Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients.

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. METHODS: In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. RESULTS: In total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis. CONCLUSIONS: PM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. PATIENTS AND METHODS: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). RESULTS: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). CONCLUSION: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00145314.

Cost-effectiveness of liver transplantation in patients with colorectal metastases confined to the liver.

BACKGROUND: Patients with non-resectable colorectal metastases are currently treated with chemotherapy. However, liver transplantation can increase the 5-year survival rate from 9 to 56 per cent if the cancer is confined to the liver. The aim of this study was to estimate the cost-effectiveness of liver transplantation for colorectal liver metastases. METHODS: A Markov model with a lifetime perspective was developed to estimate the life-years, quality-adjusted life-years (QALYs), direct healthcare costs and cost-effectiveness for patients with non-resectable colorectal liver metastases who received liver transplantation or chemotherapy alone. RESULTS: In non-selected cohorts, liver transplantation increased patients' life expectancy by 3·12 life-years (2·47 QALYs), at an additional cost of €209 143, giving an incremental cost-effectiveness ratio (ICER) of €67 140 per life-year (€84 667 per QALY) gained. In selected cohorts (selection based on tumour diameter, time since primary cancer, carcinoembryonic antigen levels and response to chemotherapy), the effect of liver transplantation increased to 4·23 life-years (3·41 QALYs), at a higher additional cost (€230 282), and the ICER decreased to €54 467 per life-year (€67 509 per QALY) gained. Given a willingness to pay of €70 500, the likelihood of transplantation being cost-effective was 0·66 and 0·94 (0·23 and 0·67 QALYs) for non-selected and selected cohorts respectively. CONCLUSION: Liver transplantation was cost-effective but only for highly selected patients. This might be possible in countries with good access to grafts and low waiting list mortality.

Population-based study on resection rates and survival in patients with colorectal liver metastasis in Norway.

BACKGROUND: Detailed knowledge about the proportion of patients with colorectal liver metastases (CLM) undergoing resection is sparse. The aim of this study was to analyse cumulative resection rates and survival in patients with CLM. METHODS: For this population-based study of patients developing CLM during 2011-2013, data were extracted from the Norwegian Patient Registry and the Cancer Registry of Norway. RESULTS: A total of 2960 patients had CLM; their median overall survival was 10·9 months. Liver resection was performed in 538 patients. The cumulative resection rate was 20·0 per cent. The cumulative resection rate was 23·3 per cent in patients aged less than 40 years, 31·1 per cent in patients aged 40-59 years, 24·7 per cent in those aged 60-74 years, 17·9 per cent in those aged 75-79 years and 4·7 per cent in patients aged 80 years or more (P < 0·001). In multivariable analysis, resection rate was associated with age, extrahepatic metastases, disease-free interval and geographical region. Overall survival after diagnosis of CLM was affected by liver resection (hazard ratio (HR) 0·54, 95 per cent c.i. 0·34 to 0·86), rectal cancer (HR 0·82, 0·74 to 0·90), metachronous disease (HR 0·66, 0·60 to 0·74), increasing age (HR 1·32, 1·28 to 1·37), region, and extrahepatic metastases (HR 1·90, 1·74 to 2·07). Three- and 4-year overall survival rates after hepatectomy were 73·2 and 54·8 per cent respectively. CONCLUSION: The cumulative resection rate in patients with CLM in Norway between 2011 and 2013 was 20 per cent. Resection rates varied across geographical regions, and with patient and disease characteristics.

NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms.

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

Age-dependent improvement in median and long-term survival in unselected population-based Nordic registries of patients with synchronous metastatic colorectal cancer.

BACKGROUND: In metastatic colorectal cancer (mCRC) trials, median survival has increased from 6 months to above 20 months during the previous decades. Uncertainty exists in how this survival improvement has translated to the general mCRC population. PATIENTS AND METHODS: Survival data from patients with synchronous mCRC were collected from the Norwegian (1980-2008), Swedish (1996-2008) and Danish (2001-09) cancer registries. RESULTS: A total of 29 628 patients were identified. From 1980-1985 to 2006-2008, median survival increased from 5 to 10 months for Norwegian patients. Three-year survival increased from 7% to 21% and 5-year survival from 4% to 9%. For patients <60 years, median survival was doubled to 16 months, 3-year survival increased fourfold up to 28% and 5-year survival threefold up to 14%. Similar improvements were seen in Sweden and Denmark. In all countries, the improved outcome was seen especially for younger patients and much less for patients >75 years of age. CONCLUSION: An increase in median and long-term survival over time was found in unselected population-based registries of patients with synchronous mCRC. The improved outcome in survival was especially seen in younger patients, raising concerns over our ability to adapt available treatment options for elderly patients.

