Search

Ifosfamide is one of the best-known alkylating agents. In advanced epithelial ovarian cancer, it has been tested in association with cisplatin, achieving results equal, if not better than cyclophosphamide, with acceptable toxicity. In second-line therapy, it shows remarkable activity, even in patients refractory to cisplatin already treated with cyclophosphamide, with more severe, but always manageable toxicity. In gynecological sarcomas, ifosfamide is, together with doxorubicin, the reference drug for chemotherapy.

It has been demonstrated that breast surgery may induce prolactin (PRL) increase. Because of the potential stimulatory role of PRL on breast cancer cells, its postoperative increase may influence the prognosis of breast cancer patients. This study was performed to evaluate the influence of surgery-induced hyperprolactinemia on recurrence rate in operable breast cancer. The study included 250 consecutive breast cancer patients, clinical stage T1-3 N0-2M0, who were observed for a median follow-up of 72 months. Surgery-induced hyperprolactinemia occurred in 108/250 patients (43%). Irrespectively of node involvement, hormonal receptor, type of surgery and adjuvant therapies, the relapse rate was significantly higher in patients who had no surgery-induced hyperprolactinemia than in those with postoperative PRL increase (64/142 vs. 23/108; p0.001). This difference was also significant in relation to node status (N0:22/63 vs. 5/56, p0.001; N+:42/79 vs. 18/52, p0.05). The present study shows that a surgery-induced rise of PRL, despite its potential stimulation of cancer cell growth, is paradoxically associated with a longer disease-free survival in operable breast carcinoma in both patients with or without axillary node involvement. Moreover, this study suggests that the prognosis of node-negative patients who did not show postoperative hyperprolactinemia tends to be similar to that of patients with node involvement and surgery-induced PRL enhancement. Therefore, the lack of surgery-induced hyperprolactinemia would have to be grouped together with the unfavorable prognostic factors of breast cancer.

Our preliminary studies in humans have shown that the pineal neurohormone melatonin (MLT) may enhance the antitumor activity of IL-2, by confirming the existence of a neuroendocrine control on cytokine effects. On this basis, a study was started to evaluate the influence of a concomitant administration of MLT and low-dose IL-2 in cancer patients, who had progressed during a previous immunotherapy with IL-2 alone. The study included 14 patients with advanced solid tumors (lung 6; kidney 4; stomach 2; liver 1; melanoma 1). IL-2 was given at a daily dose of 3 million IU s.c. for 6 days/week for 4 weeks. MLT was given orally at a daily dose of 40 mg every day, starting 7 days prior to IL-2. Objective tumor regression, consisting of a partial remission (PR), was achieved in 3/14 (21%) patients (lung 1; kidney 1; liver 1). Six other patients had a stable disease (SD), while the remaining 5 cases progressed. PR and SD were associated either with a significantly longer survival at 1 year, or with a significantly higher increase in lymphocyte and eosinophil mean number with respect to the patients with disease progression. This preliminary study suggests that advanced solid neoplasms resistant to IL-2 may become responsive to IL-2 therapy by a concomitant administration of the pineal hormone MLT, which could act by enhancing IL-2 antitumor immune effects and/or by increasing the susceptibility of cancer cells to the cytolysis mediated by IL-2-induced cytotoxic lymphocytes.

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.

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.

It is known that interleukin-2 ( IL -2) plays a fundamental role in the generation of immune cells capable of mediating tumor regression. Since IL -2 may be often re

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.

