Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial.

BACKGROUND: In a previous phase II trial, circadian (chronomodulated) delivery of fluorouracil (5-FU), folinic acid (FA; leucovorin), and oxaliplatin (1-OHP; a new platinum complex with no renal and minor hematologic toxic effects) produced an objective response rate of 58% in 93 patients with metastatic colorectal cancer. PURPOSE: To determine whether chronomodulated drug delivery affects therapeutic activity, we again tested this regimen in another trial in patients with previously untreated metastatic colorectal cancer, this time comparing chronomodulated with constant-rate drug delivery. METHODS: Seven European centers participated in this trial. Ninety-two patients with metastatic colorectal cancer were enrolled and assigned to a treatment schedule by central randomization. Treatment courses consisted of the daily administration of 5-FU (600 mg/m2 per day), FA (300 mg/m2 per day), and 1-OHP (20 mg/m2 per day) for 5 days and were repeated every 21 days (16-day intermission) in ambulatory patients with the use of a programmable in-time pump. Drug delivery was kept constant over a 5-day period in schedule A (47 patients). It was chronomodulated in schedule B (maximum delivery of 5-FU and FA infusions at 0400 hours and maximum delivery of 1-OHP at 1600 hours; 45 patients). A risk of partial chemical inactivation of 1-OHP by its 2-hour exposure to the basic pH of the 5-FU solution in the catheter was documented in schedule A. RESULTS: Severe stomatitis (grade 3 or 4, World Health Organization [WHO] grading system), the dose-limiting toxic effect of 5-FU, occurred in five times as many patients on schedule A than on schedule B (89% versus 18%; chi 2 = 46; P < .001). The cumulative dose-limiting toxicity of schedule B was peripheral sensitive neuropathy (WHO grade 2). This side effect was reversible following 1-OHP withdrawal. Higher doses of 5-FU were administered in schedule B (median: 700 mg/m2 per day) compared with schedule A (median: 500 mg/m2 per day) (P < .0001; Mann-Whitney U test). On schedule B, 24 of 45 patients (53%; 95% confidence interval [CI] = 38%-68%) exhibited an objective response compared with 15 of 47 patients (32%; 95% CI = 18%-46%) on schedule A (chi 2 = 4.3; P = .038). The median progression-free survival was, respectively, 11 and 8 months (P = .19; logrank). The median survival was 19 months (95% CI = 14.8-23.2) on schedule B and 14.9 months (95% CI = 12.1-17.8) on schedule A (P = .03; logrank). CONCLUSION: This ambulatory treatment modality was both more effective and less toxic if drug delivery was chronomodulated rather than constant over time. IMPLICATION: The respective roles of 1-OHP dose and schedule and circadian peak time of drug delivery are being investigated with regard to the high activity of this three-drug, chronomodulated chemotherapeutic regimen.

Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU-LV occurred in

Three years' experience with tropisetron in the control of nausea and vomiting in cisplatin-treated patients.

The efficacy and tolerability of tropisetron in preventing cisplatin-induced nausea and vomiting was studied in 2 open trials and compared with the efficacy and tolerability of metoclopramide plus lorazepam in a randomised crossover trial. In the first study, tropisetron 10mg was administered intravenously over 15 minutes before the cisplatin infusion and a second 10mg dose was given after the 60-minute infusion of cisplatin (greater than 50 mg/m2) in 54 patients with advanced cancers, for a total of 165 courses. Good responses for nausea and vomiting were recorded in 83.0% and 87.9% of courses, respectively, with complete protection from nausea and vomiting in 44.8% and 66.1% of courses, respectively. In the second study in 25 patients whose characteristics and cisplatin schedule were comparable with those of the first study, very similar results were achieved in 104 courses of chemotherapy, despite a reduction in tropisetron dose to a single 5mg intravenous infusion 15 minutes before cisplatin. The efficacies of intravenous tropisetron 5mg and metoclopramide 2 mg/kg plus lorazepam administered 15 minutes before cisplatin in preventing acute and delayed nausea and vomiting were compared in a randomised crossover study involving 20 patients. Tropisetron was significantly superior (p less than 0.001) in controlling both acute and delayed (day 1) symptoms. In all studies, the tolerability of tropisetron was excellent. The most frequent side effect was mild to moderate headache, occurring in 5 to 7% of patients. In conclusion, our experience suggests that tropisetron is an effective and well tolerated antiemetic drug that improves the quality of life of cancer patients administered highly emetogenic chemotherapy regimens.

Melatonin and human cancer.