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND: As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS: Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS: The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS: Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Lower treatment intensity and poorer survival in metastatic colorectal cancer patients who live alone.

BACKGROUND: Socioeconomic status (SES) and social support influences cancer survival. If SES and social support affects cancer treatment has not been thoroughly explored. METHODS: A cohort consisting of all patients who were initially diagnosed with or who developed metastatic colorectal cancer (mCRC, n=781) in three Scandinavian university hospitals from October 2003 to August 2006 was set up. Clinical and socioeconomic data were registered prospectively. RESULTS: Patients living alone more often had synchronous metastases at presentation and were less often treated with combination chemotherapy than those cohabitating (HR 0.19, 95% CI 0.04-0.85, P=0.03). Surgical removal of metastases was less common in patients living alone (HR 0.29, 95% CI 0.10-0.86, P=0.02) but more common among university-educated patients (HR 2.22, 95% CI 1.10-4.49, P=0.02). Smoking, being married and having children did not influence treatment or survival. Median survival was 7.7 months in patients living alone and 11.7 months in patients living with someone (P<0.001). Living alone remained a prognostic factor for survival after correction for age and comorbidity. CONCLUSION: Patients living alone received less combination chemotherapy and less secondary surgery. Living alone is a strong independent risk factor for poor survival in mCRC.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study.

BACKGROUND: Capecitabine- or 5-fluorouracil (5-FU)-based chemotherapy is widely used in many solid tumours, but is associated with cardiotoxicity. S-1 is a fluoropyrimidine with low rates of cardiotoxicity, but evidence regarding the safety of switching to S-1 after 5-FU- or capecitabine-associated cardiotoxicity is scarce. PATIENTS AND METHODS: This retrospective study (NCT04260269) was conducted at 13 centres in 6 countries. The primary endpoint was recurrence of cardiotoxicity after switch to S-1-based treatment due to 5-FU- or capecitabine-related cardiotoxicity: clinically meaningful if the upper boundary of the 95% confidence interval (CI; by competing risk) is not including 15%. Secondary endpoints included cardiac risk factors, diagnostic work-up, treatments, outcomes, and timelines of cardiotoxicity. RESULTS: Per protocol, 200 patients, treated between 2011 and 2020 [median age 66 years (range 19-86); 118 (59%) males], were included. Treatment intent was curative in 145 (73%). Initial cardiotoxicity was due to capecitabine (n = 170), continuous infusion 5-FU (n = 22), or bolus 5-FU (n = 8), which was administered in combination with other chemotherapy, targeted agents, or radiotherapy in 133 patients. Previous cardiovascular comorbidities were present in 99 (50%) patients. Cardiotoxic events (n = 228/200) included chest pain (n = 125), coronary syndrome/infarction (n = 69), arrhythmia (n = 22), heart failure/cardiomyopathy (n = 7), cardiac arrest (n = 4), and malignant hypertension (n = 1). Cardiotoxicity was severe or life-threatening in 112 (56%) patients and led to permanent capecitabine/5-FU discontinuation in 192 (96%). After switch to S-1, recurrent cardiotoxicity was observed in eight (4%) patients (95% CI 2.02-7.89, primary endpoint met). Events were limited to grade 1-2 and occurred at a median of 16 days (interquartile range 7-67) from therapy switch. Baseline ischemic heart disease was a risk factor for recurrent cardiotoxicity (odds ratio 6.18, 95% CI 1.36-28.11). CONCLUSION: Switching to S-1-based therapy is safe and feasible after development of cardiotoxicity on 5-FU- or capecitabine-based therapy and allows patients to continue their pivotal fluoropyrimidine-based treatment.

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer.

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer.

BACKGROUND: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil.

BACKGROUND: Oxaliplatin in combination with capecitabine prolongs survival in patients with metastatic colorectal cancer (mCRC). Chronomodulation might reduce toxicity and improve efficacy. PATIENTS AND METHODS: A phase II study examining chronomodulated XELOX(30) (XELOX(30chron)): oxaliplatin: 130 mg/m(2) on day 1, as a 30-min infusion between 1 and 3 p.m. Capecitabine: total daily dose of 2000 mg/m(2), 20% of the dose between 7 and 9 a.m. and 80% of the dose between 6 and 8 p.m. in patients with mCRC resistant to irinotecan. Seventy-one patients were enrolled. Response rate was 18%; median progression-free survival 5.1 months and median overall survival (OS) 10.2 months. Platelet count and performance status were significantly correlated to OS in multivariate analyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2% of patients, respectively, other grade 3 toxic effects were as follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experienced grade 4) and palmoplantart erytem 9%. CONCLUSION: XELOX(30chron) is a convenient second-line regimen with efficacy and safety profile similar to other oxaliplatin schedules. To further investigate chronomodulated XELOX, we have started a Nordic randomised phase II study comparing XELOX(30) and XELOX(30chron) as first-line therapy in patients with mCRC.

Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: a proposal for standardization of patient characteristic reporting and stratification.

BACKGROUND: Prognostic factors have the potential to determine the survival of patients to a greater extent than current antineoplastic agents. Despite this knowledge, there is no consensus on, first, what patient characteristics to report and, second, what stratification factors to use in metastatic colorectal cancer trials. PATIENTS AND METHODS: Seven leading oncology and medical journals were reviewed for phase II and III publications reporting on medical treatment of metastatic colorectal cancer patients during 2001-2005. One hundred and forty-three studies with 21 214 patients were identified. The reporting of patient characteristics and use of stratification was noted. RESULTS: Age, gender, performance status, metastases location, sites and adjuvant chemotherapy were often reported (99-63%). Laboratory values as alkaline phosphatase, lactate dehydrogenase and white blood cell count, repeatedly found to be of prognostic relevance, were rarely reported (5-9%). Stratification was used in all phase III trials; however, only study centre was used with any consistency. CONCLUSION: There is considerable inconsistency in the reporting of patient characteristics and use of stratification factors in metastatic colorectal cancer trials. We propose a standardization of patient characteristics reporting and stratification factors. A common set of characteristics and strata will aid in trial reporting, interpretation and future meta-analyses.

Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas.

BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are generally characterized by synchronous metastases, high aggressiveness and a dismal prognosis. Current international guidelines do not recommend surgical treatment of liver metastases, however the existing data are scarce. The aim of this study was to evaluate the results of curatively intended resection/radiofrequency ablation (RFA) of liver metastases in patients with metastatic GEP-NEC. METHODS: 32 patients with a diagnosis of high-grade gastroenteropancreatic neuroendocrine neoplasm (Ki-67 > 20%) and with intended curative resection/RFA of liver metastases, were identified among 840 patients from two Nordic GEP-NEC registries. Tumor morphology (well vs poor differentiation) was reassessed. Overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier analyses for the entire cohort and for subgroups. RESULTS: Median OS after resection/RFA of liver metastases was 35.9 months (95%-CI: 20.6-51.3) with a five-year OS of 43%. The median PFS was 8.4 months (95%-CI: 3.9-13). Four patients (13%) were disease-free after 5 years. Two patients had well-differentiated morphology (NET G3) and 20 patients (63%) had Ki-67 ≥ 55%. A Ki-67 < 55% and receiving adjuvant chemotherapy were statistically significant factors of improved OS after liver resection/RFA. CONCLUSION: This study shows a long median and long term survival after liver surgery/RFA for these selected metastatic GEP-NEC patients, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population.

Sucralfate does not ameliorate acute radiation proctitis: randomised study and meta-analysis.

AIMS: During pelvic radiotherapy, many patients develop radiation-induced gastrointestinal symptoms, which may interfere with treatment. Prophylaxis during radiotherapy should ideally prevent acute reaction and the development of delayed injury. Sucralfate, an aluminium sucrose octasulphate, has been used for acute and delayed radiation side-effects. However, conflicting results have been published. We report here a prospective, randomised, placebo-controlled study of prophylactic sucralfate during pelvic radiotherapy. In addition, a meta-analysis of available data from the literature has been carried out. MATERIALS AND METHODS: Fifty-one patients with localised pelvic tumours scheduled for curative conformal pelvic radiotherapy (total dose 64-70 Gy over 6.5-7 weeks in 2 Gy daily fractions) were included. Peroral sucralfate 2 g three times daily, or identically appearing placebo tablets, was given during the course of radiotherapy. Symptom registration, endoscopy and biopsies were carried out immediately before radiotherapy, 2 weeks and 6 weeks into the treatment course, and 2 weeks after completing radiotherapy. Mucosal cup forceps biopsies were obtained through a rigid proctoscope. Graded endoscopic appearance and quantitative histology were registered. RESULTS: On the basis of previously published negative reports, an unplanned interim analysis of 44 evaluable patients showed significantly increased diarrhoea in the sucralfate group and the trial was stopped. No difference was seen in other symptoms, endoscopic appearance or histology. A meta-analysis comprising five published studies showed no statistically significant beneficial effect of sucralfate on acute symptoms. CONCLUSION: Sucralfate cannot be recommended for prophylaxis of acute radiation proctopathy and may even worsen the symptoms.

