Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study.

This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, irinotecan 240 mg m(-2) day 1; q21) or TEGAFOX (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, oxaliplatin 120 mg m(-2) day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3-4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1-55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6-51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12-23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies.

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer.

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m(2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3-week continuous infusion of FU (200 mg/m(2)daily), modulated by LV (20 mg/m(2)weekly bolus). Mito, 7 mg/m(2), was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents.

Multicenter randomized clinical trial on high-dose epirubicin plus cis-platinum versus vinorelbine plus cis-platinum in advanced non small cell lung cancer.

BACKGROUND: High dose Epirubicin (HD-EPI) (>90 mg/m2) and Vinorelbine (VNR) demonstrated antitumor activity as single agent (about 20%) in the treatment of advanced NSCLC. This trial compares these two agents combined with cisplatin (CP). PATIENTS AND METHODS: From August 1992 to February 1996, 228 patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 as i.v. bolus plus Cisplatin (CP) 60 mg/m2 on day 1 (regimen A) or VNR 25 mg/m2 as i.v. bolus on day 1 and 8 plus CP 60 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days up to a maximum cumulative dose of EPI of 840 mg/m2 or 12 cycles. Eligible patients were 212 and 198 patients were evaluable for objective response (95 in arm A and 103 in arm B). The main characteristics of eligible patients were: male/female 179/33; median age 61 (42-72); median Karnofsky PS 80 (70-100); stage IIIA 12%, stage IIIB 40%, stage IV 41%, recurrence 7%; histotype: epidermoid 48%, adenoca 36%, others 16%. RESULTS: The following response rates were observed in regimens A and B, respectively; CR, 1 and 2%, PR, 32 and 25% (P = 0.4567). Median CR + PR duration was 9 and 8 months, respectively. Median survival was 10.5 and 9.6 months, respectively. Grade III-IV leucopenia occurred in 38 and 21% in arm A and arm B, respectively(P = 0.01), thrombocytopenia in 6 and 0% (P = 0.02), anemia in 8 and 7% (n.s.). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88 vs. 33% in arm A and B, respectively). Supraventricular arrhythmia occurred in three patients on regimen A; a >15% LVEF absolute decrease was observed in 9 (22.5%) and three (14%) patients on arm A and arm B, respectively (n.s.). No congestive heart failure was observed. CONCLUSION: HD-EPI+CP and VNR+CP are both active combinations in advanced NSCLC with a similar response rate, response duration and survival but regimen A was significantly more toxic (myelosuppression and alopecia).

Prognostic significance of estrogen receptors in 405 primary breast cancers: a comparison of immunohistochemical and biochemical methods.

Over the last few years, estrogen receptor determination by means of immunohistochemistry has been extensively used. The aim of this study was to compare this technique with estrogen receptor determination by means of dextran-coated charcoal, and to evaluate whether one of the two methods is more predictive of prognosis. Estrogen receptors were determined by means of both the dextran-coated charcoal method and immunohistochemistry in 405 patients with primary breast cancer; age, pathological tumor size, nodal status, and progesteron receptors by dextran-coated charcoal method were also recorded. The disease-free and overall survival probabilities were estimated using the product-limit method; Cox's proportional hazard model was used to evaluate the prognostic role of estrogen receptors as determined by the two methods. There appears to be a close association between estrogen receptor determination by the two methods (81.5% of concordant results) and their prognostic role was similar, even when the patients were divided into different groups (on the basis of their estrogen receptor status) and adjustments for the effect of other prognostic variables were taken into account. Our study shows that the two methods can be used indifferently to evaluate estrogen receptor status as a prognostic factor in breast cancer patients.

Detection at diagnosis of tumor cells in bone marrow aspirates of patients with small-cell lung cancer (SCLC) and clinical correlations.

BACKGROUND: Immunocytochemistry has often been used to identify tumor cells in bone marrow aspirate (BMA) of SCLC patients in order to improve the results of conventional histomorphology. However, whether the detection of bone marrow microlocalisation at diagnosis had implications for prognosis has not been clear. PATIENTS AND METHODS: Eighty-four slides (44 patients) and 66 bone marrow biopsies (from 42/44 patients) were evaluated. Cytospins of BMA were incubated with the monoclonal antibody (MAb) NCC-LU-243, recognising the cluster 1 antigen (NCAM) and then stained by the APAAP (alkaline phosphatase-anti-alkaline phosphatase) method. The relationship among BMA and PS (performance status), NSE (neuron-specific enolase), stage, survival was also studied. RESULTS: 33/84 (39%) BMA were positive for NCAM, compared with 8/66 (12%) bone marrow biopsies (p = 0.009), (17/44 and 6/42 patients, respectively). Moreover, BMA was positive for NCAM in 6/19 patients with limited disease. The presence of positive BMA did not correlate with PS, NSE or stage, but patients with positive BMA had shorter survivals than those with negative BMA (median survival: 7 and 12 months, respectively, p = 0.007). CONCLUSIONS: Bone marrow involvement detected by immunocytochemistry appears to be related to survival but not to parameters of tumor burden (NSE, stage), suggesting that this technique might help to select patients with better prognoses for new therapeutic strategies.

