A high dietary intake of soy products (eg, as in Japan and Singapore) has been associated with a reduction in the incidence of breast cancer in premenopausal women. Phytoestrogens present in soybeans inhibit human breast cancer cell proliferation in vitro and breast cancer development in animal models, but no data exist on the effects of phytoestrogens on histologically normal human breasts. This study examines the effects of dietary soy supplementation on the proliferation rate of premenopausal, histologically normal breast epithelium and the expression of progesterone receptor. Women (n = 48) with benign or malignant breast disease were randomly assigned to receive their normal diet either alone or with a 60-g soy supplement (containing 45 mg isoflavones) taken daily for 14 d. Biopsy samples of normal breasts were labeled with [3H]thymidine to detect the number of cells in S phase and were immunocytochemically stained for the proliferation antigen Ki67. The phytoestrogens genistein, daidzein, equol, enterolactone, and enterodiol were measured in serum samples obtained before and after supplementation. Serum concentrations of the isoflavones genistein and daidzein increased in the soy group at 14 d. Results showed a strong correlation between Ki67 and the thymidine labeling index (r = 0.868, P < or = 0.001). The proliferation rate of breast lobular epithelium significantly increased after 14 d of soy supplementation when both the day of menstrual cycle and the age of patient were accounted for. Progesterone receptor expression increased significantly in the soy group. Short-term dietary soy stimulates breast proliferation; further studies are required to determine whether this is due to estrogen agonist activity and to examine the long-term effects of soy supplementation on the pituitary gland and breast.

A series of meta-analyses of randomised controlled trials raised the question of whether the three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) was more or less effective than optimal-dose single-agent carboplatin for women with advanced ovarian cancer.

Docetaxel is a new antimicrotubule agent that induces a predominantly sensory neuropathy that is mild in most patients. This prospective study was performed to determine if corticosteroid co-medication reduces the incidence and severity of docetaxel-induced neuropathy. Two groups of patients treated with docetaxel in subsequent cohorts were prospectively analyzed for neurotoxicity. Group A consisted of 38 patients with a variety of solid tumors, who were treated in studies before corticosteroid co-medication was recommended, while 49 female patients in group B with metastatic breast cancer were treated after co-medication with corticosteroids was introduced as a routine. Neuropathy was evaluated by a clinical sum-score for symptoms and signs, and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to NCI Common Toxicity Criteria. In 42% of patients of group A and in 65% of patients of group B a mainly mild neuropathy was documented. There was no statistically significant difference in neurotoxicity between group A and B. The cumulative dose of docetaxel showed a significant correlation with post-treatment scores of VPT, sensory sum-score, grade of paresthesias, and grade of neurosensory and neuromotor toxicity. Corticosteroid co-medication does not reduce the development of docetaxel-related neuropathy.

Recently, Granisetron (KYT) was proved to have a strong effect for cisplatin (CDDP)-induced emesis. We compared the effect of KYT for CDDP-induced emesis between two different administration schedules. Forty micrograms/kg of KYT was administered either by 30-minute drip infusion with 100 ml of saline (Group A) or 30-second injection with 10 ml of saline (Group B). We investigated the therapeutic effect of KYT in both group A and Group B by the crossing-over method. After the patients who had a malignant tumor and were going to receive CDDP (over 50 mg/m2) in two courses were selected, KYT was administered by the method of Group A or Group B in a double-blind comparison. The clinical efficacy was at least "effective" in 70% (7/10) of Group A and Group B. The study treatment was considered "useful" in 80% (8/10) of Group A, 90% (9/10) of Group B, and "safe" in 100% of Group A and B. There was no difference between two groups in this respect. The results showed that the slow intravenous injection of KYT also has an excellent antiemetic effect on CDDP-induced emesis and a high degree of safety.

