Role of interferons in the therapy of melanoma.

The increased incidence of disease, the relative unresponsiveness of advanced tumour to conventional therapies, and high socioeconomic costs make the malignant melanoma an aggressive cancer. During the last decade, several new biological agents have been developed, some of which have shown significant activity in the treatment of disease. However, the impact on the management of melanoma patients is still far from being conclusive. Among biological response modifiers (BRMs), interferons (IFNs) have generated a great deal of interest and have been extensively employed, although incorrectly. IFNs have been used without a specific rationale and at antiproliferative rather than biologically active doses; no extensive laboratory monitoring has been performed. In this paper data available in the current literature are reviewed and the efficacies of the different IFNs, used alone or in combination and in various treatment regimens, are compared in order to understand what is the place of IFNs in the management of patients with metastatic melanoma. Results are encouraging but still disappointing with the most effective treatment, with an overall response rate of 28.5% (10.5% complete responses). However, these results need confirmation. In conclusion, IFN is effective in the therapy of advanced melanoma, but improved response rates are necessary before it may be suitable for general, rather than investigative, use. Alternative biotherapeutical approaches and strategies are suggested.

Treatment of advanced colorectal cancer with mitoxantrone, high dose folinic acid and fluorouracil.

A new combination chemotherapy including mitoxantrone 10 mg/m2 i.v. on day 1 and 5-fluorouracil 400 mg/m2 i.v. plus folinic acid 200 mg/m2 i.v. on days 1-5 was administered every 28 days to 13 patients with locally advanced or metastatic colon (1 case), ractosigmoid colon (4 cases), or rectum (8 cases) carcinoma. The median number of cycles performed was 3 (range, 1-9). No patient achieved complete or partial remission with this regimen, whereas 5 showed a stable disease lasting 3-8 months. Acute toxicity was mild/moderate in intensity and comparable to that reported with the standard 5-fluorouracil + folinic acid combination. Since we observed no major responses in our 13 consecutive patients, we consider that the overall activity of our regimen, at the doses and schedule utilized, was only moderately effective in advanced colorectal carcinoma.

Combination chemotherapy with vinblastine, BCNU and cisplatin in advanced malignant melanoma.

A combination chemotherapy including vinblastine (6 mg/m2 i.v. days 1-2), BCNU (100 mg/m2 i.v. day 3), and cisplatin (50 mg/m2 i.v. day 5) was given as salvage treatment in 46 consecutive, previously treated patients affected by metastatic malignant melanoma. Courses were planned every 4 weeks provided that a complete bone marrow recovery occurred, otherwise they were delayed for 1-2 additional weeks. Objective responses (3 CRs and 10 PRs) were observed in 13/46 (28%) patients; 12 cases had stable disease and 21 patients progressive disease during treatment. Median duration of response was 13 months (range, 5-18), and median survival was 11 months (range, 3-20) for all patients. Nausea and vomiting were the most distressing side effects, whereas a grade I leukopenia caused a delayed treatment in 90% of patients. In conclusion, the combination chemotherapy was moderately toxic and did not seem to give substantially better results than obtained with other reported regimens.

Treatment of resistant non-Hodgkin's lymphomas with cisplatin, etoposide, and bleomycin.

A combination of cisplatin (60 mg/m2 i.v. on day 1), etoposide (100 mg/m2 i.v. on days 1-3) and bleomycin (15 mg i.v. on days 1 and 8) (PEB regimen) was given every 4 weeks as salvage therapy in 10 refractory and 13 relapsing patients with poor-prognosis non-Hodgkin's lymphomas. All but one of these patients had previously been treated with anthracycline-containing combination chemotherapy. We observed 4 complete remissions (CRs) and 4 partial responses (PRs), whereas 3 patients showed only a minor response (MR) and 12 were considered to be induction failures. Therefore, the objective (CR + PR) response rate was 35%. The most frequent side effect was vomiting, registered in all patients despite antiemetic treatment. Hematologic toxicity was of moderate degree, and bone marrow recovery was observed after almost all cycles after a 3-week rest period. Since objective responses were achieved only in relapsing patients, the PEB regimen seemed to be effective in these cases, whereas it was useless in early refractory non-Hodgkin's lymphomas.

