Complete androgen blockade as treatment for advanced prostate cancer: clinical response and side-effects.

Treatment of advanced prostatic cancer is currently based on hormonal manipulation. In 1982 Labrié supported a new concept of hormonal treatment based on complete androgen blockade. The objective of this study was to evaluate the effects of total androgen suppression, achieved by the combination of a LHRH agonist (buserelin) plus a pure anti-androgen (flutamide) in the long-term treatment of advanced prostate cancer. Forty-seven untreated consenting patients with advanced prostatic cancer entered in the study, and 41 of these proved evaluable for response and toxicity. Buserelin and Flutamide were administered three times daily, intranasally and orally respectively, at a dose of 1.2 mg and 750 mg for twelve months. Circulating testosterone levels, regularly measured during the study, were reduced by the treatment to castrated levels. Clinical results are encouraging for the high rate of objective and clinical responses PR + SD = 37 (90%), for its duration (12 months), for the significant improvement of urological symptoms and for the decrease of cancer-related pain, even in cases with detectable bone metastases. Compliance was excellent in all the subjects and no patient was forced to interrupt treatment because of cardiovascular toxicity or severe side-effects, which were limited to occasional loss of libido and potency, hot-flashes, mild diarrhea and nausea.

Melatonin as biological response modifier in cancer patients.

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis. At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes. The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months). We obtained blood samples just before the start of MLT administration and after 30 days of therapy. Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN). We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences (p < 0.05). After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment. Nineteen patients (61%) showed disease progression. The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels. These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types. Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

Gemcitabine plus Epi-doxorubicin as first-line chemotherapy for bladder cancer in advanced or metastatic stage: a phase II.

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.

Creatine kinase isoenzyme BB: a lung cancer associated marker.

We investigated the diagnostic role of creatine kinase isoenzyme BB (CK-BB) in lung cancer. CK-BB was assayed using a radioimmunological system by saturation with Mallinchrodt double antibody 125I labelled (RIA Quant-CPK-BB). Sensitivity was 97% and specificity 90% in 44 cancers (T2-T3), in 36 non-cancers (chronic bronchitis) and in 48 healthy controls. Mean serum CK-BB values for patients with chronic bronchitis (2.64 +/- 1.1 ng/ml) were virtually the same as in normal subjects. Patients with lung cancer had markedly higher serum CK-BB values (9.17 +/- 2.6 ng/ml) than either the control group (healthy subjects) or the chronic bronchitis patients (p less than 0.01). These results lead us to suggest that CK-BB serum determination might prove useful in screening pulmonary disorders. However, further studies are essential to establish: 1) the relationship between serum levels of the isoenzyme and the histology and stage of the neoplastic disease; 2) the relation between CK-BB and the aggressive potential of the neoplastic clone.

Preliminary study on behaviour of atrial natriuretic factor in anthracycline-related cardiac toxicity.

The atrial natriuretic factor (ANF) plays an important role in the pathogenesis of congestive heart failure (CHF), by influencing electrolyte and water balance and by modifying peripheral vascular resistance, thus affecting left ventricular performance. Anthracycline derivatives are glycoside antibiotics, active against a wide spectrum of tumours. It is well known that acute and severe dose-related delayed cardiotoxicity constitutes the major limitation to their optimal use. A total of 26 female patients (mean age 53 years) undergoing monochemotherapy for advanced breast cancer, were studied. 4'-Epidoxorubicin (Epidx) 120 mg/m2 intravenously was administered every three weeks for a total of a mean of 6.6 therapeutic cycles (3 to 10). Left ventricular ejection fraction (LVEF) determined by radionuclide ventriculography and circulating ANF were measured periodically in all patients. Epidx administration was limited at a cumulative dose ranging between 840 and 1200 mg/m2 because of a 25% decrease in LVEF and due to a progressive rising in ANF plasma levels. Furthermore, two patients who presented clinical symptoms of CHF had also significantly increased ANF levels (56 and 49% respectively). The current evidence suggests an important pathophysiological role of ANF in anthracyclinic related CHF. Hopefully measurement of plasma ANF will provide a simple non-invasive method of assessing ventricular dysfunction related to anthracycline cardiac toxicity and might represent an additional objective indicator of the severity of haemodynamic compromise in patients with impaired cardiac function.

Osteocalcin as a biological marker in the therapeutic management of breast cancer bone metastases.

Circulating osteocalcin (BGP), the major noncollagenous bone protein, is elevated in patients with certain metabolic bone disease while its behavior in cancer patients, particularly those with bone metastases, is unclear. We measured circulating BGP in 37 healthy females, in 13 female patients with benign breast disease, and in a group of 51 cancer patients (breast, lung, prostate, and bladder) with and without bone metastases, before and after 4'-epidoxorubicin (4'-Epidx) therapy (4'-Epidx 120 mg/m2 every 3 weeks). Under basal conditions, mean BGP levels of all of these subjects fell within the normal range of 2.0-5.0 ng/ml (mean +/- SD, 4.8 +/- 1.0 ng/ml). In cancer patients without bone metastases BGP levels measured before and after 4'-Epidx therapy were not significantly different (4.4 versus 4.6 ng/ml). Only in breast cancer patients with multiple bone metastases was circulating BGP higher after the onset of antiblastic treatment and through the entire course of therapy, accompanied by bone pain remission and regression of bone lesions (BGP = 6.7 +/- 1.3 ng/ml). Thus an increase in BGP concentration can be considered as a biological marker of recovered osteoblast activity during therapeutically induced stabilization or regression of skeletal metastatic lesions.