Early phase II study of FK352, a novel adenosine A1 antagonist, in cisplatin-induced nephropathy was conducted at 7 institutions in Niigata. Patients with non-small-cell lung cancer under CVM chemotherapy including cisplatin were enrolled. We evaluated the safety and efficacy of FK352 in comparison with those of mannitol in a randomized open trial. It is suggested that the diuretic effect of FK352 is based on its natriuresis and that the potency is equal to mannitol. In addition, FK352 tended to suppress the increase in urine beta-2 microglobulin, which suggests that FK352 ameliorated the cisplatin-induced tubular damage. No serious adverse event was observed with this drug. In conclusion, it is considered that FK352 shows a diuretic effect based on natriuresis with minimal adverse effect and that it exerts a beneficial effect on the prevention of cisplatin-induced nephropathy.

Nausea and vomiting are significant side effects in bone marrow transplant (BMT) patients who receive high-dose preparative regimens. Higher than conventional ondansetron doses and continuous infusion might improve emetic control, because of the high doses and combinations of chemotherapy (CT) used in this setting. Our objective was to conduct a prospective, randomized study comparing two different administration methods of high-dose ondansetron during a BMT preparative regimen in breast cancer patients. Patients were eligible if they were nonpregnant women over 18 but under 65 years of age, undergoing highly emetogenic CT in preparation for autologous BMT. All patients received ondansetron as an intermittent (INT = 24 mg i.v. q 12 h/day) or continuous intravenous infusion (CIV = 8 mg i.v. loading dose followed by a continuous infusion of 2 mg/h per day). A total of 66 patients were enrolled in the study (n = 34, INT; n = 32, CIV). There was no statistical difference between treatment groups in the worst grade of emesis for the entire study period (P = 0.49). Greater than 90% of all patients were graded as failures (> or = 5 emetic episodes or need for rescue antiemetics). Complete control (no vomiting episodes) and complete plus major control (1-2 emetic episodes) per day ranged from 8% to 85% and 11% to 91%, respectively. There was no significant difference between the treatment arms in: grade of emesis, episodes of vomiting and retching, nausea scores, and mean number of rescue medications administered. There were no differences in efficacy when high-dose ondansetron was given as CIV or INT for the control of nausea and vomiting in breast cancer patients undergoing high-dose CT for autologous BMT. Ondansetron alone was not adequate to provide sustained control of CT-induced nausea and vomiting over the entire 5-day study period. A combination of antiemetics targeting various mechanisms of CT-induced nausea and vomiting may be necessary to improve response rates.

We carried out an open, randomized, phase III, multicenter clinical trial to compare, in neo-adjuvant setting, the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c. recombinant interleukin-2 (rIL-2) in patients with advanced (stage III IV) head and neck squamous-cell carcinoma (HNSCC). Regimen A was the classical Al Sarraf treatment: 100 mg/m2 cisplatin i.v. on day 1 plus 1000 mg m(-2) day(-1) 5-FU on days 1-5 as a continuous infusion. Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c. on days 8-12 and 15-19. Treatment was repeated every 3 weeks for three cycles. A total of 33 patients were enrolled in the study; 30 were evaluable for toxicity and 28 for response. Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients (20%) of group A and 4 (31%) of group B had a complete response, 9 patients (60%) of group A and 6 (46%) of group B had a partial response, with an overall response rate of 12 patients (80%) for group A and 10 patients (77%) for group B. Two patients (13%) of group A and 3 patients (23%) group B had stable disease; 1 patient (7%) of group A had progressive disease. Thus, there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the standard chemotherapy. Both regimens were well tolerated. There were 2 toxic deaths (6.7%), 1 from hematological causes in group A and I from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity, mainly nausea/vomiting and stomatitis, were the most frequent toxicities. The calculated number of patients for the sample has not yet been reached; however, the projection of our present results suggests that it is highly improbable that a clinically significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved.