Epirubicin in combination chemotherapy in the treatment of advanced stage non-Hodgkin's lymphomas.

From April 1981 to May 1984, 23 patients with advanced non-Hodgkin's lymphomas were treated with CEOP (cyclophosphamide, epirubicin, vincristine, and prednisone) or OEPP (vincristine, epirubicin, procarbazine, and prednisone) combination chemotherapy. CR was achieved in 58% and PR in 31% of the patients, giving an overall response rate of 89%. Nine of 15 (60%) previously untreated patients with unfavorable histology obtained a CR and 5 a PR. Median relapse-free survival was 33 months; median overall survival has not yet been reached, and the probability of survival for CRs was 91% after 54 months of follow-up. Acute toxicity was quite acceptable, and chronic cardiac toxicity was detected in 6 patients only. In conclusion, epirubicin used in combination chemotherapies induced durable remissions and prolonged survivals in advanced non-Hodgkin's lymphomas.

Radiotherapy and combination chemotherapy with carmustine, vincristine, and procarbazine (BVP) in primary brain tumors.

26 patients with astrocytoma grade II-III, and 36 with malignant glioma (astrocytoma grade IV or glioblastoma) were submitted three days after surgery to a cycle of combination chemotherapy, including BCNU, VCR, PCZ (BVP). Eighteen days after surgery, patients received 40 Gy (astrocytoma grade II-III) or 45 Gy (malignant glioma) of megavoltage whole-brain irradiation, with an additional boost to the 'tumor' bed of 20 Gy, delivered in 6 weeks. Vincristine was injected weekly during radiotherapy. At the end of radiotherapy, patients received BVP every 6 weeks for at least 8 cycles or until a recurrence or progressive disease. Performance status of grade 1 or 2 was achieved in 15 (60%) and in 5 (20%), respectively, of patients with astrocytoma grade II-III after 6 months, and in 6 ps. (29%) and in 9 ps. (42%) after 12 months of follow-up. Only 2 (5.5%) and 18 (64%) patients with malignant glioma achieved a performance status of grade 1 or 2 after 6 months, and these proportions are 6% and 35%, respectively, after 12 months. After a 5-year follow-up, 59% of patients with astrocytoma are still alive, with a median survival time of 60+ months, whereas only 4% of patients with malignant glioma are alive, with a median of 11.2 months.

Influence on response to therapy and overall survival of mediastinal involvement by Hodgkin's disease.

To assess the prognostic significance of mediastinal involvement of Hodgkin's disease, 91 patients with stage I to III disease treated at our Institute were reclassified according to size of mediastinal disease and other clinical and therapeutic characteristics. Complete remission (CR) was achieved in 46 of 67 (81%) patients without mediastinal involvement, and in 16 of 17 (94%) patients with small mediastinal masses, but only in 10 of 17 (59%) patients with large masses (P less than 0.05). Twenty-seven of 32 (84%) patients treated with irradiation alone and 26 of 28 (93%) patients treated with combined modality therapy reached a CR, whereas such a result was obtained only in 19 of 31 (61%) patients who received MOPP chemotherapy alone (P less than 0.01). In particular, none of the patients with large masses had a CR when treated with chemotherapy alone, whereas no differences in response to therapy were found between patients with large vs. small or no masses when irradiation or combined treatments were utilized. Since combined treatment seems to reach a high proportion of CR and to prevent extranodal relapse, further randomized clinical trials are needed to decide its routine utilization in patients with poor prognostic factors such as large mediastinal adenopathies.

Combination chemotherapy (CVP or CHOP)- radiotherapy approach in early stage non-Hodgkins's lymphomas.

