Treatment of inoperable non-small cell lung carcinoma stage IIIb and IV with cisplatin, epidoxorubicin, vindesine and lonidamine: a phase II study.

AIMS AND BACKGROUND: The polychemotherapeutic regimen PEV (cisplatin, epidoxorubicin and vindesine) + lonidamine proved to be valid in terms of activity and efficacy in the treatment of patients with advanced, previously untreated non-small cell lung carcinoma. The goal of the study was to verify whether a different dose of lonidamine, together with an increase in cisplatin and epidoxorubicin compared to the standard regimen, is able to improve the activity and efficacy of PEV without increasing toxicity. PATIENTS AND METHODS: Thirty-one patients were treated with cisplatin (80 mg/m2/i.v.), epidoxorubicin (70 mg/m2/i.v.) and vindesine (3 mg/m2/i.v.) every 28 days for 6 courses in combination with lonidamine (600 mg/day on days 1 and 2 of each course followed by 450 mg/day until progression of disease or intolerance). All the patients were monitored for clinical response, median duration of response and survival and for toxicity. RESULTS: The clinical response in the 29 assessable patients was: 41.4% partial remission, 48.3% stable disease, and 10.3% progression of disease. The median duration of response was 8.5 months (range, 4-26+) and median survival was 12 months (range, 4-26+). Survival was above the median in 15 stage IIIb patients, and 2 patients were long survivors at 26+ months. The toxicity of PEV + lonidamine was mild; there were no toxic deaths nor acute toxicity of grade 4 according to the WHO scoring system. CONCLUSIONS: Our polychemotherapeutic regimen proved to be valid in terms of activity and efficacy, and a further dose increase in single chemotherapeutic agents as well as lonidamine could therefore be justified.

Cisplatin-vindesine-mitomycin (MVP) vs cisplatin-ifosfamide-vinorelbine (PIN) vs carboplatin-vinorelbine (CaN) in patients with advanced non-small-cell lung cancer (NSCLC): a FONICAP randomized phase II study. Italian Lung Cancer Task Force (FONICAP).

In the present multicentre randomized phase II trial, the activity and toxicity of three platinum-based combination regimens for the treatment of advanced non-small-cell lung cancer (NSCLC) were evaluated. The three regimens were: MVP (mitomycin-C 6 mg m(-2) on day 1, vindesine 3 mg m(-2) on days 1 and 15, and cisplatin 80 mg m(-2) on day 1 every 28 days), PIN (cisplatin 80 mg m(-2) day 1, ifosfamide 3 g m(-2) day 1 and vinorelbine 25 mg m(-2) day 1 and 8 every 21 days) and CaN (carboplatin 350 mg m(-2) day 1 and vinorelbine 25 mg m(-2) days 1 and 8 every 28 days). A total of 140 chemotherapy-naive patients entered the study; 49 patients were treated with MVP, 48 with PIN and 43 with CaN. Sixty-seven per cent of the patients had stage IV disease. Response rates, calculated on an 'intention to treat' basis, were as follows: MVP, 14.3% (95% CI 5.94-27.2%); PIN, 16.7% (95% CI 7.4-30.2%); and CaN, 14% (95% CI 5.3-27.9%). The overall median survivals were 256, 269 and 243 days for patients treated with MVP, PIN and CaN respectively. Myelosuppression was the most frequent toxicity: grade 3-4 leucopenia was observed in 14.3%, 25% and 18.6% of patients treated with MVP, PIN and CaN respectively. This multicentre phase II randomized trial shows that MVP, PIN and CaN can be administered on an outpatient basis with acceptable toxicities. Unfortunately, the three regimens showed an activity significantly lower than that reported in previous single-institution phase II trials.

Combined treatment with thymosin-alpha1 and low-dose interferon-alpha after ifosfamide in non-small cell lung cancer: a phase-II controlled trial.

