Background: Vinorelbine a semisynthetic vinca alkaloid, represents a well-tolerated treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC), We explored the quality of life (QoL) of such patients in a multicenter randomized trial that compared vinorelbine treatment with supportive care alone. Methods: Eligible patients were 70 years of age or older, had stage IV or IIIB NSCLC that was ineligible for radiotherapy, and had a performance status of 0-2 (a status of fully active to a status of capable of all self-care but unable to work). Vinorelbine was given intravenously on days 1 and 8 of a 21-day treatment cycle, for a total of six cycles. QoL was evaluated with European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-LC13, and the QoL data were analyzed by fitting a linear mixed model for each QoL scale, Survival curves were plotted and were compared with the Mantel-Haenszel test, Relative hazards of death and 95% confidence intervals (CIs) were estimated by the Cox model. Results: Investigators, blinded to the results, stopped the trial early because of a low enrollment rate. (From April 1996 to November 1997, 191 of the 350 targeted patients were randomly assigned.) Data from 161 patients have been analyzed. Vinorelbine-treated patients scored better than control patients on QoL functioning scales, and they reported fewer lung cancer-related symptoms but reported worse toxicity-related symptoms. There was a statistically significant (two-sided P = .03) survival advantage for patients receiving vinorelbine; median survival increased from 21 to 28 weeks in the vinorelbine-treated group. The relative hazard of death for vinorelbine-treated patients was 0.65 (95% CI = 0.45-0.93), Conclusion: Vinorelbine improves survival of elderly patients with advanced NSCLC and possibly improves overall QoL.

PURPOSE The nucleoside analog, gemcitabine, has shown activity as a single agent in the treatment of metastatic non-small-cell lung cancer (NSCLC). Its combination with cisplatin in preclinical models suggested synergy between the two drugs. The aim of the study was to evaluate the clinical efficacy and toxicity of the cisplatin-gemcitabine combination in advanced NSCLC. PATIENTS AND METHODS Forty-eight consecutive previously untreated NSCLC patients entered the trial from January to June 1994. The median age was 60 years (range, 37 to 70) and performance status (PS) was 0 or 1; 22 patients had unresectable stage III disease (21 stage IIIB and one stage IIIA) and 26 had stage IV disease. Gemcitabine 1 g/m2 was administered weekly (days 1, 8, and 15) followed by a 1-week rest and cisplatin 100 mg/m2 on day 2 of each 28-day cycle. Survival and response were determined in accordance with the intention-to-treat principle in all enrolled patients. RESULTS Of 48 assessable patients, one (stage IV) had a complete response (CR) and 25 achieved a partial response (PR). The overall response rate was 54% (95% confidence interval [CI], 40% to 68%). Thrombocytopenia was the main side effect, with 52% of patients experiencing grade III to IV toxicity, which was usually short-lived and responsible for the omission of gemcitabine administration on day 15 in 50% of chemotherapy courses. The median survival time was 61.5 weeks (95% CI, 40 to 71). CONCLUSION The combination of gemcitabine and cisplatin induced a high response rate in both stage IIIB and IV NSCLC, with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.

BACKGROUNDCisplatin-based chemotherapy is generally considered the most active treatment for advanced non-small-cell lung cancer. The combination of cisplatin and etoposide had for some time been the standard treatment at our center. Of the other active regimens, cisplatin in combination with mitomycin-C, vindesine or ifosfamide (MVP or MIC) showed the highest response rates. We decided to perform a comparative trial of the three 'best' regimens in order to define a possible standard regimen in advanced NSCLC.MATERIALS AND METHODSFrom May 1989 to April 1992, 393 consecutive, previously untreated NSCLC patients, stages IIIB and IV, were randomized to receive either cisplatin (120 mg/sqm day 1) + etoposide (100 mg/sqm days 1-3) every 3 weeks (PE) or cisplatin (120 mg/sqm every 4 weeks) + mitomycin-C (8 mg/sqm days 1-29-71) + vindesine (3 mg/sqm days 1-8-15-22) (MVP) or cisplatin (120 mg/sqm day 1) + mitomycin-C (6 mg/sqm day 1) + ifosfamide (3 mg/sqm day 2) every 3 weeks (MIC). Of these, 382 were evaluable for survival and 360 for response.RESULTSResponse rates were statistically higher for both MIC (40%) and MVP (36%) than for the PE arm (23%). Survival estimates analyzed by the log-rank test showed a significant benefit (p < 0.04) for patients treated with three-drug regimens (MVP; MIC) as compared to those in the PE arm. The main toxicity was myelosuppression; thrombocytopenia WHO grade 3-4 was worse in the MIC arm; nephrotoxicity grade 3-4 was also more frequent in the MIC arm.CONCLUSIONSA three-drug cisplatin-based regimen (MVP; MIC) should be considered as reference treatment in NSCLC.