A number of studies performed in vitro and on experimental animals supported the view that pineal gland inhibits neoplastic growth. Data in humans are scanty and controversial. In the present study we measured serum melatonin (MT), prolactin (PRL) and growth hormone (GH) concentrations, at 08.00 and 24.00, in 132 cancer patients and in 58 healthy control subjects. The patients were stratified according to histology and stage of disease as follows: 30 stage I-II and 45 stage III-IV breast cancer (BC); 39 stage III-IV lung cancer; 18 advanced gastrointestinal (GI) cancer. We also measured MT levels, at the same time-points, in 20 women with primary BC before and after radical mastectomy. Finally, we evaluated the circadian rhythm of serum MT in 18 patients with advanced cancer. On the whole, the patients with advanced tumors showed serum MT levels significantly higher than controls, without any correlation with PRL and GH values. When looking at stage III-IV vs stage I-II BC patients, significantly higher MT levels have been found in the former group. The surgical removal of the primary BC was not associated with any changes in MT values at both time points considered. A highly significant rhythm of serum MT was recorded in advanced cancer patients and the rhythmic parameters were substantially superimposable on those of the control subjects.

Combination chemotherapy with carboplatin and methotrexate in the treatment of advanced urothelial carcinoma. A phase II study.

The activity and toxicity of a carboplatin (300 mg/m2, day 1) and methotrexate (50 mg/m2, days 8 and 15) combination chemotherapy in the treatment of advanced urothelial cancer (UC) was evaluated in the present study. A total of 49 patients entered the study: 44 patients were evaluable for response, and 48 for toxicity. A complete response (CR) was found in 4/44 patients (9.1%) and a partial remission (PR) in 12/44 patients (27.2%) for an overall response rate of 16/44 (36.3%). Stable disease was found in 21/44 patients (47.7%), and progressive disease in 7/44 patients (15.9%). Survival was significantly longer in responding patients than nonresponders (median: 62 weeks vs 50 weeks, P < .05). Hematologic and renal toxicities were mild, thrombocytopenia and leukopenia being the most relevant side effects. The first consecutive 7 patients received methotrexate also on day 22; 5 of them underwent grade III-IV hematologic toxicity, so methotrexate on day 22 was omitted in the subsequent patients. No toxic deaths were reported. CBDCA and MTX combination chemotherapy is well tolerated and moderately active in the treatment of advanced urothelial cancer and may represent a valid alternative to cisplatin-containing regimens in patients with poor performance status and/or impaired renal function.

Third-line chemotherapy with mitomycin C and lonidamine in advanced bladder cancer. Partial response in a patient with skin and lung metastases.

Skin metastases from transitional cell carcinoma are quite rare. The present case report describes the results of a combination of mitomycin C and lonidamine administered as third-line chemotherapy in a patient with pulmonary and skin involvement from bladder cancer. The partial response obtained suggests that further testing should be carried out on the activity of this association in a second-line approach.

Prevention of nausea and vomiting in cisplatin-treated patients by a selective 5-hydroxytryptamine (5-HT3) receptor antagonist, ICS 205-930.

The results of an open study designed to evaluate the prevention of cisplatin-induced emesis by the specific 5-HT3 receptor antagonist ICS 205-930 are reported. Fifty-four cancer patients, treated with diverse chemotherapy regimens, all including cisplatin (greater than = 50 mg/m2), received ICS 205-930 for a total of 165 courses. ICS 205-930 (10 mg) was given i.v. immediately before the cisplatin infusion and a second 10-mg dose was given immediately after. In 109 courses (66%) the patients did not have any vomiting episodes. Nausea was absent in 44.8% of courses. More than 3 vomiting episodes occurred only in 17 (10.4%) courses, and severe nausea only in 11 (6.6%). ICS 205-930 was extremely well tolerated. Mild headache occurred during 7 courses (4.2%) in 4 patients, hypotension during 5 courses (3%) in 3 patients and lipothymia in 2 courses (1.2%) in 2 patients. These results suggest that ICS 205-930 is an effective and well tolerated antiemetic drug in patients receiving cisplatin chemotherapy.

Treatment of advanced colorectal cancer (CRC) in daily practice: results of a survey in two Italian regions, Piemonte and Valle d'Aosta.

