Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine.

BACKGROUND: The modest improvement in median survival of advanced non-small-cell lung cancer (NSCLC) by cisplatin-based chemotherapy has led to the current opinion that clinical benefit for the patient is at least as important an end-point as objective response rate (ORR) or survival. Clinical benefit response was the primary end-point of this prospective randomised trial in symptomatic, advanced stage IIIB/IV NSCLC, comparing single agent gemcitabine (GEM) to cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m2, days 1, 8 and 15) or cisplatin (100 mg/M2, day 1) plus Vindesine (3 mg/m2, days 1 and 15) (PV), both every four weeks. Clinical benefit was measured by a simple metric based on changes in a visual analogue symptom score list, the Karnofsky performance status and the weight. RESULTS: One hundred sixty-nine patients were randomised (84 GEM, 85 PV). Prognostic factors and baseline symptoms were well balanced between the two arms. Most of the the objective responders and about half of the patients with disease stabilisation experienced clinical benefit. Compared to PV, a significantly larger number of GEM-treated patients experienced a clinical benefit (48.1 vs. 28.9%, P = 0.03) that lasted significantly longer (median duration 16 vs. 10 weeks, P = 0.01). No important differences in ORR, time-to-progression or median survival were observed. Grade 3 + 4 toxicity was significantly higher in the PV-group for leukopenia (P = 0.0003), neutropenia (P < 0.0001), nausea/vomiting (P = 0.0006), alopecia (P < 0.0001), and neurotoxicity (P = 0.04). Some severe pulmonary toxicity to GEM was noted. CONCLUSION: Comparison of GEM with cisplatin-based therapy in symptomatic, advanced NSCLC demonstrates that GEM produces significantly a stronger and longer-lasting clinical benefit, probably due to its equal effectiveness in terms of ORR, time-to-progression or survival, combined with significantly less severe therapy-related toxicity.

Combination chemotherapy with vindesine-ifosfamide-cisplatin (VIP) in locally advanced unresectable stage III and in stage IV non-small cell lung cancer: a phase II trial.

UNLABELLED: The efficacy and toxicity of a regimen adding ifosfamide to the more classical cisplatin-vindesine combination was studied in patients with advanced non-small cell lung cancer. Sixty-four good performance patients with inoperable stage III or stage IV were treated with VIP: vindesine 3 mg/m2 days 1 and 8, ifosfamide 1200 mg/m2 and platinum 30 mg/m2 days 1, 2 and 3, repeated every 4 weeks, up to a maximum of six cycles. Response rate, clinical data and radiological tests were rigourously reviewed by a panel. Overall response rate was 39% (95% confidence interval, 27%-51%) with three patients achieving a complete response; response rate in stage III was 48%. Median survival was 9 months. Toxicity consisted mainly of bone marrow toxicity and nausea/vomiting, but was manageable. There was no renal toxicity greater than grade 2, four severe infections, but no treatment-related deaths. CONCLUSION: VIP as mentioned above is very active in good performance patients with advanced non-small cell lung cancer. Its activity, together with its manageable toxicity--without severe renal or pulmonary toxicity--makes it an attractive candidate for induction chemotherapy.

Immunological alterations induced by adjuvant treatment of postoperative colon carcinoma Duke's B or C with levamisole in combination with 5-FU.

BACKGROUND: Postoperative 5-FU combined with levamisole increases 5 year survival in colon cancer patients (Duke C) by 30% (1). In order to investigate the potential immunological mechanism, we determined lymphocyte subtypes and markers of immune activation in 22 patients before and during one year of postoperative adjuvant treatment. METHODS: Before and regularly during treatment, according to the scheme described by Moertel (1), major lymphocyte subsets were quantified by flow cytometry. Serum neopterin, soluble IL2-receptors, beta 2-microglobulin, TNF-alpha and interferon-gamma were determined by Elisa. RESULTS: The CD4/CD8 ratio increased significantly after levamisole was added to the treatment, as did the levels of soluble IL2-receptors. The percentages of T-cells expressing the interleukin 2 receptor followed a similar trend. The levels of neopterin tended to decrease during the combined treatment course. This was paralleled by a progressive fall in the proportion of T-cells expressing HLA-DR. CONCLUSIONS: The treatment induced significant and consistent alterations in major immunological mediators and lymphocyte subtypes. It remains to be established whether these changes are related to the therapeutic effect.

Phase I trial of erbulozole (R55104).

Erbulozole (R55 104) is a water soluble congener of the microtubule inhibitor tubulozole, which has proven to possess anti-invasive, antitumoral and radiosensitizing capacities. A dose-finding study was performed on respectively 9 patients (every three weeks; doses ranging from 20 mg/m2 to 100 mg/m2; maximum 2 cycles per patient) and 6 patients (weekly; doses ranging from 20 mg/m2 to 50 mg/m2; maximum 60 cycles per patient). At all dosages, hematological and biochemical toxicity was very limited. Seven patients complained of pain at the tumor site (grade I to III). Dose limiting toxicity appeared at respectively 100 mg/m2 (one administration every three weeks) and 50 mg/m2 (weekly administration). At this level, 2 patients displayed a dose-limiting Wernicke's encephalopathy-like syndrome. Other secondary effects were headache, fever, exacerbation of dyspnea and moderate nausea and vomiting.

Levamisole in the treatment of cancer: anything new? (Review).

Recently, levamisole combined with 5-FU was shown definitively to increase the survival of patients after surgery for colon cancer (9, 10). In the light of these findings the experimental and clinical findings with levamisole in the field of oncology are reviewed. The conclusion is reached that levamisole has proven activity, although its mechanism of action remains elusive. The progress that has been made in our understanding of immunology in general, the remarkable advance in experimental and diagnostic tools and the recent emergence of new indications of levamisole's interaction with immunosuppressive factors and interleukins all together warrant sufficient optimism to engage in a renewed clinical and experimental research effort. The outcome may be rewarding not only in terms of optimised treatment of patients with levamisole but also a more rational search for more potent successors may become feasible.

The effects of short-term treatment with levamisole on cytokines in volunteers and cancer-patients.

In search for clues to the potential immunomodulating mechanism of action of levamisole which might be used as monitoring parameters, we have determined a variety of cytokines in the peripheral blood of volunteers and carcinoma patients before and after a single or a 3-day-treatment with 150 mg/day. In cancer patients no changes could be detected 4 days after a 3-day-treatment course in the levels of TNF-alpha, IL-1beta, IL-2 or IL-6. In a placebo-controlled volunteer study the same treatment did not affect the levels of beta2-microglobulin, IL-1beta, IL-1alpha, IL-2 or IL-6. However, 24hr after the last treatment the concentration of neopterin was slightly but significantly increased and the concentration of soluble IL-2 receptors decreased. A single treatment failed to produce such an effect. It is suggested that the measurement of neopterin and soluble IL-2 receptors may provide useful information in future trials.