Clinical and pharmacokinetic phase II study of pegylated liposomal doxorubicin and vinorelbine in heavily pretreated recurrent ovarian carcinoma.

BACKGROUND: This multicenter phase II study evaluated feasibility, clinical efficacy, toxicity and pharmacokinetics of the combination of pegylated liposomal doxorubicin (PLD) and vinorelbine (VNR) in patients with platinum-paclitaxel pretreated recurrent ovarian cancer. PATIENTS AND METHODS: All patients received prior treatment with platinum and paclitaxel. Thirty-two heavily pretreated (median number of chemotherapy regimens two, range one to six) ovarian cancer patients received treatment with PLD 30 mg/m(2) and VNR 30 mg/m(2) every three weeks for six cycles. Ten patients entered the pharmacokinetic study, five receiving the PLD-VNR and five the VNR-PLD sequence. RESULTS: In 30 patients evaluated for response and toxicity, the overall response rate was 37% and 10% of patients achieved stable disease. Median time to progression and overall survival were 5.5 months (range 1-10) and 9 months (range 2-16), respectively. Toxicity was generally mild and reversible. VNR AUC(tot) and plasma levels were considerably higher in the PLD-VNR sequence. CONCLUSIONS: The PLD-VNR regimen exhibits significant activity in heavily pretreated patients, is well tolerated and is associated with encouraging survival. Preliminary pharmacokinetic results suggest the PLD-VNR sequence for further clinical applications. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.

Ifosfamide in the treatment of head and neck cancer.

Ifosfamide (IFO) has demonstrated activity in recurrent/metastatic squamous cell head and neck carcinoma with an overall response rate of 24-26%. Better results are reported for chemotherapy-naive patients; in heavily pretreated cases results are poor and toxicity unacceptable. Cisplatin-IFO combination in stage III-IV is probably more active than IFO alone (ORR = 60-72 vs. 50%) but is indicated in patients who desire aggressive treatment and are physically able to tolerate the drugs. The carboplatin-IFO scheme is better tolerated than the cisplatin-IFO regimen with superimposable clinical results (ORR = 69%; CR = 15%). Carboplatin-taxol-IFO is one of the most active regimens in recurrent (ORR = 59%; CR = 17%) and in locally advanced (ORR = 81%; CR = 31%) head and neck cancer. Its role in the multidisciplinary treatment of advanced head and neck cancer is under investigation. In recurrent/metastatic undifferentiated nasopharygeal carcinoma, IFO combinations have proven to be effective as first- and second-line treatment.

Update and perspectives on non-surgical treatment of salivary gland malignancies.

Surgery is the treatment of choice for major and minor salivary gland malignancies. Herein, the role of radiation and medical treatment in the multidisciplinary management of salivary gland tumours is discussed. Neutron irradiation and hyperfractionated external beam mega voltage irradiation improve local control. Combination of three dimensional conformal radiotherapy and intensive-modulated radiation therapy provide better local tumour delineation, better field design to encompass the tumour allowing dose escalation to target while sparing the surrounding normal tissue. Cisplatin-based chemotherapy provides a response rate > or = 45%, in a palliative setting. Concomitant chemo-radiotherapy could improve local control. Recent studies evaluated the expression of molecular targets in salivary gland carcinomas (c-kit = 53-90%, EGFR = 25-85%, c-erb-B2 = 11-58%, p53 = 11-67%, H ras = 18%); these targets are very important since new targeted drugs are now available. Anti-androgen therapy might have a role in the management of patients with ductal carcinoma. These new targeted drugs could be integrated with chemotherapy and radiotherapy in the treatment of locally advanced/metastatic salivary gland malignancies.

Multimodal treatment with primary single-agent epirubicin in operable breast cancer: 5-year experience of the Michelangelo Cooperative Group.

BACKGROUND: To assess the efficacy of primary single-agent epirubicin (120 mg/m(2) every 3 weeks for three cycles) in reducing tumor burden in operable breast cancer >or=2.5 cm in largest diameter at diagnosis and its effect on the rate of conservative surgery. PATIENTS AND METHODS: A total of 319 eligible patients, who were all candidates for mastectomy, were enrolled on to a multicenter prospective non-randomized study. Tumor response was assessed clinically and pathologically. Relapse-free and overall survival were assessed on major prognostic variables. RESULTS: After primary epirubicin, complete disappearance of invasive neoplastic cells accounted for only 2.6% of patients, but 40% of patients had their primary tumor downstaged to

Surgery for carcinoma of the gallbladder. Our experience.