22 patients with advanced non-small-cell lung cancer were randomized to receive chemotherapy (ifosfamide) or chemotherapy followed by thymosin alpha1 + low-dose IFNalpha. Chemo-immunotherapy induced an enhanced response rate compared with chemotherapy alone (33% and 10% respectively). Although these differences were not significant, the difference in time to progression was (p=0.0059). CD4+, CD8+ and NK cell counts were significantly depressed after two cycles of chemotherapy, while no difference in cell count were seen in chemo-immunotherapy treated patients. Hematologic toxicity was reduced by the immunotherapy, with no grade 3/4 toxicity seen compared to 50% in patients treated with chemotherapy alone.

Lonidamine plus cyclophosphamide in the treatment of adanced non-small cell lung cancer in the elderly: a phase II study.

AIM AND BACKGROUND: The aim of this Phase II trial was to verify the therapeutic activity and tolerability of chemotherapy with lonidamine (LND) plus cyclophosphamide (CTX) in advanced non-small cell lung cancer (NSCLC) in the elderly. The rationale of the combination is reported. CTX showed mild toxicity, with a 12% objective response (OR) in monochemotherapy; LND potentiated the in vitro antiproliferative activity of alkylating agents, mainly CTX, without increasing myelotoxicity, particularly important in the elderly. METHODS: The schedule consisted of CTX, 600 mg/m2/i.v. on day 1 every 21 days for 6 cycles; LND, 450 mg/die/p.o. from day 1 to progression. RESULTS: Between November 1990 and April 1991, 41 patients with stage III-IV NSCLC were enrolled; 35 were assessable for response. Median age was 73 years (range, 71-79 years); 13 patients (32%) presented stage III A, 20 (49%) stage III b, and 8 (19%) stage IV disease. Cardiovascular conditions and/or chronic respiratory failure contraindicated surgical treatment in stage III A patients. Of enrolled patients, 14.6% experienced PR, 48.8% SD and 14.6% dropped out of the study. Median time to progression was 4 months (range, 2-9 months) and median survival 9 months (range 3-45 months). No patient showed WHO grade IV LND-related toxicity. In 1 patient (2.5%), LND was discontinued after 5 therapy cycles due to WHO grade III myalgia; in 80% of patients, LND oral dosage was reduced to 300 mg/day due to WHO grade II myalgia, and 20% of patients completed treatment with the full dose. CONCLUSIONS: CTX plus LND can be considered a well tolerated therapeutic approach in the elderly with NSCLC with good PS and good liver, renal and cardiac conditions, but 14.6% PR is a slightly better result as compared with 12% PR obtainable with CTX alone as reported in the literature, even though most patients presented with advanced disease and no specific toxic effect was observed. Therefore, a confirmatory randomized trial (CTX vs CTS plus LND) would hardly be useful.

Combination of chemotherapy and recombinant alpha-interferon in advanced non-small cell lung cancer. Multicentric Randomized FONICAP Trial Report. The Italian Lung Cancer Task Force.

BACKGROUND: Preclinical data suggested that alpha-interferon (IFN) may potentiate chemotherapy cytotoxicity. METHODS: A prospective multicentric randomized trial was initiated to assess the clinical benefit of adding recombinant alpha-2-IFN to combination chemotherapy in patients with metastatic non-small cell lung cancer. A total of 182 patients were randomized to receive either cisplatin-epidoxorubicin-cyclophosphamide (CEP) combination chemotherapy (cisplatin, 60 mg/m2; epidoxorubicin, 50 mg/m2; and cyclophosphamide, 400 mg/m2 intravenously) alone on day 1 or the same chemotherapy plus recombinant alpha-2-IFN at the dose of 5 MU intramuscularly from day -2 to +4, then 3 times weekly. RESULTS: The median survival was 6 months in the CEP plus IFN arm versus 5.5 months in the control arm. The log-rank test showed a marginal statistically significant difference (P = 0.045) in favor of CEP chemotherapy, which disappeared when survival curves were adjusted for prognostic factors. Progression-free survival was similar in the two treatment arms. Considering all eligible patients, the response rate was 7.6% in the CEP arm versus 18.9% in the CEP plus IFN arm (P = 0.042). Nearly 40% of the patients receiving IFN had grade 3-4 nadir leukopenia versus 15% in the control arm (P = 0.01) and 12.5% versus 4.2% had grade 3-4 thrombocytopenia. Apart from the usual constitutional symptoms, IFN was also responsible for increased emesis and mucositis. CONCLUSIONS: This study indicates that the addition of recombinant alpha-IFN to CEP chemotherapy can increase response rate and toxicity to treatment without a positive effect on progression-free survival and survival.

