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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. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the jaw (ONJ) has recently been reported as a potentially serious complication of prolonged treatment with intravenous bisphosphonates. We studied its frequency in prostate cancer patients receiving intravenous zoledronate. The medical and dental records of 52 consecutive patients with prostate cancer and bone metastases treated at our institute between January 2002 and October 2005 were reviewed. All patients received intravenous zoledronate 4 mg every 3 or 4 weeks and concomitant conventional prostate cancer treatments. We analysed the association of ONJ with the number of administrations of zoledronate and exposure to chemotherapy. At a median follow-up of 7 months (range 1-41) after the initiation of zoledronate, ONJ occurred in six patients (12%, 95% C.I. 5.4-23.0%). All six ONJ cases occurred after the 9(th) administration of zoledronate. The median number of zoledronate administrations was 17 (range 9-24) and 8 (range 1-32) for patient developing and not developing ONJ, respectively (p =0.02). Chemotherapy with docetaxel was also associated with a strong, but not statistically significant, trend towards increased risk of ONJ (OR 3.8, 95% C.I. 0.4-35.6, p =0.24). The length of exposure to zoledronate was associated with an increased frequency of ONJ in prostate cancer patients. A possible role of chemotherapy with docetaxel as a cofactor for ONJ merits further evaluation.

Purpose: New chemotherapy agents and integrated treatments have improved the prognosis of patients with metastatic colorectal cancer., Methods: From January 2000 to December 2002, 229 consecutive metastatic patients were prospectively followed and their outcomes were analyzed. They were divided initially into four treatment groups: A, palliative chemotherapy for extensive extrahepatic disease with or without hepatic disease (97 patients); B, palliative chemotherapy as in Group A for extensive hepatic disease unlikely to become resectable (36 patients); C, neoadjuvant chemotherapy for potentially resectable liver metastases if responsive to therapy (33 patients); D, immediate surgery for liver metastases (63 patients)., Results: The series was analyzed after a median follow-up of 22.6 months. The median progression-free survival was 9, 7.3, 11.5, and 26 months in Groups A, B, C, and D, respectively. The median overall survival was 20.1, 17.2, 24.8, and >48 months in Groups A, B, C, and D, respectively. The outcome was considered for the 69 patients with metastases confined to the liver (Groups B and C), who were treated initially with chemotherapy. Surgery was performed in 21 patients (5 from Group B, and 16 from Group C) and was R0 in 16. In resected patients, the median progression-free survival was 14.7 months and the median overall survival was 40.5 months. In unresected patients, the median progression-free survival was 7.6 months and the median overall survival was 17.5 months., Conclusions: Neoadjuvant therapy may prolong overall survival in a subset of patients with multiple hepatic metastases. The global impact on progression-free survival is low; less than one-half of the patients resected after chemotherapy are disease-free at three years. However, patients resected after chemotherapy obtained overall survival similar to that of primary surgery, suggesting a positive role for integrated approaches.

Background: Only 10% to 25% of patients with liver metastases from colorectal cancer are suitable for resection. Methods for increasing the resectability of liver metastases are based on specific surgical techniques and neoadjuvant chemotherapy., Methods: We collected retrospective data on patients from various Italian hospitals from 1996 to 2002. Data from colorectal cancer patients with liver metastases treated with oxaliplatin-based neoadjuvant chemotherapy were considered. Analysis focused on patients and treatment description and on longterm survival. We considered 107 patients from 36 Italian hospitals., Results: Of the 105 patients assessable for response, 8.4% achieved a complete response, 70.1% a partial response and 19.6% stable disease. Ninety-nine patients were treated with surgery for liver metastases. A radical resection was achieved in 79% of patients. Median survival time was 42 months. Thirteen patients experienced grade 3-4 hematologic toxicity, and 10 patients had grade 3-4 nonhematologic toxicity. Neurologic toxicity of grade >1 was observed in 21% of patients., Conclusions: Neoadjuvant chemotherapy can be useful to increase the number of liver resections for metastatic colorectal cancer patients. Nevertheless, randomized trials are necessary to confirm this retrospective survey as well as the few single-institution experiences reported so far in the medical literature.

Background: To test safety and activity of 3-weekly doses of docetaxel and a weekly dose of trastuzumab in women with HER2-overexpressing advanced breast cancer., Patients and Methods: Forty-two women, median age 53 years (range 36-73 years), with HER2-overexpressing advanced breast cancer were enrolled in a study of docetaxel, 75 mg/m(2) q3w for 6 cycles, and trastuzumab, 4 mg/kg loading dose, 2 mg/kg weekly thereafter. Thirty-four patients (81%) had visceral metastatic involvement. Thirty-five patients had received prior chemotherapy as part of their treatment: adjuvant/neoadjuvant (26), metastatic (2) and both (7). Thirty-one patients had been previously exposed to an anthracycline and 11 to paclitaxel. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplant., Results: 226 cycles (median 6, range 1-6) were administered. The median delivered dose intensity for docetaxel was 24 mg/m(2)/week (range 16-25 mg/m(2)/week). The intent to treat overall response rate was 67% (95% confidence interval, 52-79%). Median progression-free survival, time to treatment failure, and duration of response were 9, 8 and 12 months, respectively. Symptomatic cardiotoxicity (grade 3) occurred in 1 patient. The most common grade 3/4 toxicity was neutropenia (76% of the patients), although febrile neutropenia did not occur., Conclusions: Three-weekly doses of docetaxel and a weekly dose of trastuzumab is an active and safe combination in patients with HER2-overexpressing advanced breast cancer., (Copyright 2004 S. Karger AG, Basel)

We conducted a pilot phase II trial of trastuzumab administered concurrently with docetaxel in women with HER2-overexpressing advanced breast cancer. Twenty-five women with HER2-positive (3+ by immunohistochemistry = 16, 2+ = 9) metastatic breast cancer received docetaxel (75 mg/m every 3 weeks for 6 cycles) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-three patients (92%) had visceral metastatic involvement. Twenty-three patients had received prior chemotherapy as part of adjuvant (18), metastatic (2), and both (3) treatment. The number of cycles administered was 121 (median 6, range 1-6). Symptomatic cardiotoxicity (GIII) occurred in one patient. The most common grade GIII/IV toxicity was neutropenia (80% of the cycles), although febrile neutropenia did not occur. No other GIII/IV toxicities were observed. Response rate was 70% (1 complete response and 15 partial responses) in 23 evaluable patients. The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity.

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.

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.

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.

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.

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.