BACKGROUND: Carcinoma of the gallbladder is a gastrointestinal malignancy with a very poor prognosis. The 5-year survival rate amounts to less than 5% in most series. In this study we reviewed the results of surgical treatment for gallbladder carcinoma with special reference to extended radical procedures. METHODS: Between 1995 and 2000 we enrolled 36 patients (17 males and 19 females), 24 of whom were treated with simple cholecystectomy and 12 with radical resection (partial hepatectomy, regional lymphadenectomy, and common bile duct resection). The tumours were classified by stage using the criteria of the American Joint Committee on Cancer (AJCC). Stages, operative procedures, results of pathologic examinations and the outcome of the resected cases were reviewed. RESULTS: There were 2 postoperative deaths (0.55%). The mean follow-up period was 19.1 months (range 1-60). For stage I and II disease extended cholecystectomy had a better result than simple cholecystectomy: the 5-year survival rates were 38.4 versus 19%, respectively. For the patients with advanced stage III or IV gallbladder carcinoma, a significant advantage of survival resulted in case of liver resection as compared to surgical treatment without liver resection: the 5-year survival rates were 20 and 0%, respectively. CONCLUSIONS: The survival of stage I-II patients was good. For the patients in higher stages the prognosis was significantly worse. In these cases more aggressive surgery may be needed.

A sequence-dependent combination of docetaxel and vinorelbine: pharmacokinetic interactions.

We studied possible pharmacokinetic interactions between docetaxel (DTX) and vinorelbine (VNR) in patients affected by different types of cancer. Patients with metastatic breast cancer or recurrent head and neck cancer received the following schedules: Protocol A: 11 patients were i.v. infused for 1 h with DTX (80 mg/m2) at once, followed by VNR (25 mg/m2) as slow i.v. bolus; Protocol B: VNR (25 mg/m2) as a slow 10 min i.v. bolus was administered to 12 patients, immediately followed by 1 h i.v. infusion of DTX (80 mg/m2). In both schedules, VNR and DTX plasma concentrations versus time were analysed by HPLC obtaining the corresponding non-compartmental pharmacokinetic parameters. VNR appeared pharmacokinetically affected by the sequential administration of DTX, since with protocol B, Cmax and AUC were significantly higher and clearance lower than in protocol A. Moreover, a significant increase in the VNR plasma level was observed in correspondence with the peak plasma level of DTX. By contrast, Cmax, AUC and clearance of DTX did not vary in the two protocols. Also the number of neutrophils at nadir on day 8 of treatment varied significantly in the two schedules. In conclusion we observed altered pharmacokinetic parameters between protocol A (DTX, VNR) and protocol B (VNR/DTX). In particular, patients following protocol B seemed to be exposed to higher VNR plasma concentration and to higher haematological toxicity.

A preliminary pharmacokinetic study of docetaxel, carboplatin and concurrent radiotherapy for regionally advanced squamous cell carcinoma of the head and neck.

This work investigates the pharmacokinetics and toxicity resulting from the concomitant use of low dose carboplatin (CBCA)/docetaxel (DTX) plus concurrent radiotherapy in patients with head and neck cancer. The study comprised 11 patients with stage III-IV head and neck cancer. All patients received 2 Gy radiotherapy daily, 5 fractions per week, up to a planned total of 70 Gy over 7 weeks. CBCA (AUC 0.4 mg/ml, min/day) was also administrated as 20 min i.v. infusion, starting 1 day before the first radiotherapy fraction. CBCA was administered for 5 consecutive days every 2 weeks (weeks 1, 3, 5 and 7). DTX 30 mg/m2 (1 h i.v. infusion) was given as a single dose on days 10, 24 and 38. CBCA on day 1 and DTX on day 10 were analysed to determine the concentration-time curves during the first 24 h. CBCA Cmax and Cmin in 2-5 days and on day 15 and 29, as well as total plasma platinum on days 2, 3, 4, 5, 29 and 43 were also assayed. By calculating the non-compartmental pharmacokinetic parameters of the two drugs from the available plasma concentrations we found in the first week values similar to those reported in the literature as single agents. In contrast, during subsequent weeks (weeks 3 and 5), a significant and progressive increase of platinum levels was observed. So, it could be assumed that after 2 weeks of CBCA and DTX treatment a bias in dose calculation occurred because the linear relationship between creatinine clearance (used to calculate the expected AUC through the Calvert formula) and CBCA clearance was no longer observed.

