HER 2/neu protein expression in colorectal cancer.

BACKGROUND: Conflicting data exist about the prevalence of HER-2/neu overexpression in colorectal cancer ranging from 0 to 83 %. In our study we tried to clarify the extent of expression and its relationship to clinicopathological parameters. METHODS: This study involved 77 specimens of malignant colorectal cancer lesions of surgically resected patients. HER-2/neu immunohistochemistry was performed using the Hercep-Test Kit. RESULTS: Out of 77 specimens, 56 were Her-2/neu negative (70%), 20 (26%) showed a barely immunostaining (1+), only 1 (1%) was moderately (2+) and 2 (3%) were strongly positive (3+). Her-2/neu staining (moderately and strongly positive) was only detected in primary tumours of patients with confirmed metastases. No relationship was found between membranous HER-2 expression and patients' gender or differentiation. The median survival time of patients with positive HER-2/neu immunostaining was 21 versus 39 months in patients without HER-2/neu expression (p = 0.088). CONCLUSION: The c-erbB protein expression was observed in colorectal cancer but rarely in the therapeutic range (2+ and 3+). There was no significant association with tumour grade, gender, localization of the primary tumour or survival. These data indicate that c-erbB-2 is unlikely to play a major role in the therapeutic management of colorectal cancer.

Side effects during chemotherapy predict tumour response in advanced colorectal cancer.

To investigate whether a relationship between chemotherapy-associated adverse events and treatment efficacy exists, we have analysed the toxicity, objective response and survival data of 303 patients with advanced colorectal cancer. Patients were divided into two groups: the first with beneficial effect (I, n = 245), and the second with progressive disease (II, n = 58). Differences in terms of incidence rates, type and severity of ad verse events were analysed with univariate and multivariate models. The median number of side effects in group I was 6 vs 4 in group II (OR=1.342; P= 0.0001). An inverse correlation between disease control and treatment tolerance was confirmed when side effects were analysed according to severity and type of treatment-associated toxicities (haematological: P = 0.0005 vs nonhaematological P = 0.0001). When median survival was analysed according to the number of adverse events, it was 10 (95% CI, 3-7), 16 (14-18), and 18 (16-20) months in case of 0-1, 2-5, and > or =6 adverse events, respectively (P = 0.01). In conclusion, the results of this analysis suggest that occurrence of side effects during chemotherapy in advanced colorectal cancer is an independent and reliable prognostic indicator for response and survival.

Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial.

BACKGROUND: Patients with advanced biliary tract carcinoma face a particularly dismal prognosis, and no standard palliative chemotherapy has yet been defined. Among several different single agents, mitomycin C and, more recently, the oral fluoropyrimidine capecitabine and the nucleoside analogue gemcitabine, have been reported to exert antitumour activity. In view of a potential drug synergy, the present randomised phase II trial was initiated. The aim was to investigate the therapeutic efficacy and tolerance of mitomycin C (MMC) in combination with gemcitabine (GEM) or capecitabine (CAPE) in previously untreated patients with advanced biliary tract cancer. PATIENTS AND METHODS: A total of 51 patients were entered in this study and randomly allocated to treatment with MMC 8 mg/m2 on day 1 in combination with GEM 2000 mg/m2 on days 1 and 15 every 4 weeks, or MMC 8 mg/m2 on day 1 plus CAPE 2000 mg/m2/day on days 1-14, every 4 weeks. In both arms, chemotherapy was administered for a total of 6 months unless progressive disease occurred earlier. RESULTS: Pretreatment characteristics were well balanced between the two treatment arms. The overall independent review committee-confirmed response rate among those treated with MMC + GEM was 20% (five of 25) compared with 31% (eight of 26) among those treated with MMC + CAPE. Similarly, median progression-free survival (PFS; 4.2 versus 5.3 months) and median overall survival (OS; 6.7 versus 9.25 months) tended to be superior in the latter combination arm. Chemotherapy was fairly well tolerated in both arms, with a comparably low rate of only grade 1 and 2 non-haematological adverse reactions. Also, only four (17%) patients in both treatment arms experienced grade 3 leukocytopenia, and three (13%) and four (17%) had grade 3 thrombocytopenia in the MMC + GEM and MMC + CAPE arm, respectively. CONCLUSIONS: The results of this study indicate that both combination regimens are feasible, tolerable and clinically active. The MMC + CAPE arm, however, seems to be superior in terms of response rate, PFS and OS, and should therefore be selected for further clinical investigation in advanced biliary tract cancer.

Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy.

BACKGROUND: To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with fluoropyrimidine leucovorin-based chemotherapy. PATIENTS AND METHODS: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines leucovorin +/- irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m2 and raltitrexed 3.0 mg/m2 both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease. RESULTS: The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%-51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-free survival was 6.5 months (range 1.2-14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively. CONCLUSIONS: Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine leucovorin + irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.