AIMS AND BACKGROUND: Colorectal cancer (CRC) is one of the most important health problems in Western countries: it is the fourth cancer in terms of incidence and the second cause of cancer death. Surgery is the main therapeutic choice and there is broad consensus on the role of adjuvant chemotherapy (CT) after resection. Unfortunately, 50% of the patients will relapse and die of the disease. Palliative CT based on 5-fluorouracil (5FU) may induce a 9-48% response rate with a median survival of 11.5 months. At present there is no gold standard for CT In advanced CRC and the situation has become more complicated since the advent of new drugs (Raltitrexed, Irinotecan, Oxaliplatin). The aim of this study was the identification of the different approaches to treatment of advanced CRC among the clinicians (oncologists, radiologists, internal medicine specialists, surgeons) who practice CT. METHODS AND STUDY DESIGN: Forty-six clinicians from two Italian Regions (Piemonte and Valle d'Aosta) were interviewed by telephone. RESULTS: 5FU modulated with Lederfolin according to the classic Machover scheme is the main option in daily practice. More sophisticated therapies are reserved to patients with a good performance status (PS) and are prescribed only in the larger centers. The planned therapies usually consist of six courses. Restaging may be performed after three or six courses. A marked difference has been recorded in the evaluation of a situation of no change (NC): 25.5% of the clinicians evaluate stable disease as a positive result. In the event of disease progression or relapse, 35% of the clinicians do not prescribe second-line CT. In case of further treatment, the options are totally subjective. CONCLUSIONS: A national survey on this issue is necessary under the auspices of AIOM (Associazione Italiana Oncologia Medica) and involving oncologists, epidemiologists and statisticians, in order to define the reasons for variations in therapy in advanced CRC and determine the differences between clinicians of different age, specialization and location. This survey could lead to a definition of guidelines for the treatment of advanced CRC.

Phase II trial of primary radiation therapy and concurrent chemotherapy for patients with locally advanced pancreatic cancer.

OBJECTIVES: Primary chemoradiotherapy for locally advanced pancreatic cancer (LAPC) may improve local control, curative resection rate and long-term survival. We performed a phase II study to evaluate toxicity and activity of primary radiation therapy and concurrent chemotherapy with gemcitabine (GEM) twice weekly in patients (pts) with LAPC. METHODS: From 6/1999 to 6/2003, 23 LAPC pts received GEM 100 mg/m2 twice weekly in the first 15 pts and 50 mg/m2 in the last 8 pts, concurrently with radiotherapy (1.8 Gy/day for a total dose of 45 Gy). RESULTS: The treatment was completed in 19/23 pts. Toxicities: G3-4 hematological toxicity occurred in 35 and 4% respectively; G3 nausea and vomiting and gastrointestinal toxicity in 30%. Clinical benefit was found in 10/18 pts (55%). Overall response: partial response rate 4/18 (22%); stable disease 13/18 (72%); progressive disease 1/18 (6%). Six pts underwent pancreaticoduodenectomy with extended lymphadenectomy (5/6 pts pT3, 1/6 pts microscopic cancer foci, 1/6 N+, 5/6 negative retroperitoneal margin). MEDIAN SURVIVAL: 14 months for the entire group, 12 months for unresected pts, 20 months for resected pts. CONCLUSIONS: The treatment with GEM twice weekly at 50 mg/m2 associated with radiotherapy (45 Gy) is feasible and permits to obtain clinical benefit in a good percentage of pts. Objective response, median survival, and local and systemic control are similar to other studies and need further improvement.

Effect of ethanol infusion on the pituitary-testicular responsiveness to gonadotropin releasing hormone and thyrotropin releasing hormone in normal males and in chronic alcoholics presenting with hypogonadism.

Nine chronic male alcoholics presenting with hypogonadism but without overt liver failure were examined under baseline conditions and after acute injection of gonadotropin releasing hormone (GnRH, 100 micrograms iv) and thyrotropin releasing hormone (TRH, 200 micrograms iv), performed at 60 min of a 3-h infusion of saline and 0.4 g/kg ethanol, respectively. Controls were 10 male adult volunteers examined under the same conditions. Six alcoholics and six controls underwent a third test with the infusion of 0.8 g/kg ethanol. Subjects were hospitalized and the infusion was started after a 48-h period of abstinence from alcohol. Tests were performed in random order at intervals of at least three weeks, always at 15:00 following a standard meal in the morning. Plasma levels of FSH, LH, prolactin (PRL) and testosterone (T) were measured by radioimmunoassay. Significantly higher levels of FSH, LH and PRL, and significantly lower levels of T were recorded in alcoholics vs. controls on plasma samples drawn at about 08:00 for three consecutive days. Ethanol infusion at the dose of 0.4 g/kg did not change the pattern of response to GnRH and TRH of controls and alcoholics. Doubling the alcohol dosage yielded a significant reduction of LH response in normal subjects whereas did not result in a similar effect in alcoholics. The mean LH increment of alcoholics was significantly less than that of normals at all times during saline and infusion of 0.4 g/kg ethanol; significance was not attained when the dose of ethanol was 0.8 g/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenohypophyseal hormone levels in the cerebrospinal fluid of patients with pituitary disease.