Gastric carcinogenesis in rats given hypertonic salt at different times before a single dose of N-methyl-N'-nitro-N-nitrosoguanidine.

A 1-ml dose of 4.5 M NaCl was given intragastrically to male Wistar rats at 10 min, 1 h, 4 h, 12 h, 24 h or 48 h before a single intragastric dose of 250 mg/kg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 52 weeks the incidence of forestomach squamous cell carcinoma was 21% in control animals receiving MNNG alone. The cancer incidence in the forestomach varied with the time elapsed between application of NaCl and MNNG, and was significantly increased in animals pretreated with NaCl 4 h (43%), 12 h (54%) and 24 h (41%) before MNNG. These results show that salt has a cocarcinogenic effect on initiation of forestomach carcinogenesis in rats, and that this effect depends on the time interval between pretreatment with NaCl and application of MNNG. Gastric adenocarcinomas occurred more frequently in the antrum (78%) than in the corpus (22%). The incidence of gastric adenocarcinoma in animals pretreated with salt before application of MNNG (11%-22%) was not significantly influenced by the time elapsed between pretreatment with salt and application of MNNG, and did not differ from animals receiving MNNG alone (18%). The lack of a cocarcinogenic effect of NaCl on glandular gastric carcinogenesis might be due to the use of dimethyl/sulfoxide as solvent for MNNG.

Effect of salt on cell proliferation and N-methyl-N'-nitro-N-nitrosoguanidine penetration to proliferative cells in the forestomach of rats.

We have studied the effect of intragastric instillation of 4.5 M NaCl on cell proliferation and carcinogen penetration into the forestomach of Wistar rats at different time intervals after salt exposure. Cells in the S-phase were labelled by incorporation of bromodeoxyuridine and located after immunohistochemistry. N-[3H]Methyl-N'-nitro-N-nitrosoguanidine ([3H]MNNG) was used as the carcinogen and penetration of [3H]MNNG to proliferative cells was determined by autoradiography. The number of cells in S-phase per millimetre epithelium length 12 h and 24 h after salt exposure (32.2 +/- 11.9 and 20.6 +/- 7.4) was significantly higher than in the control animals (9.4 +/- 3.6). No increase in cell proliferation occurred during the first 2 h after salt exposure. Microscopy also revealed oedema in the lamina propia. The forestomach blood flow was not influenced by the application of hypertonic saline. [3H]MNNG at a concentration of 40 micrograms/ml did not penetrate to the proliferative cells in the forestomach and no effect of salt pretreatment on carcinogen penetration was seen. The low penetration of [3H]MNNG to proliferative cells in the forestomach epithelium may explain why this concentration of MNNG given in drinking water over several weeks usually does not induce squamous cell carcinomas in the forestomach. The previously observed cocarcinogenic effect of salt on squamous cell cercinogenesis in the upper gastrointestinal tract could be due to the observed increase in cell proliferation after salt exposure.

Rhythmic patterns in incidence of peptic ulcer perforation over 5.5 decades in Norway.

The incidence of ulcer perforation in 1480 patients treated in the Bergen area of Norway between 1935 and 1990 was analyzed for daily (circadian), weekly (circaseptan), and yearly (circannual) time effects. A circadian rhythm was found overall that was reproducible and fairly stable across seasons, decades, and days of the week. After subgrouping, a circadian rhythm was found in younger patients, males, and duodenal perforations, while a 12 h (circasemidian) rhythm characterized ulcer perforation for women and for gastric ulcers. Duodenal perforations showed highest incidence in the afternoon, while gastric perforations showed a major peak around noon and a secondary peak near midnight. For duodenal ulcer perforation, the circannual pattern was characterized by a 6-month rhythm, with significantly higher incidence in May-June-July and in November-December in most subgroups. A circaseptan rhythm was not found, but there was a significantly higher incidence on Thursday-Friday as compared to Sunday-Monday. The pathophysiological mechanisms underlying the perforation of an ulcer thus seemed to show pronounced circadian and 6-month rhythmic variations, much less so circaseptan or circannual rhythms. While it is likely that exogenous environmental and/or societal factors play a significant role, variations in ulcer perforation may be related to endogenous biological rhythms in pathophysiological factors since the circadian pattern of duodenal perforation follows that for gastric acidity. Knowledge of the temporal patterns in peptic ulcer perforation and associated pathophysiologic factors should prove useful in optimizing the chronotherapeutic management of ulcer disease.