Gabriele Tancini

Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles.

We report the 5-yr results of a prospective randomized study comparing 12 versus 6 cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) with the aim to evaluate the possibility of reducing the duration of adjuvant treatment without compromising the therapeutic effect of the multimodal approach. At 5-yr from mastectomy, both relapse-free survival (CMF 12: 59%; CMF 6: 65.6%) and total survival (CMF 12: 72.7%; CMF 6: 76.9%) were not significantly different in the two treatment groups. Within the two series, no difference was detected between pre- and postmenopausal patients (CMF 12: 59.3% versus 57.6%; CMF 6: 66.5% versus 63.1%), while findings were inversely related to the number of involved axillary nodes. The analysis of relapse-free survival confirmed that in both menopausal groups, relapse-free survival was not significantly affected by estrogen receptor status. Acute toxic manifestations were moderate and reversible. In particular, no drug-induced leukemia nor increased incidence of solid tumors other than breast cancer were documented in this series. Present results after 12 CMF cycles are almost identical to those of our first CMF adjuvant study. Current findings are sufficiently mature to indicate that the maximum tumor cytoreduction with CMF occurs within a relatively short period of time. To improve the results achieved with a single multidrug regimen, more intensive forms of treatment, i.e., utilizing non-cross-resistant combinations, warrant careful evaluation.

Increased Survival Time in Brain Glioblastomas by a Radioneuroendocrine Strategy with Radiotherapy plus Melatonin Compared to Radiotherapy Alone

The prognosis of brain glioblastoma is still very poor and the median survival time is generally less than 6 months. At present, no chemotherapy has appeared to influence its prognosis. On the other hand, recent advances in brain tumor biology have suggested that brain tumor growth is at least in part under a neuroendocrine control, mainly realized by opioid peptides and pineal substances. On this basis, we evaluated the influence of a concomitant administration of the pineal hormone melatonin (MLT) in patients with glioblastoma treated with radical or adjuvant radiotherapy (RT). The study included 30 patients with glioblastoma, who were randomized to receive RT alone (60 Gy) or RT plus MLT (20 mg/daily orally) until disease progression. Both the survival curve and the percent of survival at 1 year were significantly higher in patients treated with RT plus MLT than in those receiving RT alone (6/14 vs. 1/16). Moreover, RT or steroid therapy-related toxicities were lower in patients concomitantly treated with MLT. This preliminary study suggests that a radioneuroendocrine approach with RT plus the pineal hormone MLT may prolong the survival time and improve the quality of life of patients affected by glioblastoma.

Second malignancies after CMF for resectable breast cancer.

From June 1973 to May 1978, a total of 845 women with resectable breast cancer and positive axillary nodes were entered into two consecutive randomized studies evaluating adjuvant chemotherapy. All patients were subjected to radical or modified radical mastectomy, none received postoperative radiation, and 666 were administered adjuvant CMF (cyclophosphamide, methotrexate, and fluorouracil). After a median follow-up in excess of 10 years, no cases of acute nonlymphocytic leukemia were detected, but 21 second solid tumors other than contralateral breast carcinoma were documented. The cumulative frequency was 4% +/- 1.9% after surgery alone, and 4.2% +/- 1.03% following adjuvant CMF. No differences were observed between patients aged up to 50 years (surgery, 3.1% +/- 2.2%; CMF, 3.3% +/- 1.3%) or older than 50 years (surgery, 4.5% +/- 2.6%; CMF, 5.2% +/- 1.8%). During the same period, a total of 29 contralateral breast carcinomas were documented for a cumulative frequency of 3.7% +/- 1.7% after surgery alone and of 5.2% +/- 1.4% following adjuvant CMF, respectively. We conclude that, at present, there is no evidence for an increased risk of second malignancies following adjuvant CMF as given in this series. Our findings would suggest that second tumors documented so far cannot be entirely ascribed to treatment with adjuvant chemotherapy, but they could be due to a chance association.

A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates

Chemotherapy with 5-fluorouracil (5-FU) and folates represents the first-line standard therapy for metastatic colorectal cancer, whereas at present there is no conventional second-time treatment. Because of its importance in generating an effective anticancer immune response, interleukin-2 (IL-2) could constitute a new promising therapy of advanced colon cancer. Generally, IL-2 may determine tumor regressions in colon cancer only when it is given at high toxic doses. Our preliminary studies have shown that the pineal hormone melatonin may amplify IL-2 activity, which becomes active also at low doses in several tumor histotypes. On the basis, we have performed a clinical trial to evaluate the impact of low-dose IL-2 plus melatonin on the survival time in metastatic colon cancer, which progressed in response to 5-FU plus folates. The study included 50 metastatic colorectal cancer patients, who did not respond or progressed after initial response to first-line chemotherapy with 5-FU and folates. Patients were randomized to receive supportive care alone or low-dose subcutaneous IL-2 (3 million IU/day for 6 days/week for 4 weeks) plus melatonin (40 mg/day orally). No spontaneous tumor regression occurred in patients receiving supportive care alone. A partial response was achieved in 3/25 patients treated with immunotherapy. Percent survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with supportive care alone (9/25 vs. 3/25, p < 0.05). This study suggests that low-dose subcutaneous IL-2 plus melatonin may be effective as a second-line therapy to induce tumor regression and to prolong percent survival at 1 year in metastatic colorectal cancer patients progressing under 5-FU and folates.