The population pharmacokinetics and pharmacodynamics of cisplatin (CDDP) were evaluated based on a mixed-effect model using the NONMEM program. Unchanged CDDP in plasma was measured as a biologically active platinum species during CDDP chemotherapy, using high-performance liquid chromatography. Plasma concentration measurements (157) of unchanged CDDP from 26 patients with cancer receiving 80 mg/m2 CDDP by infusion over 2 hours, 3.5 hours, or 4 hours were analyzed according to a one-compartment model. The influences of individual characteristics such as body weight, dose schedule, course, and clinical laboratory values (renal function markers, albumin) on total body clearance (Cl) and volume of distribution (Vd) were examined. In the final pharmacokinetic model, body surface area and dose schedule affected Cl of unchanged CDDP. The Cl of CDDP was increased by 27.3% after the 2-hour infusion schedule compared with Cl after the longer infusions. The Vd was estimated as 13.4 L/m2. The interindividual variability for Cl and Vd and residual variability were 22.9%, 30.9%, and 35.5%, respectively. The relationships between maximum concentration (Cmax) of unchanged CDDP and maximum blood urea nitrogen (BUNmax), or minimum creatinine clearance (ClCr,min) over a 1-month period after CDDP administration were evaluated according to linear, exponential, or maximum response (Emax) models. The linear or Emax model described pharmacodynamics most successfully, with relatively large interindividual variability for both slope and EC50 (more than 25%). Residual variability was 15.3% and 17.1% in BUNmax and Clcrmin, respectively. The population means and interindividual and residual variability of pharmacokinetics and pharmacodynamics of CDDP were evaluated using the NONMEM program. The results of this study show that the population pharmacokinetic and pharmacodynamic approach could be useful to manage CDDP nephrotoxicity using sparse data in a clinical setting.

This randomised controlled multicentre trial evaluated the effectiveness of recombinant human erythropoietin (rhEPO) in preventing anaemia and reducing the need for blood or erythrocyte transfusion in 122 ovarian cancer patients receiving platinum-based chemotherapy. The patients were randomly allocated to receive rhEPO 150 U/kg or 300 U/kg subcutaneously, three times a week, or open control. Patients also received up to 6 cycles of carboplatin or cisplatin, alone or in combination with other cytotoxic agents. Intention-to-treat analysis showed that 39.4% of patients in the control group received at least one blood transfusion, compared with 9.2% of patients treated with rhEPO. Patients treated with rhEPO experienced a significantly longer time to first erythrocyte transfusion than the control group and were less likely to experience nadir haemoglobin levels < 10 g/dl (P < 0.001 and < 0.05, respectively). A haemoglobin decrease < 1 g/dl during the first chemotherapy cycle, as well as a low baseline serum erythropoietin concentration, predicted a low transfusion need in rhEPO-treated patients but not in controls. During the study, 103 patients suffered at least one adverse event, but no serious, and only nine non-serious adverse events were considered possibly related to rhEPO therapy. These results indicate that treatment with rhEPO prevents anaemia, it reduces the need for blood or rhEPO erythrocyte transfusion in patients with ovarian cancer receiving platinum-based chemotherapy, and it is well tolerated. A starting dose of 150 U/kg of rhEPO, three times a week, may be recommended.

