Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer.

Two meta-analyses were conducted to quantify the benefit of combining alpha-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU +/- LV vs. 5FU +/- LV + alpha-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no alpha-IFN vs. 24% for patients receiving alpha-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no alpha-IFN vs. 11.5 months for patients receiving alpha-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + alpha-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + alpha-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26;P = 0.042), and of a borderline significance for overall survival (HR = 1.11;P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that alpha-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + alpha-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer.

The prognostic value of the presence of mutations at the codons 12, 13, 61 of K-ras oncogene in colorectal cancer.

The predictive and prognostic value of the c-K-ras mutation is still unequivocal despite extensive and intensive studies. Investigation of the occurrence of mutations in 88 colorectal cancer patients' specimens using the polymerase chain reaction (PCR) is reported: age: 61.9 years (27-80), gender: 48 male, 42 female, Dukes' stages: 43 at B, 35 at C, 10 at D, primary of tumour: 52 colon, 36 rectal adenocarcinoma. Mutation of one of the three ras-codons was detectable in the 54 cases, more frequently at the Dukes' stage C (p < 0.05). The ras-mutation correlated to a more elevated death-rate in the Dukes' B and C stages (p < 0.01). Mean survival time and time to progression were significantly longer at the Dukes' stage B if mutation was not detected (p < 0.01). The genetic alteration occurred significantly more frequently at tumours of the right-side colon, than the left side (p < 0.02) or rectum (p < 0.05). However, in the age group of 41-50 years, it was more significantly identified in the cases of rectal cancer (p < 0.01). At the age of 51-60 years mutations were detected in men at a higher rate (p < 0.05). The mutation of the codon 13 appeared more frequently in the cases of local recurrences (p < 0.05). The occurrence of the ras-oncogene is a sign of an extremely malignant potential of tumour. This fact manifested itself in the time to progression and mean survival time of patients at the same clinical or pathological stage. The higher frequency of genetic alterations at the proximal colon may be the reason for more unfavourable prognosis of the disease localised to this site. Reconstructing the molecular events, the presence of the ras mutation proved to be an important element for prognosis of the disease and should be a basis of potentially individualised therapeutic intervention.

Colorectal cancer risk in relation to genetic polymorphism of cytochrome P450 1A1, 2E1, and glutathione-S-transferase M1 enzymes.

Chemical carcinogens generally require metabolic activation in order to be able to bind to DNA and contribute to cancer causation. Most of the human metabolizing enzymes are genetically polymorphic, and these polymorphisms may affect the enzyme activity or inducibility. In our present study we investigated the connection between genetic polymorphism of cytochrome P450 1A1, 2E1 (phase I enzymes) and glutathione-S-transferase M1 (a phase II enzyme) and colorectal cancer occurrence in a Hungarian population. The CYP 2E1 c2 allele proved to be in significant association with colorectal cancer (OR: 1.91, 95% CI: 1.05-3.52), the CYP 1A1 Val allele was also overrepresented among colon cancer patients (OR: 1.57, 95% CI: 0.90-2.74), and the frequency of GSTM1 homozygous 0 genotype showed only minor difference (OR: 1.19, 95% CI: 0.75-1.35). Combined analysis of the polymorphisms showed that individuals carrying all the three "high-risk" alleles have a strikingly increased risk for sporadic colorectal cancer (OR: 4.62, 95% CI: 1.23-25.68).

[Prognostic value of the presence of the mutation of the codons 12, 13 and 61 in K-ras oncogene in colorectal cancer]. / A K-ras onkogén 12, 13 és 61 kodonjai mutációjának prognosztikus értéke colorectalis carcinomában.