To evaluate the efficacy of a three-drug regimen vs. a two-drug CDDP based combination in the treatment of NSCLC, we conducted a three-arm randomized parallel trial comparing (a) CDDP (120 mg/m2 day 1) + etoposide (100 mg/m2 days 1–3) every 3 weeks (PE —arm A); (b) CDDP (120 mg/m2 every 4 weeks) + mitomycin (8 mg/m2 days 1, 29, 71) + vindesine (3 mg/m2 days 1, 8, 15, 22 every 2 weeks) (MVP —arm B); and (c) CDDP (120 mg/m2 day 1) + mitomycin (6 mg/m2 day 1) + ifosfamide (3 g/m2 day 2) every 3 weeks (MIC —arm C). From May 1989 to April 1992, 393 consecutive previously untreated patients with NSCLC Stage IIIB and IV entered the trial; 373 were evaluable for survival and 360 for response. The response rate was significantly better for both the three-drug regimens compared with PE (Table 3). Logistic regression model showed a significantly better response in patients with a good P.S. and in Stage IIIB. Main toxicity consisted of myelosuppression: neutropenia Grade III —IV was recorded in 14% (arm A), 15% (arm B) and 21% (arm C). Thrombocytopenia Grade III —IV was worst in arm C: 10% vs. 5% (arm A) and 3% (arm B). Nephrotoxicity Grade III —IV was more common in arm C: 3.5%. Toxic deaths were 11 (3%: three in arm A, five in arm B, three in arm C). From our data, the three-drug containing regimens, MVP and MIC, appear more active than the two-drug combination PE in treatment of advanced NSCLC.

The clinical efficacy and safety profile of a gemcitabine-cisplatin combination was investigated in a 12-centre phase II trial. 48 consecutive previously untreated NSCLC patients were entered. Median age was 60 years (range 37–70); performance status 0–1; 21 patients had locally advanced unresectable stage IIIb disease and 27 disseminated stage IV disease. Gemcitabine 1000 mg/m2 was administered weekly (days 1, 8, 15) followed by one week rest and cisplatin 100 mg/m2 monthly (day 2) of each 28-day cycle. This schedule was chosen because of experimental and clinical evidence of synergy when the 2 drugs are given in close sequence, and to assess separately acute side effects. Forty-six patients were evaluable for response and toxicity (≥ 1 measurable lesion and ≥ 2 cycles). 1 complete response and 26 partial responses were observed for an overall response rate of 58% (95% CI 44–72%), 11 stage IIIb (52%, CI 3l–73%) and 16 in stage IV (59%, CI 41–77%). Thrombocytopenia was the main side effect with 51% grade 3–4 toxicity, usually short-lived and responsible for the omission of gemcitabine administration on day IS in 90 courses of chemotherapy, and no serious bleeding episodes. Nonhaematological toxicity was usually mild with one acute but reversible renal failure. The combination of gemcitabine and cisplatin induced a significant response rate both in stage IlIb and IV NSCLC with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial. The clinical efficacy and safety profile of a gemcitabine-cisplatin combination was investigated in a 12-centre phase II trial. 48 consecutive previously untreated NSCLC patients were entered. Median age was 60 years (range 37–70); performance status 0–1; 21 patients had locally advanced unresectable stage IIIb disease and 27 disseminated stage IV disease. Gemcitabine 1000 mg/m2 was administered weekly (days 1, 8, 15) followed by one week rest and cisplatin 100 mg/m2 monthly (day 2) of each 28-day cycle. This schedule was chosen because of experimental and clinical evidence of synergy when the 2 drugs are given in close sequence, and to assess separately acute side effects. Forty-six patients were evaluable for response and toxicity (≥ 1 measurable lesion and ≥ 2 cycles). 1 complete response and 26 partial responses were observed for an overall response rate of 58% (95% CI 44–72%), 11 stage IIIb (52%, CI 3l–73%) and 16 in stage IV (59%, CI 41–77%). Thrombocytopenia was the main side effect with 51% grade 3–4 toxicity, usually short-lived and responsible for the omission of gemcitabine administration on day IS in 90 courses of chemotherapy, and no serious bleeding episodes. Nonhaematological toxicity was usually mild with one acute but reversible renal failure. The combination of gemcitabine and cisplatin induced a significant response rate both in stage IlIb and IV NSCLC with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.

