High-versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: a 'GISCAD' phase III study. Italian Group for the Study of Digestive Tract Cancer.

BACKGROUND: Although leucovorin (LV) + 5-fluorouracil (5-FU) is considered the treatment of choice for advanced colorectal cancer in most countries, the optimal schedule of this combination has not yet been established. Low-dose LV appears to be as active as high-dose LV in the daily-times-five regimen, but no randomized study of the levorotatory stereoisomer (6S-LV) given at two different dose levels has been published. PATIENTS AND METHODS: Between November 1991 and June 1994, 422 patients (all with measurable disease previously untreated with chemotherapy) were randomized to 6S-LV (100 mg/sqm/i.v.) + 5-FU (370 mg sqm/15 min i.v. infusion), both administered for 5 days every 28 days (arm A), or to 6S-LV (10 mg/sqm/i.v./5-FU (doses as above), also given for 5 days every 28 days (arm B). The primary endpoint of the study was the comparison of response rates (WHO criteria): the secondary endpoint was the assessment of survival and tolerability. No evaluation of the quality of life or the symptomatic effect of treatment was planned. RESULTS: The response rate was 9.3% in arm A (95% CI: 5.4-13.1), with 2 CR and 18 PR, and 10.7% in arm B (95% CI: 6.5-14.9), with 3 CR + 19 PR, without any significant difference (P = 0.78). The median time to progression was eight months in both groups and overall survival was 11 months, with no difference between treatments. Toxicity mainly consisted of gastrointestinal side effects (mucositis and diarrhoea), which were rarely severe (grade 3-4: 5%-10% of patients) and similar in the two groups. CONCLUSIONS: In this large-scale multicentre trial, the low and high doses of 6S-LV appeared to be equivalent in terms of the biochemical modulation of 5-FU in advanced colorectal cancer although, for several reasons (including the timing and the strict criteria of response evaluation, the high number of patients with unfavourable prognostic factors, the multi-institutional nature of the study, the dose and modality of 5-FU administration), the response rate was lower than that reported in some of the other published studies. Given the considerable difference in economic cost between the two dosages, the use of high-dose 6S-LV in the daily-times-five regimen is not recommended in clinical practice.

Retrospective analysis of 156 cases of metastatic renal cell carcinoma: evaluation of prognostic factors and response to different treatments.

BACKGROUND: Metastatic renal cell carcinoma is a "capricious" tumor. Many prognostic factors have been evaluated, treatment is still controversial, and results are not coincident. METHODS: We reviewed 156 patients with metastatic renal cell carcinoma. Survival from the time of diagnosis was the end point of the study. The influence on survival of age, sex, nephrectomy, disease-free interval, performance status, site and number of metastases was analyzed. Univariate and multivariate analysis were done. Survival according to different therapies was also evaluated. RESULTS: In our study, no nephrectomy, a disease-free interval < 24 months, > 2 metastatic sites and a performance status > 2 proved to be risk factors. According to the number of risk factors, 3 groups of patients were identified (low, intermediate and high risk). We observed 3 kinds of responses to treatments: 1) in untreated patients (n = 48), median overall survival was 6 months, and the 24-month survival rate was 8%; 2) in patients treated with hormone therapy and/or chemotherapy (n = 73), median overall survival was 13 months, and the 24-month survival rate was 24%; 3) in patients treated with interferon and/or interleukin-2 (n = 35), median overall survival was 16 months and the 24-month survival rate was 34%. CONCLUSIONS: Our results are only partially in accordance with those observed by other authors. Risk factors and treatment must be determined in more defined and selected studies.

Possible correlation between some biologic effects and the clinical course in patients treated with continuous infusion of interleukin-2 plus alpha-2 interferon for metastatic renal cell carcinoma.