From January 1978 to December 1980, 42 patients with early stage non-Hodgkin's lymphoma other than of the gastrointestinal tract were treated with radiotherapy and combination chemotherapy. Eighteen patients in stage I were submitted to locally extended-field radiotherapy up to a mean dose of 48 Gy with a Co60 source and, after a 3-week rest period, to 6 cycles of combination chemotherapy. Twenty-four patients in stage II received 3 cycles of combination chemotherapy before and after irradiation, the same as for stage I. Combination chemotherapy consisted of cyclophosphamide, vincristine and prednisone (CVP) for 15 cases with favorable histology (3 NWDL, 1 NPDI, 11 DWDL), whereas it included cyclophosphamide, adriamycin, vincristine and prednisone (CHOP) for 27 cases with unfavorable histology (20 DPDL, 3 DM, 4 DH). Complete remission (CR) was achieved in 35/42 (83%) patients, with a highly significant difference between stage I (100%) and stage II (71%). After 42 months of follow-up, the probability of survival for all patients was 72%. Survival was better for stage I (88%) than for stage II (68%) and for favorable histology (87%) as compared to unfavorable histology (70%). Furthermore, survival was highly influenced by response to therapy. Indeed, actuarial survival rate for CR was 91% as compared to a median survival time of 10.2 months for the remaining patients. Four patients, all with poor histology, relapsed after 5-24 (mean 11) months of CR. Only one of them had an extension in extranodal sites and eventually died, despite the salvage treatment utilized. In our experience, locally extended-field irradiation combined with chemotherapy gave a high proportion of CR and seemed to prevent relapses, particularly in extranodal site.

[Effect of bleomycin on DNA-dependent RNA polymerase purified from normal and neoplastic tissues]. / Effetto della bleomicina sulie RNA polimerasi DNA-dipendenti purificate da tessuti normali e neoplastici.

The effect of bleomycin was investigated using two forms of DNA-dependent RNA polymerase (A and B) purified from normal tissues and experimental tumours in presence either of Mn2+ or Mg2+ and native or denatured homologous DNA. THe results show that the antibiotic inhibits the enzyme activity of both classes, and the degree of inhibition appears to be influenced by the nature of cation, the highest values being reached with Mg2+. Moreover, the denaturation of DNA modify the bleomycin effect significantly. With regard to cellular damage induced by the drug, the data here reported show that there is not a substantial difference between normal and tumour tissues.

Combination chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP) for non-Hodgkin's lymphomas with unfavorable histology: preliminary results.

From January 1978 to June 1979, 29 selected, previously untreated patients with unfavorable histology of non-Hodgkin's lymphomas (12 DPDL, 7 DM, 9 DH and 1 DU) were submitted to the combination chemotherapy CHOP (cyclophosphamide, 750 mg/m2 i.v. on day 1; adriamycin, 50 mg/m2 i.v. on day 1; vincristine, 1.4 mg/m2 i.v. on day 1, and prednisone, 100 mg p.o. on day 1 through 5) every 21 days. Eighteen patients were in early stage (I or II) and 11 of them were also submitted to involved field radiotherapy (60Co), immediately before (stage I) or during (stage II) the chemotherapy, with a mean dosage of 4,500 rad. The remaining 11 patients were in advanced stage (III or IV) of disease and were treated with chemotherapy alone. We obtained 20 complete remissions (68%), 8 partial remissions (28%) and 1 no response (4%) to therapy. Sixteen of 18 patients (89%) in early stages and 4 of 11 patients (36%) in advanced stages achieved a complete remission. The bone marrow toxicity of the chemotherapy was moderate. Nausea, vomiting and diarrhea were frequent but well controlled by the support therapy. The actuarial survival rate of patients, after 18 months of follow-up, is 41% (40% in complete remission). The patients who achieved a complete remission are alive and 65% of them still relapse free. We believe that the combination chemotherapy CHOP improves the complete remission rate as well as the survival of patients with unfavorable histology of non-Hodgkin's lymphomas.