Treatment of gastric cancer still presents a challenge in cancer chemotherapy. In our Institute, from January 1981 to November 1984, 45 patients were given 5-fluorouracil (5FU) 600 mg/m2 Days 1, 8, 29, and 36; doxorubicin (A) 30 mg/m2 Days 1 and 29; mitomycin-C 10 mg/m2 Day 1 (FAM regimen) every 8 weeks. From December 1984 to October 1986, 26 patients were treated with 5FU 300 mg/m2 on Days 1-5, A 40 mg/m2 on Day 1, cisplatin (P) 100 mg/m2 on Day 1 (FAP regimen) every 3 weeks. In the FAM group, 42 patients are evaluable for response; 5 (12%) partial remission (PR), 9 stable disease (SD), and 28 progressions (PRO) were observed. Median duration of response (MDR) was 21 weeks (range 13-45) and the median survival (MS) in the whole group was 27 weeks. In the FAP group, 23 patients are evaluable: 2 CR (9%), 11 PR (47%), 2 SD (9%), and 8 PRO (34%) were observed; CR duration was 24 and 107+ weeks, respectively, MDR of PR was 22 weeks (5-35). The MS of all patients was 16 weeks. Toxicity (WHO criteria) was mild in the FAM group and severe in the FAP group. In spite of a higher objective response rate, the short MS and the severe toxicity observed in the FAP group do not merit recommendation of this regimen in patients with gastric cancer; therefore neither FAM nor FAP appear to be an ideal standard therapy.

Centro Operative) AIDS, Istituto Superiore di Sanità, Rome, Italy, and the *Gruppo Italiano Cooperativo AIDS e Tumori (GICAT), Aviano, Italy.

Nodular bilateral pulmonary histoplasmosis: cyto-histological correlation. A case of nodular pulmonary histoplasmosis is reported. A 29 year old man was admitted to hospital with temperature and general weakness following a short stay in a tropical country. Laboratory investigation showed an increased E.S.R. and a routine chest-roentgenogram revealed multiple bilateral nodular lesions confirmed by CT scan. Smears obtained from fine-needle-aspiration biopsy showed the presence of epithelioid cell's clusters with a few giant-cells in a background of inflammatory elements and necrotic debris. The cytological picture was consistent with an inflammatory process with necrotizing granulomatous features. The clinical evolution and the radiological picture progression caused, nevertheless, suspicion of a metastatic tumor. The histological examination of a resected peripheral nodule confirmed the inflammatory nature of the process, revealing the presence of multiple roundish encapsulated conidia 2-4 microns in diameter scattered within a granulomatous and necrotic tissue. The fungi are clearly pinpointed by using special stains like Grocott method. Serological and microbiological investigations are necessary in order to confirm the diagnosis.

Patients with histologically confirmed advanced colorectal cancer were randomized to receive folinic acid (FA; 500 mg/mq in 2-hour intravenous infusion) and 5-fluorouracil (5FU; 600 mg/mq given as an intravenous bolus 1 hour after FA), beginning every week for 6 weeks, followed by a 2-week rest period, either without hydroxyurea (HU, arm A) or with HU (35 mg/kg per day) given orally in three administrations (every 8 hours) starting 6 hours after 5FU administration (arm B). Six weekly doses were considered one course. One hundred eighty-two patients were randomized in this trial and 162 (89%) were evaluable for response: 81 patients in arm A and 81 patients in arm B. Objective response was observed in 18 (one complete response and 17 partial responses) of 81 evaluable patients (22%; 95% confidence interval, 13-31%) in arm A, and 24 (nine complete responses and 15 partial responses) of 81 patients (30%; 95% confidence interval, 20-40%) in arm B. There was no difference in terms of median time to progression and median survival. Gastrointestinal toxicity was the most frequently observed toxicity in both arms. The double modulation of 5FU, FA plus HU does not appear to be better than the classic 5FU plus FA schedule. This trial confirms that 5FU and FA reached a plateau of 20% to 30%.

The pharmacokinetics of etoposide (VP 16) and teniposide (VM 26) were studied after intrapleural administration to 3 patients with lung cancer and malignant pleural effusion. Comparison with the kinetic behavior of intravenously infused VP 16 and VM 26 in the same patients suggests that intrapleural drug delivery achieves higher and longer-lasting pleural concentrations, thus providing a theoretical basis for the palliative treatment of malignant pleural effusions. Although no systemic toxicity was observed after intrapleural administration of either drug, 1 of the 3 patients developed a transient asymptomatic hemorrhagic pleurisy during the first 2 days after the drug, alerting to the possible local toxicity of such treatment.

