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One hundred nine previously untreated patients with small cell lung cancer were treated for five consecutive days with 20 mg/m2/day of cisplatin and 600 mg/m2/day of 5-fluorouracil. One cycle of chemotherapy was administered every three weeks. The patients received a median number of three cycles. Then they were transferred to CAE chemotherapy. A 77% overall response rate (95% confidence interval of 0.70-0.85) was observed after initial cisplatin-5FU treatment. Twenty-three complete responses (21%) and 62 partial responses (56%) were obtained. In cerebral metastases the response rate was high at 91% (21 out of 23), with 43% complete responses. In the limited forms, statistical survival at 1 year was 25%. A Grade 3-4 thrombocytopaenia was observed in 10 patients (9%) and a Grade 2-3 leukopaenia in four patients. Three patients suffered from a Grade 2 cardiac toxicity. The cisplatin-5-fluorouracil combination demonstrates promising initial response rate in small cell lung cancers. Its main interest is in its important action on cerebral metastases and its moderate haematological toxicity.

Histologically distinct lung tumor and normal cell lines were treated with a variety of potential inhibitors of cell growth such as inducers of cell differentiation, inhibitors of protein kinase C and inhibitors of tumor promotion. The response was assessed by 3H thymidine incorporation and cloning efficiency. Both phorbol retinoate acetate and mezerein stimulated growth in lung normal cell lines (human fibroblastic PEH cells and rat epithelial TP9 cells) while inhibiting growth in lung tumor cell lines (human small-cell cancer-derived cell line IRSC-10M and adenocarcinoma-derived cell line A549). Likewise, the hydrophobic peptide melittin did not inhibit growth and cloning efficiency of normal cells at 1 microM, a concentration which prevented proliferation in tumor cells. Protein kinase C inhibitors, chlorpromazine, trifluoperazine and 1-(5 isoquinolinylsulfonyl) 2-methylpiperazine, were much more effective on proliferation of IRSC-1OM than of A549 cells. In contrast, the latter cells were more susceptible to anti-promoters such as glycyrrhetic acid, an anti-inflammatory agent, and 3,4',2', 4'-tetrahydroxychalcone or 2,3,5-trimethyl-6 (12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone, two inhibitors of lipoxygenase, a key enzyme in arachidonate metabolism. Our results provide evidence that small-cell carcinoma-derived cells, in contrast with adenocarcinoma-derived cells, are growth-inhibited by protein kinase C inhibitors and poorly dependent on the arachidonate metabolism. This difference in responsiveness suggests that different growth signalling pathways are preferentially triggered in these histologically distinct lung tumor cell lines. As a consequence, the proper susceptibility of tumor cells to phenotype modifiers has to be taken into account in cancer therapy.

Eighteen patients with advanced renal cancer received a combination of IFN alpha 10 x 10(6) U/m2/Day (D) x 5D followed by Interleukin 2 (IL2) 18 x 10(6) UI/m2/D x 5 D. The median follow-up is 10 months. Four partial responses were observed lasting 7 to 13 months (22.2%). The clinical safety was satisfactory. The survival for responding patients is 12 months (median). The safety of treatment is an argument in favour of future trials in an attempt to demonstrate the benefit of combinations of biomodulators.

Palliative chemotherapy in cases of epidermoid bronchogenic carcinoma, initially judged to be inoperable, made it possible to perform operative resection in 50 cases. An association of cis-platinum and bleomycin was used, this combination having previously been considered synergistic. In certain cases the tumour seemed to have disappeared on macroscopic examination of the resected specimen, and in some instances no tumoral cells could be found on histological examination. This series brought out several positive features: chemotherapy made it possible to operate on patients previously judged to be inoperable; it ensured maximum local efficiency of drugs because of the absence of abnormal vascularity; and it made it possible to anticipate the cure of occult metastases. However, three negative aspects were also present: modification of postoperative TNM classification making it difficult to establish a prognosis; difficulty in determining therapeutic strategy for pNo; and inadequate long-term follow-up. On the whole the positive points appeared to outweigh the negative aspects, but a randomized study is necessary to confirm this.

