the Common Terminology Criteria (version 3.0) and Radiation Therapy Oncology Group scoring systems. Treatment-related surgical complications were evaluated for up to 30 days after discharge from hospital using the modified Clavien-Dindo classification. RESULTS: Some 147 patients were analysed. The mean cumulative dose of capecitabine was 95 per cent and 98·0 per cent of patients received at least 45 Gy. One patient died from sepsis following haematological toxicity. Grade 3-5 toxicity developed in 32 patients (21·8 per cent), especially diarrhoea (10·2 per cent) and radiation dermatitis (11·6 per cent). There were no deaths within 30 days after surgery. Anastomotic leakage and perineal wound complications developed after 13 of 47 low anterior resections and 23 of 62 abdominoperineal resections. Surgical reintervention was required in 30 patients. Twenty-seven patients (19·6 per cent) of 138 patients who had a laparotomy were readmitted within 30 days after initial hospital discharge. CONCLUSION: Preoperative CRT with capecitabine is associated with acceptable acute toxicity, significant surgical morbidity but minimal postoperative mortality.

Multidisciplinary discussion and management of rectal cancer: a population-based study.

BACKGROUND: The purpose of the present study was to evaluate the value of discussing rectal cancer patients in a multidisciplinary team (MDT). METHODS: All treated rectal cancer patients (>T1M0) diagnosed in 2006-2008 were included. According to the national guidelines, neoadjuvant (chemo)radiotherapy should be given to all rectal cancer patients. Patients were scored as "discussed" (MDT+) only if documented proof was available. The primary endpoint was the number of positive circumferential resection margins (CRM ≤ 1 mm). RESULTS: Of the 275 patients included, 210 were analyzed (exclusions: (recto)sigmoid tumor, acute laparotomy, and inoperability). Neoadjuvant treatment was applied in 174 (83%) patients and followed by total mesorectal excision in 171 (81%) patients. Patients considered not to require downstaging, received short-course radiotherapy (SCRT) (n = 116) or no radiotherapy (no RT) (n = 36), whereas 58 more advanced patients received chemoradiotherapy (CRT). The MDT discussion took place in 116 cases (55%). In the MDT+ group an MRI was used more often (p = 0.001) and TNM staging was more complete (p < 0.001). The proportion of patients with advanced disease was higher in the MDT+ group (88% ≥T3/N+ versus 68%; p = 0.001). The overall CRM+ rate was 13% and did not differ between the MDT+ and the MDT- group (p = 0.392). In patients receiving SCRT or no RT, the CRM+ rate was 10%, whereas the rate was 20% for patients receiving CRT. CONCLUSIONS: Although no difference in CRM+ rate was found for those patients who were discussed and those who were not, our results demonstrate room for improvement, especially in the selection of patients for SCRT or no RT. We advocate standardized documentation of treatment decisions and pathology reports.

Postoperative chemoradiotherapy in gastric cancer--a phase I-II study of radiotherapy with dose escalation of weekly cisplatin and daily capecitabine chemotherapy.

BACKGROUND: Postoperative chemoradiotherapy with concurrent 5-fluorouracil improves gastric cancer outcome. We previously demonstrated that chemoradiotherapy with a more intensified--and therefore potentially more effective--schedule with daily cisplatin and oral capecitabine is feasible. Because such an intensive schedule requires an extensive logistic infrastructure which is not available in every hospital, we additionally investigated the tolerability of this combined regimen with weekly instead of daily cisplatin in a dose-escalation study. PATIENTS AND METHODS: After R0 or R1 resection, treatment initiated with capecitabine 1000 mg/m(2) b.i.d. for 2 weeks and 1-week rest. Subsequently, patients received capecitabine (575-650 mg/m(2) orally b.i.d., 5 days/week) and cisplatin (20-25 mg/m(2) i.v., once weekly) according to a predefined dose-escalation schedule concurrent with radiation. Radiotherapy was given to a fixed total dose of 45 Gy in 25 fractions. RESULTS: Thirty-one patients were eligible and started treatment. During chemoradiotherapy, seven patients developed 10 items of grade III and one episode of grade IV (mainly hematological) toxicity (National Cancer Institute-Common Toxicity Criteria version 3.0). The maximum tolerable dose was determined to be for cisplatin 20 mg/m(2) i.v. weekly and for capecitabine 575 mg/m(2) b.i.d. orally. CONCLUSIONS: This phase I-II study demonstrated that postoperative chemoradiotherapy with weekly cisplatin and daily capecitabine is feasible in gastric cancer at the defined dose level. This schedule is currently being tested as the experimental arm in a phase III multicenter study (CRITICS: chemoradiotherapy after induction chemotherapy in cancer of the stomach; Clinicaltrials.gov NCT 00407186).

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.