It has been demonstrated that surgery may induce immunosuppression. This finding could influence the clinical course of surgically treated cancer patients. Moreover, preliminary experimental studies have shown that a preoperative injection of IL-2, whose importance in generating the antitumor immune response is well known, may neutralize surgery-induced immunosuppression. At present, however, it is still unknown whether preoperative IL-2-induced immune improvement in the postoperative period may influence the prognosis of surgically treated cancer patients. The present study was performed to evaluate the prognostic impact of IL-2 presurgical therapy in advanced colorectal cancer patients. The study included 50 colorectal cancer patients, Dukes’ stage D, who were randomized to be treated with or without IL-2 pre-operatively (18 • 106 IU/day subcutaneously for 3 consecutive days). After surgery, all patients underwent chemotherapy with 5-FU and folates until disease progression. Postoperative mean numbers of lymphocytes, T lymphocytes, natural killer cells and activated lymphocytes were significantly higher in IL-2-treated patients than in controls. Moreover, the percent of lymphocytic and/ or eosinophilic tumor infiltration was significantly higher in IL-2 group than in controls. Finally, both survival curve and the percent of survival at 1 year were significantly greater in patients pretreated with IL-2 than in controls. This clinical trial demonstrates that preoperative IL-2-induced neutralization of postoperative lymphocytopenia is associated with a prolonged survival time in advanced colorectal cancer patients.

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.

The production of cytokines involved in platelet generation, including interleukin (IL)-3, IL-6 and IL-11, is stimulated by IL-2. However, the platelet number has been shown to decrease on IL-2 cancer therapy, and this side effect depends on the enhanced peripheral platelet destruction following the activation of the macrophage system by IL-2 itself. Our previous studies showed that IL-2-induced macrophage activation may be counteracted by the pineal hormone melatonin (MLT). On this basis, a pilot study with IL-2 plus MLT was performed to evaluate its influence on the platelet number in cancer patients with persistent thrombocytopenia. The study included 20 advanced solid tumor patients, who received IL-2 at 3 million IU/day s.c. for 6 days/week for 4 weeks in association with MLT (40 mg/day orally). A normalization of the platelet number was achieved in 14/20 (70%) patients. This pilot study shows that the therapy with low-dose IL-2 plus MLT, in addition to its previously described antitumor activity, may also be effective in the treatment of cancer-related thrombocytopenia.

Recent evidence has shown that endocrine tumors are under an endocrine and an immune regulation, and that biotherapies with interferon or the long-acting somatostatin analog octreotide may be effective in the control of tumor growth and clinical symptomatology. Within the biotherapies of tumors, interleukin-2(IL-2) has appeared to play an essential role in the antitumor immune response. Despite its important antitumor role, very few studies have been carried out to investigate the possible use of IL-2 in the treatment of advanced endocrine tumors. Its potential toxicity would represent the main limiting factor for the clinical experiments with IL-2. Our previous studies have shown that the pineal hormone melatonin (MLT) may amplify the antitumor activity of IL-2, either through immunomodulating mechanisms or through a direct cytostatic activity by inhibiting tumor growth factor production. On this basis, we have performed a phase II pilot study with low-dose IL-2 plus MLT in 14 patients with untreatable endocrine tumors because of disseminated disease, lack of response to previous standard biotherapies or chemotherapies, or tumors for whom no effective therapy is available. Thyroid cancers, carcinoid and endodrine pancreatic tumors were the most frequent neoplasms. IL-2 was given at 3 million IU/day s.c. at 8 p.m. for 6 days/week for 4 weeks, corresponding to one cycle. MLT was given orally at 40 mg/day at 8 p.m. every day. In nonprogressed patients, a second cycle was given after a 21-day rest period. Patients were considered as evaluable when they received at least one complete cycle, and 12 patients were fully evaluable. According to WHO criteria, a partial response was achieved in 3/12 (25%) patients (carcinoid tumor: 1; neuroendocrine lung tumor: 1; pancreatic islet cell tumor: 1). Another patient with gastrinoma had a more than 50% reduction of tumor markers. Toxicity was low in all patients. This preliminary study suggests that low-dose IL-2 immunotherapy in association with the pineal hormone MLT may constitute a new well-tolerated and potentially active therapy of untreatable advanced endocrine tumors.

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.