Salvage treatment of patients suffering relapse after adjuvant CMF chemotherapy

The efficacy of salvage treatments in 243 patients with operable breast cancer and positive axillary nodes who failed during or after adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and fluorouracil) was analyzed. Results were compared with those achieved in 100 patients who had relapses after radical mastectomy alone (control group). Salvage treatments consisted primarily of endocrine therapy (castration in premenopausal patients and tamoxifen in postmenopausal women) and chemotherapy (CMF or Adriamycin [doxorubicin] regimens). In 20 patients, however, first salvage treatment consisted of local therapy only (i.e., radiation therapy with or without surgery). In women previously treated with adjuvant CMF, complete plus partial remissions after first salvage treatment were 37% with a median duration of 17 months. In the control group, the response rate was 43% with a median duration of 16 months. The findings also indicated that drug‐induced amenorrhea did not lower the objective response to salvage castration. In patients failing with a disease‐free interval in excess of 12 months from end of adjuvant CMF, retreatment with the same combination was able to induce remission in 52% of the patients. Current data, derived from prospective controlled studies, confirm that, despite relatively high remission rates, all forms of salvage treatment failed to provide, in unselected cases, long‐term control of relapsed breast cancer. Most important, prior adjuvant chemotherapy with CMF did not adversely affect results compared to concomitant controls.

A Study of the Mechanisms Involved in the Immunostimulatory Action of the Pineal Hormone in Cancer Patients

The mechanisms responsible for the immunostimulatory role of the pineal hormone melatonin (MLT) are still obscure. To investigate the influence of MLT on interleukin-2 (IL-2)-induced immune effects in cancer, we compared the results obtained in 14 cancer patients treated with IL-2 (6 x 10(6) IU/day s.c. for 5 days/week for 4 weeks) plus MLT (10 mg/day orally) with those seen in 14 patients treated with IL-2 alone and with those obtained from 14 other patients treated with MLT only. All patients were affected by metastatic solid neoplasms. The increase in the mean number of lymphocytes, T lymphocytes, natural killer cells, CD25-positive cells and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those receiving IL-2 alone. On the contrary, the increase in mean serum levels of the macrophage marker neopterin was significantly higher in patients treated with IL-2 alone than in those treated with IL-2 plus MLT. Finally, MLT alone has no significant effect on immune cell mean number and on neopterin secretion. These results would suggest that the immunostimulatory action of MLT requires the concomitant presence of IL-2 and that two of the main target cells for MLT activity in humans are represented by T helper lymphocytes of type 2, which are involved in IL-2-induced eosinophilia by the release of IL-5, and macrophages, which may inhibit IL-2-dependent immune functions.

A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer

Aims and Background The theraputic role of chemotherapy in advanced non-small cell lung cancer (NSCLC) is controversial because of its potentially detrimental action on host anticancer defenses. On the contrary, IL-2 would seem to prolong survival time by improving the immune status, even though it is generally less effective in determining tumor regression in NSCLC. Our previous studies have suggested the possibility of increasing tumor sensitivity to IL-2 by concomitant administration of immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On this basis, a study was carried out to evaluate the efficacy of immunotherapy with low-dose IL-2 plus MLT versus chemotherapy in advanced NSCLC. Methods The study included 60 patients with locally advanced or metastatic NSCLC, who were randomized to receive immunotherapy or chemotherapy. The immunotherapy consisted of IL-2 (3 million IU/day subcutaneously for 6 days/week for 4 weeks) and MLT (40 mg/day orally every day, starting 7 days before IL-2); in nonprogressing patients, a second cycle was repeated after a 21-day rest period, then they underwent a maintenance period consisting of one week of therapy every month until progression. Chemotherapy consisted of cisplatin (20 mg/m2) and etoposide (100 mg/m2)/day intravenously for 3 days; cycles of chemotherapy were repeated every 21 days until progression. Results No complete response was obtained. A partial response was achieved in 7/29 patients treated with chemotherapy and in 6/31 patients receiving chemotherapy. The difference was not significant. In contrast, the mean progression-free period and the percentage survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with chemotherapy. Toxicity was substantially lower in patients receiving immunotherapy than in those given chemotherapy. Conclusions This randomized study showed that immunotherapy with low-dose IL-2 plus MLT is a better tolerated and more effective therapy in terms of survival time than chemotherapy containing cisplatin in patients affected by advanced NSCLC.