BACKGROUND: Interleukin-2 therapy is known to cause many biologic effects, which are enhanced by the administration of interferon prior to or immediately after interleukin-2 infusion. Some of these effects could be related to the clinical response. METHODS: Sixteen patients with metastatic renal cell carcinoma were treated with continuous infusion of interleukin-2 plus alpha-2 interferon. Differential leukocyte count and lymphocyte subset evaluation were performed every 3 days during interleukin-2 treatment. At each cycle, the presence of the following antibodies was tested: antithyroid, antinuclear, antiplatelet and antierythrocyte. RESULTS: Fifteen patients were evaluable for response. No complete response was observed. Five patients obtained partial response (33%) and 3 stable disease (20%): 2 of them underwent surgical resection of metastases and obtained complete response. Some of our patients showed a significant increase in eosinophils, CD25+ lymphocytes and antithyroid antibodies. The association of these parameters, calculated with a "score" system, was also related to a better clinical response. CONCLUSIONS: Eosinophils, CD25+ lymphocytes and antithyroid antibodies could have a predictive value for the efficacy of interleukin-2 and alpha-2 interferon therapy in metastatic renal cell carcinoma.

Proliferation index as a prognostic marker in breast cancer.

BACKGROUND: The proliferative activity of tumors has been extensively investigated with different approaches, among which the use of the monoclonal antibody Ki-67 represents an easy and reliable means of assessing cell proliferation. In this study, the proliferative activity of 129 primary breast cancers was investigated, and the results were related to prognosis. METHODS: Tumor samples, obtained from 129 patients who underwent surgery between January 1987 and December 1988, were processed for staining by an immunohistochemical procedure (avidin-biotin complex). The median time of observation was 42 months (range, 31-55 months). Life-table analysis (Mantel-Cox) was used to assess the probability of disease-free survival (DFS) and overall survival (OS). RESULTS: Tumors with high Ki-67 proliferation indices (> 20%) were associated with a higher 4-year probability of relapse of disease (55.3% versus 79.1%; P = 0.003) and death (71% versus 95.6%; P = 0.00005) when compared with tumors with low Ki-67 values. In addition, this proliferative parameter maintained its prognostic significance when the patients were stratified according to lymph node involvement, menopausal status, and nuclear estrogen receptor content. CONCLUSIONS: Tumor proliferative activity as evaluated by the monoclonal antibody Ki-67 seems to be an effective indicator of prognosis in breast cancer for DFS and OS.

General-hospital experience in treating neck nodes from unknown primaries.

Forty cases of cervical (excluding supraclavicular) node metastases from unknown primary tumors were observed at the medical oncology department of a large general hospital. Histologically they were epidermoid carcinoma (18 cases), undifferentiated carcinoma (16 cases) and adenocarcinoma (6 cases). In 8 patients the primary was subsequently diagnosed. Four patients were untreatable or refused treatment when diagnosed. The 3-year survival of the 36 treated patients was only 22% - indicating a poor prognosis is for this uncommon form of presentation. Patients should be treated as aggressively as possible in an attempt to eradicate the occult primary.

[Clinical and prognostic usefulness of Ki67 determination in breast carcinoma]. / Utilità clinica e prognostica della determinazione del ki67 nel carcinoma mammario.

We studied the correlation between tumor size, nodal status, menopausal status, nuclear oestrogen receptors, disease free survival and Ki67 (proliferation rate) measured by mean of immunohistochemical analysis with monoclonal antibody. Median value was 10%. From December 1986 to October 1989 we studied 236 consecutive patients (pts). Median follow up was 34 months (range 7-51 months). Median age was 56 years (r. 26-82). We observed: 1) lower levels in smaller tumors; 2) poor correlation with nodes involvement; 3) lower levels when nuclear oestrogen receptors were positive. Preliminary data seem to suggest longer disease free survival when Ki67 is low.

Correlation between histochemically assessed hormonal receptor content and clinical course in breast cancer. Presentation of 1,005 cases.

Lee's histochemical method was used to assess hormonal receptors in 1,005 patients with breast cancer. Patients were from 8 oncological departments in northern Italy. The group was subdivided into four subgroups in relation to menopausal status and presence or absence of axillary node metastasis. Overall survival (OS) and disease-free survival (DFS) were analysed in all subgroups in relation to receptorial status. We observed: (1) when hormonal receptors are present, OS and DFS are longer in all subgroups; (2) the presence of hormonal receptors influences favourably both DFS and OS, but it seems to play a more important role for DFS; (3) the positive receptorial status is a better prognostic factor in groups without axillary node metastasis, especially in premenopausal patients. We conclude that the histochemical assessment of hormonal receptors is a valid method for the prognostic evaluation of patients with breast cancer.