Measurement of adenohypophyseal hormones in the cerebrospinal fluid (CSF) was recently proposed as an useful procedure to differentiate pituitary intra and extrasellar tumors. So far, data reported are conflicting. We measured the concentrations of GH, TSH, LH and PRL in CSF and plasma in 30 controls and in 37 patients with various pituitary diseases (18 intrasellar adenomas, 14 extrasellar adenomas and 5 empty sella syndromes). The concentrations of examined hormones in CSF were very low or undetectable in all control subjects. In most patients with pituitary tumors, adenohypophyseal hormones were found to be present in CSF, in great amounts. No significant differences were found between intra and extrasellar tumors. In agreement with recently reported data, no significant correlation was found between GH, TSH, FSH and LH levels in CSF and plasma, while a significant correlation (p less than 0.01) was obtained between CSF and plasma levels of PRL, either in all patients or in those with extrasellar tumors only. All patients bearing an empty sella had PRL detectable in CSF: in 2 cases PRL levels were very high. In conclusion our data do not confirm that measurement of adenohypophyseal hormones in CSF represents an useful screening to differentiate tumors with extrasellar extension. PRL data deserve interest in order to gain understanding of the hormone dynamics between CSF and vascular compartments.

Prolactin and thyrotropin response to thyrotropin-releasing hormone in premenopausal women with fibrocystic disease of the breast.

Plasma PRL, TSH, total and free T4, total and free T3, and 17 beta-estradiol were evaluated in 29 premenopausal women with well-documented fibrocystic disease of the breast and in 29 healthy matched controls. Plasma PRL and TSH dynamics after acute TRH injection (200 micrograms i.v.) were also determined. All hormonal measurements were performed in the follicular phase of the menstrual cycle. Neither patients nor controls showed any thyroid function impairment. Basal plasma levels of the examined hormones were in the normal range in both groups. When considering data pertinent to PRL and TSH secretory patterns after TRH stimulation, no difference was recorded between patients and controls for TSH secretion, evaluated in terms of maximum peak, net (delta) and percent (delta %) increase above the baseline level and integrated area of response. On the contrary, the response of PRL was significantly higher in patients than controls (maximum peak at 20 min, mean +/- SE, 119.9 +/- 14.1 vs. 60.8 +/- 5.5 ng/ml, p less than 0.001; integrated area of response, 5,725 +/- 908 vs. 3,243 +/- 266 ng/ml/120 min, p less than 0.01). The results are compatible with the view that, in most patients with fibrocystic disease of the breast, there are abnormalities in the control of PRL secretion, which lead to enhanced release of the hormone after stimulation. In such cases the control of TSH appears to be operating normally.

Thyroid hormone levels in human breast cyst fluid.

Radioimmunoassayable levels of total and free 3,5,3'-triodothyronine (T3) and thyroxine (T4), thyroid stimulating hormone (TSH), thyroxine binding globulin (TBG) and prolactin (Prl) were measured in a series of samples of breast cyst fluid (BCF) aspirated from 73 pre-menopausal women with gross cystic disease of the breast and in coincidental blood samples. In BCF free T3 and free T4 were consistently higher than in plasma (P less than 0.001) as was also total T3 in the majority of cases (P less than 0.05). Total T4, TBG and Prl were much lower than in plasma (P less than 0.001). TSH was roughly as in plasma. No correlation was found between plasma and BCF values. The results indicate that thyroid hormones may be accumulated in their effective form in the cyst fluid. A highly significant inverse correlation was found between intracystic free T3 and log (Prl). Our data, considered in relation to previous experimental evidence, suggest the possibility that thyroid hormones act at the breast level in concert with Prl. Accumulation of thyroid hormones in BCF could play a role in the development or maintenance of gross cystic disease of the breast or be a mere consequence of the cystic changes.

Relationship between CA 15-3 serum levels and disease extent in predicting overall survival of breast cancer patients with newly diagnosed metastatic disease.

In order to study the relationship between circulating levels of CA 15-3 and the disease extent in predicting survival, we prospectively followed 312 breast cancer (BC) patients, from October 1988 to March 1995, from the time of first relapse. CA 15-3 values were assessed before treatment onset. Disease extent was defined as the percentage of liver or lung involvement and the number of bone segments positive at scintigraphy. The covariates were primary tumour characteristics (T, N and hormone receptor status) and patient characteristics at recurrence (menopause, performance status and age). Higher CA 15-3 serum levels were found in patients with visceral metastases or with pleural effusion. A logistic regression model selected disease extent in liver, lung and bone as independent variables for the determination of abnormal CA 15-3 values. Univariate survival analysis confirmed the positive prognostic influence of low CA 15-3 serum levels, absence of visceral metastases and the presence of only one metastatic site. Multivariate Cox's survival analysis selected disease extent in liver, lung, bone and soft tissue but not level of CA 15-3 as prognostic factors. In conclusion, CA 15-3 is not an independent variable in determining survival, its prognostic role being linked to the disease extent. This association suggests that CA 15-3 may be useful in assessing disease extent when this is not easily assessable.