Subjective and metabolic effects of clodronate in patients with advanced breast cancer and symptomatic bone metastases.

Twenty postmenopausal women (aged between 46 and 67 years old) with skeletal metastases from breast carcinoma were treated with clodronate 450 mg i.v. daily for 5 days and thereafter with 100 mg i.m. daily for 10 days. All patients received standard hormonal therapy (tamoxifen). Symptomatic pain (evaluated according to a linear analog scale), performance status (according to Karnofsky), serum alkaline phosphatase, serum creatinine and osteocalcin were measured before and after treatment on days 5, 15, 30 and 45. Scanning by radiology were performed pre- and post-therapy. Bone pain was significantly reduced in 15 out of 20 patients. After clodronate treatment the base line value of circulating osteocalcin (3.2 +/- 1.6 ng/ml) showed a significant increase on days 30 and 45 (p less than 0.001). Radiological assessment of bone lesions showed stable disease in 18 patients and progression in two patients. No adverse side effects were observed. These data show that clodronate provided pain relief in 75% of treated patients and the increase in circulating osteocalcin levels can be considered a marker of the stabilization of skeletal metastatic lesions.

Epidoxorubicin and high dose leucovorin plus 5-fluorouracil in advanced gastric cancer: a phase II study.

We conducted a multicentric phase II study on advanced gastric cancer to determine the efficacy and toxicity of treatment with epidoxorubicin (EPI) plus high doses of leucovorin (LV) and 5-fluorouracil (5-FU). Thirty-seven patients with measurable disease were enrolled into the trial and treated with EPI 75 mg/m2 on day 1 and LV 200 mg/m2 plus 5-FU 450 mg/m2 from day 1 to 3, the cycle being repeated every 3-4 weeks from a median of five cycles per patients. The response rate was 49% in 35 evaluable patients, with two complete remissions and 15 partial responses. Median response duration was 12.4 months; median survival for responding patients was 17.3 months, which was significantly longer than 8.7 months for non-responding patients. General toxicity was usually mild, myelotoxicity was moderate and there was no evidence of cardiac toxicity. These results show that EPI-LV-5-FU is an effective regimen for advanced gastric carcinoma. The efficacy of this combination should now be tested as an adjuvant therapy in resectable gastric cancer.

Results of leucovorin and doxifluridine oral regimen in the treatment of metastatic colorectal cancer.

We conducted a multicentric phase II study on advanced colorectal cancer to determine the efficacy and toxicity of oral treatment with leucovorin (LV) plus doxifluridine (5'DFUR), a novel fluoropyrimidine derivative with proven antitumor activity in different experimental models. Thirty-six outpatients with measurable disease entered the trial and received orally LV 20 mg in the morning and in the afternoon, and 2 h later 5'-DFUR 500 mg/m2 every 2 days for 3 months. Thirty-four evaluable patients underwent a total of 408 weeks of treatment. The response rate was 35%, with two complete remissions and 10 partial responses. The median survival of patients who responded to treatment (responders) was 17.1 months (range 4-32), which was significantly longer (p<0.001) than the 6.5 months (range 2-11) of the patients who did not respond (non-responders). Therefore, after 4-8 weeks of treatment, 14 patients (41%) had an improvement in their performance status and/or stabilization of pain. General toxicity was usually mild, myelo and gastrointestinal toxicity were moderate, and there was no evidence of relevant neurological toxicity. These results show that a home therapy with oral LV-5'DFUR is a safe and effective treatment regimen for metastatic colorectal carcinoma.

Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer.

PURPOSE: Since metastatic renal cell carcinoma has a poor prognosis and treatment strategies, including hormone therapy, chemotherapy and immunotherapy, have little impact on the quality of life and global survival statistics, new interest has recently focused on the combination of immuno-chemotherapy using pyrimidine analogues, such as gemcitabine. MATERIALS AND METHODS: In a phase II study 16 patients with metastatic renal cell carcinoma were treated with 1,000 mg./m. gemcitabine intravenously on days 1, 8, 15 and 28 for 6 months, 3 MU (1 MU = 1 x 10(6) IU) interferon (IFN)-alpha intramuscularly 3 times a week and 4.5 million IU interleukin (IL)-2 subcutaneously daily for 5 days a week for 2 consecutive weeks every month for 6 months. Responding and nonprogressing cases were maintained on immunotherapy consisting of IFN-alpha and IL-2 for further 6 months. RESULTS: In 15 evaluable patients overall response rate (1 complete response plus 3 partial response) was 28% while stable disease was achieved in 7 (47%). Median survival duration was 20 months (range, 9 to 26+) and median time to tumor progression was 14 months (6 to 26+). The complete response lasted 24+ months and partial response lasted 16 months. The regimen was well tolerated with only 1 case of neutropenia (WHO grade 3), while anorexia, fatigue and flu-like symptoms were the most common toxicity problems but were never greater than grade 2. CONCLUSIONS: Despite the small sample size, this study demonstrates that gemcitabine combined with standard doses of IFN-alpha and low doses of IL-2 is effective treatment for metastatic renal cell carcinoma. This biotherapy was well tolerated and resulted in an optimum objective response and relatively long-term survival.