Two hundred and fifty-eight patients with small cell carcinoma and 185 patients with adenocarcinoma were centrally randomized to receive either cyclophosphamide (1000 mg/m2 every 3 weeks) iv or cyclophosphamide (700 mg/m2 every 3 weeks) iv plus CCNU (70 mg/m2 every 6 weeks) orally. Those patients who were initially treated with the single agent were then treated with CCNU (130 mg/m2 every 6 weeks) at the time of cyclophosphamide failure. Objective tumor regression occurred more frequently with the combination regimen in patients with small cell carcinoma (43% vs 22%, P = 0.002), but no difference in response rates was apparent in patients with adenocarcinoma. In both cell types patients survived somewhat longer following treatment with the combination. The overall incidence of severe toxicity was equal for the two regimens in both cell types; however, the therapeutic index of the combination was superior to that of the single agent in small cell carcinoma. Severe drug toxicity was more frequent in small cell carcinoma patients with extensive disease, and survival was reduced in both cell types with extensive disease. Survival was better for ambulatory patients in both cell types and women survived longer than men. In women with small cell carcinoma, ambulatory status also was associated with a higher incidence of tumor regression. In patients with small cell carcinoma those who had prior lung surgery survived longer than those without prior surgery. Previous radiation therapy was associated with a reduced incidence of objective regression in men with small cell carcinoma. In both cell types patients with tumor regression lived longer than nonresponders; however, objective disease stability was associated with improved survival only in patients with adenocarcinoma. Stratification in future studies should consider extent of disease, performance status, sex, and prior therapy.

The action of piroxicam, an inhibitor of prostaglandin synthesis, was evaluated in 31 cases of measurable pulmonary metastases of several primary cancers. In each case, the spontaneous doubling time was measured prior to and after a minimum of 3 months of treatment with piroxicam as a single drug, 20 mg daily po. The doubling time of metastatic lung nodules was significantly increased in 18/31 cases (58%) of which 10 cases had their spontaneous doubling time multiplied by two. Minor regressions were observed in 5/31 cases (16%) and one case of metastatic fibrosarcoma had a complete radiologic response. No effect was observed in 8/31 cases (26%). Prostaglandin synthesis inhibitors may be useful for treating metastatic cancer. Possible mechanisms of action are discussed.

After irradiation of locally unresectable epidermoid bronchial carcinoma, 1 year of chemotherapy is significantly superior in delaying both local recurrences and distant metastases and prolonging the disease-free interval. However, BCG immunotherapy alone seems to be superior in terms of survival to no therapy, chemotherapy, and immunochemotherapy. This could be due to a better tolerance to secondary treatments given at time of recurrence.

Variations in the dimensions of 65 bronchogenic epidermoid tumors of known spontaneous doubling time were studied under the influence of four chemotherapeutic regimens: cyclophosphamide, 19 cases; Mitomycin C, 20 cases; CCNU, 9 cases; and a five-drug combination, 17 cases. Several parameters were measured, and escape was defined as the moment in time when the growth curve during treatment became parallel to the spontaneous growth curve. The parameters measured were nature and distribution of responses (unchanged progression, slowing-down, plateau, regression), duration of response, time required to achieve maximum response, and time lapse between maximum response and escape. Regarding application to lung cancer, we have concluded from out results that Mitomycin C should replace cyclophosphamide in combination chemotherapeutic regimens. With regard to general strategy, our results suggest that the drug regimen should be changed as soon as maximum response is reached or immediately following the first course if progression continues unchanged. Moreover, in all of the 27 patients whose tumors regressed, escape occurred within less than three months from the onset of the treatment. In view of this fact and insofar as chemotherapy is considered for adjuvant therapy aiming at complete eradication, sequential combinations would be preferable to prolonged administration of a single agent or combination.