Despite of extensive and intensive investigations, the predictive and prognostic value of c-K-ras mutation is not unequivocal. There has been reported about investigation the occurrence of mutations in the 88 colorectal cancer patient's specimen using polymerase chain reaction. Age: 61.9 years (27-80), gender 8 male, 42 female. Dukes' stages: 43 at the B, 35 at C, 10 at D. Primary of tumour: 52 colon, 36 rectal adenocarcinoma. Mutation out of one of the three ras-codons was detectable in the 54 cases, more frequently at the stage Dukes' C (p < 0.05). The ras-mutation concerned to more elevated death-rate in the stages Dukes' B and C (p < 0.01). Mean survival time to progression was significantly longer at the stage Dukes' B if mutation had not been detected (p < 0.01). The occurrence of the rate of genetic alteration was significantly more frequent at tumours of right-side colon, than left side (p < 0.02) or rectum (p < 0.05) one's. However, at the age of 41-50 years it was significantly more presented at the cases of rectal cancer (p < 0.01). At the age of 51-60 years mutations were detected among men at higher rate (p < 0.05). The cases of local recurrences concerned by mutation at the codon of 13 (p < 0.05). Occurrence of ras-oncogene is the sign of extremely malignant potential of tumour. This fact manifested itself in the time to progression and mean survival time of patients at same clinical or pathological stage. The higher frequency of genetic alterations at the proximal colon may be the reason of more unfavourable prognosis of the disease localised to this site. Reconstructing the molecular events, the presence of ras mutation can serve as a basis for prognosis of the disease and permit of potentially individualised therapeutic intervention.

[Low-dose leucovorin and interferon-alpha as modulators of 5-fluorouracil for adjuvant chemotherapy of colorectal cancer]. / Colorectalis carcinomák kis dózisú leukovorin és interferon-alpha modulált adjuváns 5-fluorouracil kemoterápiája.

It has recently been published the results of a prospective, comparative study for adjuvant chemotherapy of 164 colorectal cancer patients. Pathological stages were Dukes B 79, C 85 of the cases. The site of primary tumour was colon 108, rectum 56 of the patients. The treatment protocols were as follows: 425 mg/m2 5-fluorouracil plus 20 mg/m2 leucovorin on days 1-5 at 28 days cycles six times (LV group). The IFN group received the same chemotherapy completed with weekly 3 x 3 MIU interferon alpha. Both treatment groups were well balanced. The mean follow up time was 38.1 months. There were 91 patients of relapse and 65 deaths this time. The time to progression was 15 months in the LV group and 12.7 months in the IFN group (p < 0.05). The mean survival time was 24 months in the LV group compared to 22.3 of the IFN group. The frequency and sites of relapses did not differ statistically between the both groups. The preoperative CEA-level was elevated in 42 cases. The mean survival time was 26.4 months in the cases having normal CEA-level compared to 16.1 months of the cases with high-level (p < 0.001). The side-effects were transient and mild, while in the group treated with interferon were more instances of fever, fatigue, flu-like syndrome, psychic disorders, depression and agitation. The administration of interferon had to be interrupted in 4 cases. The results of interim analysis suggest choosing the so-called Mayo protocol for the standard adjuvant treatment of colorectal cancer.

[Combined therapy of metastatic liver neoplasms: intrahepatic chemoembolization and systemic chemotherapy]. / Colorectalis carcinomák májmetastasisainak kombinált kezelése: intrahepaticus chemoembolisatio és szisztémás chemotherapia.

Chemoembolisation has been an effective treatment-option for unresectable colorectal liver metastases, however it frequently fails because of tumour progression outside the liver. We conducted a pilot study to assess the toxicity and efficacy of combined regional and systemic chemotherapy for patients having liver dominant disease. Three cycles of chemoembolisation using 50 mg adriamycin, 8 mg mitomycin C, 50 mg cisplatinum admixed with 10 ml of lipiodol were given at 6 weeks intervals. The systemic therapy consisted of 425 mg/m2 5-fluorouracil and 20 mg/m2 leucovorin by intravenous infusion 1-5 days repeated every 28 days. 41 patients were treated for the period 1st January 1994-31st December 1996. Out of these 27 were male, 14 female with a medium age of 62 years (40-78). Primary site of tumour was colon in 30 cases and rectum in 11 cases. 14 patients received prior chemotherapy (5 adjuvant, 9 palliative). Mean follow up time is 18 months (4-36) in this study. 27 partial and 1 complete remissions were achieved at the average response rate of 68%. Mean time of progression was 10.7 months (4-18), overall survival time was 15 months (4-36). Common toxicity was the postembolisation syndrome consisting of abdominal pain, fever, chills, reversible elevated liver enzymes. Four patients had drug-induced cholangiohepatitis. At 15 patients we experienced grade 3, toxicity (5 diarrhoea, 3 mucositis, 2 vomiting, 2 leukopenia, 2 thrombocytopenia, one skin rush). No treatment related death or catheter complications were observed. Although these treatment results are superior to our historical experience, a controlled clinical trial will be acquired to establish this approach.