This open, comparative, randomized, multicentre equivalence study compared cefepime 2 g bd and imipenem-cilastatin 1 g tds (50 mg/kg/day) as empirical monotherapy for febrile episodes in a homogeneous cohort of cancer patients with short duration neutropenia following chemotherapy for solid tumour, lymphoma or myeloma. The study was conducted in 17 French anti-cancer centres in 1995 and 1996. Response to monotherapy was assessed 7 days after treatment and was based on resolution of fever and signs and symptoms, eradication of pathogens, absence of new infection, relapse, and death of infectious origin, without addition of other antibiotics. Patients were treated for a minimum of 4 days. Of the 400 episodes randomized, 344 (86%) were evaluable for efficacy. Patient characteristics were comparable between treatment groups. Success of monotherapy was observed in 79% of episodes with cefepime and 72% with imipenem-cilastatin (equivalence, P <0.0001). The response rate for microbiologically documented infections was 66% with cefepime and 61% with imipenem-cilastatin (bacteraemic episodes: 63% for cefepime; 44% for imipenem-cilastatin). A second antibiotic (usually a glycopeptide) was added in 20% and 21% of the cases, respectively. Overall, the response to therapy, with or without an additional antibiotic, was 95% (cefepime) and 90% (imipenem-cilastatin). Survival was similar in both groups (95% and 98%, respectively). Cefepime treatment was better tolerated, with 9% of the patients experiencing related intercurrent events compared with 19% in the imipenem-cilastatin group (P = 0.003). Nausea/vomiting was significantly more frequent in the imipenem-cilastatin group (15%) than in the cefepime group (5%; P = 0.001). Cefepime monotherapy was as effective as, and better tolerated than, imipenem-cilastatin in the empirical treatment of fever during short duration neutropenia.

To assess the cardiac effects of two different cumulative doses of adjuvant doxorubicin and radiation therapy (RT) in breast cancer patients.

Preclinical studies have demonstrated that recombinant IFN-alpha (rIFN-alpha) can enhance the tumor associated glycoprotein 72 (TAG-72) on tumors. To determine whether rIFN-alpha could enhance TAG-72 expression in vivo in patients, 15 women with breast cancer were randomized to receive daily injections of rIFN-alpha (3 x 10(6) units/m2 for 14 days) beginning on day 1 (group 1 = 7 patients) or on day 6 (group 2 = 8 patients). On day 3, all patients received a 10-20-mCi tracer dose of 131I-CC49, a high-affinity murine monoclonal antibody reactive against TAG-72, followed by a therapy dose of 60-75 mCi/m2 of 131I-CC49 on day 6. Whole body and single-photon emission computed tomography scans along with whole blood pharmacokinetics were performed following tracer and treatment phases. Hematological toxicity was considerable; reversible grade 3-4 neutropenia and thrombocytopenia was observed in 12 of 15 patients. Twelve of 14 patients tested developed human antimouse antibodies 3-6 weeks after treatment. For group 1 patients, whole blood residence time increased significantly between that predicted from the tracer doses and therapy doses (42.6 +/- 4.7 versus 51.5 +/- 4.8 h, respectively; P < 0.01). The calculated radiation absorbed dose to red marrow from therapy compared to tracer activity was also significantly higher for this group (1.25 +/- 0.35 versus 1. 07 +/- 0.26 cGy/mCi; P < 0.05). Treatment with rIFN-alpha was found to enhance TAG-72 expression in tumors from patients receiving rIFN-alpha (group 1) by 46 +/- 19% (P < 0.05) compared to only 1.3 +/- 0.95% in patients not initially receiving IFN (group 2). The uptake of CC49 in tumors was also significantly increased in rIFN-alpha-treated patients. One partial and two minor tumor responses were seen. In summary, rIFN-alpha treatment altered the pharmacokinetics and tumor uptake of 131I-CC49 in patients at the expense of increased toxicity.

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.

Nausea and vomiting following antineoplastic therapy in patients receiving chemotherapy remains a problem. To prevent nausea and vomiting due to antineoplastic therapy, many types of drugs have been used. Ondansetron and the combination metoclopramide-diphenhydramine have been widely used in children. In this prospective randomized study these drugs were compared both for their efficacy and side-effects in children treated with antineoplastic chemotherapy (with and without cisplatin) the number of chemotherapy courses being equal in both groups. Ondansetron gave complete anti-emetic cover in five of nine courses in patients treated with cisplatin. Metoclopramide-diphenhydramine gave complete anti-emetic cover in one out of nine courses, and 17 out of 23 courses in patients treated without cisplatin. Metoclopramide-diphenhydramine produced side effects in nine courses whereas ondansetron produced side-effects in three courses.