Cisplatin pharmacokinetics in elderly patients.

The treatment of elderly patients with cancer may be difficult because of the narrow therapeutic index of antineoplastic drugs, the decline in the performance of organs and functions, and frequent comorbidity. In these patients, therapeutic drug monitoring may be useful in optimizing chemotherapy. Six patients older than 70 years with a variety of solid tumors received a total of 21 cycles of cisplatin (DDP)-based chemotherapy program (DDP dose, 50-65 mg/m2). Total and ultrafilterable platinum (Pt) were determined in plasma and urine during the first cycle of the therapy by means of atomic absorption spectroscopy. Pharmacokinetic parameters were analyzed with use of a two-compartment open model. The treatment was generally well tolerated. The most important side effects were a significant increase in serum creatinine level (from 0.98 to 1.23 mg/dl) and a decrease in creatinine clearance (from 44.4 to 38.9 ml/min) in comparison with pretreatment values. The mean decrease in hemoglobin levels was slight. The values of the main pharmacokinetic parameters of total Pt agreed well with the data obtained with other adult patients. Total and ultrafilterable Pt had a short distribution phase (t1/2 alpha = 0.35 and 0.54 h, respectively) followed by a prolonged elimination phase (t1/2 beta = 63.08 and 58.91 h, respectively). A reduced ability to clear ultrafilterable Pt (ClT = 123.52 ml h-1 kg-1) was evident and, as a result, the area under the curve increased (15.47 mg h L-1). The limited number of patients and the concomitant use of other agents prevent any firm conclusions.(ABSTRACT TRUNCATED AT 250 WORDS)

[The use of monoclonal antibodies that recognize the neural cell adhesion molecule (NCAM) in the diagnosis of bone marrow localization of small cell lung cancer]. / L'uso di anticorpi monoclonali che riconoscono la neural cell adhesion molecule (NCAM) nella diagnosi delle localizzazioni midollari di microcitoma polmonare.

We have used immunocytochemistry to identify tumor cells in bone-marrow aspirates of 40 untreated patients with small cell lung cancer and we compared the results with conventional histomorphology. The monoclonal antibodies (MAbs) used were NCC-LU-243 and NCC-LU-246 (both cluster 1). For each MAb 76 slides were evaluated. Sixty bone-marrow biopsies were also obtained from these patients. The positivity rate between the 2 MAbs was not statistically different (46% for NCC-LU-246 and 43% for NCC-LU-243). Bone-marrow biopsies detected tumor localization in 8/60 specimens (13%), significantly less than immunocytochemistry with anti-NCAM MAbs (p = 0.003). Moreover, bone-marrow aspirates were positive for cluster 1 antigen in 6/16 patients with limited disease at diagnosis. The results confirm that NCC-LU-243 and NCC-LU-246 have equivalent ability to identify bone-marrow involvement; immunocytochemistry appears to be better suited for this purpose than conventional bone-marrow biopsy; a non-negligible proportion of patients with "limited disease" might be understaged; the clinical value of detecting bone marrow involvement by immunocytochemistry is still unclear.

Treatment patterns in elderly patients (greater than or equal to 70 years) with breast carcinoma. A retrospective study of the Gruppo Oncologico Clinico Cooperativo del nord-Est (GOCCNE).

The pattern of treatment used in elderly women affected by breast carcinoma was evaluated in a retrospective study by the North-East Clinical Cooperative Group in Italy (GOCCNE). Six divisions were involved in the study. The medical records of 115 elderly women were reviewed; the women's median age was 75 years (range, 70-93). Surgery was used in 70/72 operable patients (97%), although limited surgery plus radiotherapy was used in only 7.5%. Most stage II patients were treated with adjuvant tamoxifen, as were younger postmenopausal patients, according to the guidelines of the Bethesda Consensus Meeting. Comorbid conditions are of particular concern in therapy planning, considering that more stage III patients died of competing causes than for disease progression. The role of chemotherapy was very marginal.