It is known that major surgery may determine immunosuppression. This side effect might have a prognostic significance particularly in cancer patients, in whom the decrease in host defenses during the postoperative period could promote the proliferation of possible micrometastases. Since antitumor immune response is an IL-2-dependent phenomenon, a study was started to evaluate the effects of a preoperative injection of IL-2 on surgery-induced immune changes in cancer patients. The study included 12 colon cancer patients, treated subcutaneously with IL-2 at a dose of 9 x 10(6) IU/m2 twice daily for 3 consecutive days before surgery. Patients underwent surgery within 36 h from IL-2 interruption. The results were compared to those found in a control group of 18 colon cancer patients. Mean number of lymphocytes, T lymphocytes and NK cells significantly decreased after surgery in control patients; on the contrary, no postoperative decrease in immune cells was seen in IL-2 group. No anesthesiologic or surgical complication was seen in patients pretreated with IL-2 before surgery. This preliminary study would suggest that a preoperative therapy with IL-2 is an effective and well tolerated medical approach to neutralize surgery-induced immunosuppression in cancer patients.

It is known that interleukin-2 (IL-2) plays a fundamental role in the generation of immune cells capable of mediating tumor regression. Since IL-2 may be often reduced in patients with disseminated cancer, a pilot study was started to evaluate which relation exists between IL-2 levels and survival in metastatic solid neoplasms. The study included 25 patients with metastatic disease (breast cancer: 12; non-small-cell lung cancer: 13). Serum IL-2 levels were measured by radioimmunoassay on venous blood samples collected before the start of chemotherapy. Breast cancer was treated with weekly epirubicin and lung cancer with cisplatin plus etoposide. Low levels of IL-2 were seen in 10/25 patients. Irrespectively of response to therapy and of dominant metastasis sites, the mean survival time was significantly lower in patients with reduced IL-2 concentrations than in those with normal values. These results would suggest that the evidence of low IL-2 levels negatively influences the clinical course of patients with metastatic solid neoplasms.

Recent observations showed that host may regulate either endocrinologically or immunologically tumor growth and differentiation, perhaps by modulating oncogene expression. Within the endocrine system, the pineal hormone, melatonin, seems to play an important antineoplastic role. To investigate its secretion in relation to tumor growth, we have evaluated the daily serum levels of melatonin in a group of 25 untreated breast cancer patients with a locally limited disease. Tumor cell proliferation was established by measuring Ki-67 labeling rate. As controls, 46 healthy women were considered. Breast cancer patients showed significantly higher mean values of melatonin than controls. Moreover, patients with negative Ki-67 labeling rate had significantly higher levels of the pineal hormone than those with a positive Ki-67 rate. Since tumors with high growth fraction present a worse prognosis, this study would suggest that the relief of an increased melatonin secretion represents a favorable prognostic sign, because of its association with less proliferating breast cancers.

Neoplastic disease affect the immunity in cancer patients. The immune alterations in human neoplasms, however, need to be further defined. The present study was carried out to analyze T lymphocyte subsets in patients with solid tumors. The study included 93 patients suffering from early or metastatic solid neoplasms. T helper and T suppressor subsets were measured on venous blood samples by using flow cytometry and monoclonal antibodies. As controls, 58 healthy subjects were included in the study. The T mean helper/suppressor ratio (CD4/CD8) was significantly lower in metastatic cancer patients with respect to that observed either in controls or in patients without metastases. A low CD4/CD8 ratio was seen in 25 of 93 cancer patients (26.9%), 8 of whom had no metastases, while the other 17 showed a metastatic disease. Within the nonmetastatic group, the decline in the CD4/CD8 ratio was due to increases in the T suppressor subset alone in 7. On the contrary, the percentage of cases with decreased T helper subset was significantly higher in metastatic than in the nonmetastatic patients. The results of this study suggest that the decrease in the CD4/CD8 ratio mainly depends on an increase in T suppressor cells in patients without metastases whereas it is due to a decrease in the T helper subset in most patients with metastatic diseases.