Randomized Study with the Pineal Hormone Melatonin versus Supportive Care Alone in Advanced Nonsmall Cell Lung Cancer Resistant to a First-Line Chemotherapy Containing Cisplatin

At present, there is no effective medical therapy in metastatic nonsmall cell (NSC) lung cancer patients who progressed under a first-line chemotherapy containing cisplatin. Since recent data have demonstrated the antineoplastic properties and the lack of toxicity of the pineal hormone melatonin (MLT), a randomized study was designed to evaluate the influence of an MLT treatment (10 mg/day orally at 7.00 p.m.) on the survival time at 1 year from the progression under chemotherapy in respect to supportive care alone in a group of metastatic NSC lung cancer patients, who did not respond to a first-line chemotherapy containing cisplatin. The study includes 63 consecutive metastatic NSC lung cancer patients, who were randomized to receive MLT (n = 31) or supportive care alone (n = 32). The percentage of both stabilizations of disease and survival at 1 year was significantly higher in patients treated with MLT than in those treated only with supportive care. No drug-related toxicity was seen in patients treated with MLT, who, on the contrary, showed a significant improvement in performance status. This randomized study shows that the pineal hormone MLT may be successfully administered to prolong the survival time in metastatic NSC lung cancer patients who progressed under a first-line chemotherapy with cisplatin, for whom no other effective therapy is available up to now.

Prognostic factors of the clinical response to subcutaneous immunotherapy with interleukin-2 alone in patients with metastatic renal cell carcinoma

The intravenous immunotherapy with interleukin 2 (IL-2) represents one of the most active therapies of metastatic renal cell carcinoma (RCC). Recently, it has been demonstrated that IL-2 given subcutaneously in association with interferon alpha (IFN) may determine a response rate in RCC comparable to that obtained with an intravenous route of administration, but with a lower toxicity. Moreover, our previous data have suggested that IFN is not essential for IL-2 efficacy. On the basis of these data, we have designed a protocol of immunotherapy with IL-2 alone given subcutaneously in the treatment of metastatic RCC. The study included 48 consecutive evaluable patients. IL-2 was given at a daily dose of 6 million IU for 5 days/week for 6 consecutive weeks, corresponding to one IL-2 cycle. The overall response rate was 14/48 (29%; CR:1; PR:13). Response rate was significantly higher in nephrectomized than in nonnephrectomized patients, and in patients with a good compared to those with a low performance status. Patients with an interval between the diagnosis of primary renal tumor and of its metastases longer than 1 year did better than those with a lower interval, as did patients with a single metastasis compared to those with multiple metastases, while no significant difference was seen in relation to sex, age and previous IFN therapy. As far as dominant metastasis sites are concerned, patients with liver metastases showed a response rate significantly lower than that seen in patients with metastases in sites other than liver. Toxicity was low in all patients. This study shows that the subcutaneous immunotherapy with IL-2 alone is a well tolerated and effective therapy of metastatic RCC. The evidence of a low PS, disseminated tumor and liver metastases represents the most important negative prognostic factor for the response to therapy.

Clinical Results with the Pineal Hormone Melatonin in Advanced Cancer Resistant to Standard Antitumor Therapies

The pineal hormone melatonin (MLT) is able to exert an oncostatic action. Its possible use in the treatment of human tumors, however, has not yet been investigated. The present study was carried out to evaluate the effects of MLT in patients with metastatic solid tumors resistant to conventional therapies. The study included 54 patients, most of them were affected by lung cancer or colorectal carcinoma. MLT was given intramuscularly at a daily dose of 20 mg at 3.00 p.m. for 2 months; this induction phase was followed by a maintenance period at a dose of 10 mg orally in responder patients or in those with an improvement in performance status (PS). The clinical response was as follows: 1 partial response (cancer of pancreas), 2 minor responses (colon cancer and hepatocarcinoma) and 21 with stable disease. The remaining 30 patients rapidly progressed within the first 2 months of therapy. An evident improvement in PS was achieved in 18 of 54 (33%) cases. These results, by showing an apparent control of the neoplastic growth and an improvement in the quality of life in a reasonable number of cancer patients for whom no other standard therapy is available, would justify further clinical trials to better define the impact of MLT therapy on the survival and quality of life of untreatable advanced cancer patients.