The increased incidence of malignancies associated with AIDS has been the subject of several reports in the North American literature: besides Kaposi’s sarcoma and other tumours, such as squamous carcinoma of the tongue and cloacogenic carcinoma of the anorectum [1–22], malignant lymphomas have been demonstrated to be one of the major problems among the neoplastic complications of AIDS [12–24]. According to the North American experience, non-Hodgkin’s lymphomas in patients with AIDS or AIDS-related clinical conditions present at an advanced stage in which lesions are concentrated in extranodal and often unusual locations, notably the CNS. Disease confined to the lymph nodes is uncommon. These lymphomas are predominantly high-grade B-cell neoplasms classified as immunoblastic and Burkitt’s-like lymphomas. A variety of severe opportunistic infections and Kaposi’s sarcoma affect these patients. At the same time, the association with AIDS is strengthened by the regular demonstration of reversed ratios of helper (T4+) and suppressor (T8+) lymphocytes in the peripheral blood and by the presence of antibodies to human immune deficiency virus (HIV) [22]. The prognosis is dismal: response to chemotherapy does not positively affect median survival. Mortality rates analysed by histological grade are higher than the currently reported rates for comparable patient populations [18].

A total of 52 consecutive, previously untreated patients with small-cell lung cancer (SCLC) were scheduled to receive six cycles of a combination of etoposide (75 mg/m2 per day) and cisplatin (20 mg/m2 per day), each cycle given over 5 consecutive days. In all, 28 patients had extensive disease (ED) and 24, limited disease (LD). After three cycles of chemotherapy, all responding patients were given chest radiotherapy (RT) (45 Gy in two split courses and 30 Gy in LD and ED, respectively); only patients with LD who achieved complete remission (CR) after three cycles of chemotherapy were given prophylactic brain irradiation (30 Gy). In the 51 evaluable patients, the overall response rate was 90%, with a 31% CR and a 59% partial remission (PR) rate. In LD and ED patients, 57% and 11% CR rates and 30% and 82% PR rates were noted, respectively. Myelosuppression was the most frequently observed toxicity. The median duration of response was 12 months in LD (range, 3–41+months) and 7 months (range, 2–12 months) in ED; the median survival was 15 months in LD and 9.3 months in ED, respectively. In all 30% of LD patients are alive and well at a minimal follow-up of 18 months. This trial confirms the activity of the cisplatinetoposide combination in SCLC.

Twenty-seven evaluable patients with small cell lung cancer (SCLC) resistant to, or relapsed after induction combination chemotherapy (CT) were treated with etoposide (VP16) plus cisplatin (DDP). Previous treatment was: alternating CT with cyclophosphamide (C), adriamycin (A), methotrexate (M), procarbazine (P) (CAMP)/VP16, BCNU (B), hexamethylmelamine (H) (VP16 BH) in 16 patients; C, A, vincristine (CAV) in 6 patients; C, A, and VP16 (CAVP16) in 5 patients. We observed 2 (7%) complete responses (CR) and 9 (33%) partial responses (PR). Duration of CRs was 8 and 14 weeks, respectively. PRs lasted a median of 22 weeks (range 16-44). Seven of 21 (33%) patients previously treated with VP16 responded to DDP plus VP16 (D-V). These results confirm D-V regimen as active in SCLC patients even when heavily pretreated. Our 33% response in patients who had VP16 in their induction treatment regimen provides further evidence of an important potentiating effect of DDP, as reported in animal system.

The pharmacokinetics of 7-con-O-methylnogarol were investigated by HPLC assay with fluorometric detection in nine cancer patients with normal hepatic and renal function, after a 2-h infusion of 160 or 200 mg/m2. The drug disappeared from plasma biexponentially with a mean elimination half-life of 38±3 h; the mean apparent volume of distribution and the plasma clearance were 805±91 l/m2 and 14±2 l/h per m2. Within 48 h of administration, urinary excretion of the drug and its metabolite 7-con-O-methyl-N-demethylnogarol accounted for 2%–15% and 0.1%–6% of the dose, respectively. Neither 7-con-O-methylnogarol nor its N-demethyl derivative was conjugated with glucuronic acid or sulfate in detectable amounts.