In phase II studies, irinotecan is active in metastatic colorectal cancer, but the overall benefit has not been assessed in a randomised clinical trial.

To test whether use of music as a diversional intervention during high-dose chemotherapy administration would affect perception of nausea and episodes of vomiting.

In this study we compared two methods of granisetron administration. One method was via a drip infusion with 100 ml of normal saline 30 minutes prior to administration of CDDP (Group A). The other method was direct injection of granisetron into the CDDP containing bottle (Group B). By employing a randomized cross-over method, we evaluated the acute response (less than 24 hours) according to Furue's criteria in 34 patients. Each of the patients received more than two cycles of chemotherapy containing more than 50 mg of CDDP. In both arms of the study nausea, vomiting and anorexia showed no difference. Moreover, there was no evidence of toxicity due to granisetron. The overall response rate of granisetron to nausea was 84.4%. We conclude that granisetron is an effective drug as an antiemetic, and the direct injection of granisetron into the CDDP containing bottle has the same effect when compared to the normal method of administration, together with an equivalent safety profile.

47 patients with progressive, painful, predominantly lytic bone metastases from breast cancer were included in a randomised double-blind phase II trial comparing the effects of pamidronate 150 and 300 mg daily. Oral pamidronate produced either sclerosis or stabilisation of lytic metastases for at least 24 weeks in 5 of 24 and 3 of 23 patients at the 300 and 150 mg dose levels, respectively. Evidence of symptomatic improvement was observed in 5 of 22 (23%) and 7 of 22 (32%) patients for symptomatic disease at the respective doses. These improvements were accompanied by a reduction in the rate of bone resorption as shown by suppression (P = < 0.01) of urinary calcium and a non-significant fall in deoxypyridinoline. No obvious differences in efficacy were observed between the two dose levels. Gastrointestinal adverse events, principally comprising nausea and vomiting, were the most commonly reported side-effects leading to discontinuation of trial treatment in 4 of 24 and 2 of 23 patients at 300 and 150 mg dose levels, respectively. The poor tolerability of oral pamidronate coupled with the modest clinical effects reported here suggest that oral pamidronate will not replace the current strategy of regular intravenous infusions of pamidronate for the treatment of osteolytic bone disease.

Oxidative stress is recognized as one of the major contributors of increased risk of cancer. Many recent population studies have established a close link between dietary intake of tomatoes, a major source of the carotenoid antioxidant lycopene, and lowered risk of cancer. A study was conducted on 19 healthy human subjects to evaluate the uptake and in vivo antioxidant properties of lycopene, using a randomized, crossover design. Dietary lycopene was provided by tomato juice, spaghetti sauce, and tomato oleoresin for a period of one week each. Blood samples were collected at the end of each treatment. Serum lycopene was extracted and measured by high-performance liquid chromatography using an absorbance detector. Serum thiobarbituric acid-reactive substances, protein thiols, and 8-oxodeoxyguanosine contents of lymphocyte DNA were assayed to measure lipid, protein, and DNA oxidation. Lycopene was the major carotenoid present in the serum. Dietary supplementation of lycopene resulted in a significant increase in serum lycopene level and diminished amounts of serum thiobarbituric acid-reactive substances. Although not statistically significant, a tendency of lowered protein and DNA oxidation was observed. There was also indication that the lycopene levels increased in a dose-dependent manner in the case of spaghetti sauce and tomato oleoresin. These results indicate that lycopene is readily absorbed from tomato products and may act as an in vivo antioxidant. It may, therefore, play an important role in the prevention of cancer.

For patients with metastatic prostate cancer, treatment is primarily palliative, relying mainly on the suppression of systemic androgen hormone levels. To help document the achievement of palliation and to characterize positive and negative effects of treatment, we evaluated quality-of-life (QOL) parameters in patients with metastatic prostate cancer who were randomly assigned to two methods of androgen deprivation.