Combination chemotherapy and interferon alpha 2b in the treatment of advanced non-small-cell lung cancer. The Italian Lung Cancer Task Force (FONICAP).

Thirty-four patients with previously untreated advanced non-small-cell lung cancer were treated with a combination of polychemotherapy and recombinant interferon. Chemotherapy consisted of cyclophosphamide, 400 mg/m2, epidoxorubicin, 50 mg/m2, and cisplatin, 40 mg/m2 (CAP) i.v. on day 4; recombinant alpha 2b interferon (r alpha 2b IFN) was given i.m. daily at the dose of 3-5 MU from days 1 to 7. The treatment was repeated every 4 weeks. In the 32 eligible patients the overall response rate was 19.3% (95% C.L. 7.4-37.4%). Non-hematologic toxicity consisted formerly in flulike symptoms and fatigue complained of by 37.5% and 31.2% of patients, respectively, and vomiting reported in 68.7% of patients; grade III-IV myelotoxicity was observed in 12.5% of cases. In no case was the toxicity life threatening. The median overall actuarial survival and progression-free survival were 37 and 20 weeks, respectively. This study indicates that the combination of CAP chemotherapy and r alpha IFN is feasible and active in the treatment of advanced non-small-cell lung cancer.

Chemotherapy/radiation therapy plus/minus lonidamine in the treatment of non-small cell lung cancer (limited disease): preliminary results.

One hundred sixteen patients with unresectable locally advanced non-small cell lung cancer (NSCLC) were accrued in a prospective randomized trial comparing (A), chemotherapy (cisplatin and etoposide [VP-16]) for two courses plus radiation therapy (30 + 20 Gy split course), followed by an additional two courses to (B), the same regimen plus the addition of lonidamine (LND). There were 93 patients evaluable for response (46 in the chemotherapy/radiation arm and 47 in the chemotherapy/radiation/LND arm). One hundred fifteen patients were evaluable for toxicity. The overall response rates, median time to progression, and median survival time were similar in both arms. For the group of patients with squamous cell histology, time to progression was 27 weeks on arm A and 38 weeks on arm B (P = 0.01). Two-year survival in the squamous cell group in arm A was 9%, in arm B, 39%. LND does not give rise to additional toxicity, although myalgia and testicular pain are characteristic side effects.

Plasma carcinoembryonic antigen and tissue polypeptide antigen levels in lung cancer: correlation with cell types and stage.

This investigation was carried out to evaluate the plasma CEA and TPA levels in normal subjects and in 140 patients with lung cancer: 116 patients with nonsmall cell lung cancer (NSCLC) and 24 patients with small cell carcinoma (SCLC). The CEA and TPA levels were determined simultaneously by radioimmunoassay. The cutoff limit of CEA was found to be 17 U/SORIN, and the cutoff of TPA was 99 U/L. TPA has shown a sensitivity almost twice that of CEA. The relationship between the mean values of CEA and TPA and the stages of NSCLC was statistically significant (P less than 0.01), whereas only the mean values of TPA significantly (P less than 0.05) correlated with extensive and limited disease in SCLC. The determinations of combined CEA and TPA levels (CEA X TPA) (P less than 0.001) correlated significantly with the stage of disease in patients with NSCLC; conversely, the use of CEA X TPA did not correlate with the stage of SCLC.