Concomitant chemoradiotherapy followed by adjuvant chemotherapy in parotid gland undifferentiated carcinoma.

AIMS AND BACKGROUND: Undifferentiated carcinoma of the parotid gland is a poor-prognosis lesion. Results in unresectable lesions, treated with radiotherapy alone, are very disappointing. METHODS: Six patients with T3-4 N0-1 inoperable lesions were treated with conventional radiotherapy (64-70 Gy, 2 Gy per fraction 5 times a week) and concomitant cisplatin (100 mg/m2, days 1, 22 and 43). Four weeks after radiotherapy, adjuvant chemotherapy (cisplatin, 80 mg/m2, day 1, + VP16, 100 mg/m2, days 1, 3 and 5, q = 3 weeks, for 3 cycles) was given. RESULTS: A median dose of 66 Gy (range, 64-70 Gy) was delivered, and all patients received 3 courses of cisplatin during radiotherapy. Five of 6 patients received all three chemotherapeutic adjuvant courses. Two months after the end of treatment, 3 CR (50%), 2 PR (33%) and 1 NC (16%) was observed. Median CR and PR duration was 26+ and 10 months, respectively. Median overall survival was 18 months. No severe acute or late toxicity was observed. CONCLUSIONS: Concomitant chemoradiotherapy followed by adjuvant chemotherapy in advanced unresectable undifferentiated parotid carcinoma is feasibile and well tolerated. The high percentage of long-lasting CR is encouraging.

Feasibility and long-term results of autologous PBSC transplantation in recurrent undifferentiated nasopharyngeal carcinoma.

BACKGROUND: Recurrent undifferentiated nasopharyngeal carcinoma (UNPC) is a chemosensitive illness. Here we report long-term results of high-dose chemotherapy (HDC) as late intensification, with autologous peripheral blood stem cell (PBSC) support. METHODS: Six patients (5 men, 1 woman; median age 41years; median ECOG PS = 0) with recurrent UNPC (local, 2; local + nodal, 2; bone metastasis, 2) have been enrolled. All patients had been previously treated with neoadjuvant chemotherapy and radiotherapy; 3 of 4 local relapses had received a re-irradiation. Every patient received three courses of cisplatin + epirubicin and 1 cycle of epirubicin followed by PBSC collection. A median of 7.2 x 10(6)/kg (range, 4.5-18) CD34+ cells were reinfused. HDC was according ICE scheme: ifosfamide, 2.5 g/m(2)/d, + carboplatin, 300 mg/m(2)/d, + VP-16, 300 mg/m(2)/d days 1 through 4. RESULTS: After conventional chemotherapy, we had 1 CR (16%), 3 PR (50%), and 2 NC (34%). After HDC, we had 4 CR (66%),1 PR (17%), and 1 MR (17%). Toxicity was manageable. After a median follow-up of 30 months (range, 14-50), two patients are alive without disease (34%), one is alive with bone disease (16%), and three (50%) died of disease at 16, 18, and 24 months. CONCLUSIONS: HDC has an acceptable toxicity, can convert PR in CR, and seems effective, with long-lasting CRs.

Paclitaxel administration on days 1 and 8 every 21 days in anthracycline-pretreated metastatic breast cancer patients. A multicenter phase II trial.

Paclitaxel is now included in second- and even first-line regimens in advanced breast cancer. The optimal dose and schedule of this drug, however, still remain a matter of investigation. A group of 57 consecutive patients with advanced breast cancer previously treated with anthracycline-containing regimens were submitted to treatment with single-agent paclitaxel administered at 130 mg/m2 on days 1 and 8 every 21 days. Of the 57 patients, 56 were fully evaluable, and of these 25 had an absolute anthracycline resistance, 14 a relative resistance and 17 were potentially sensitive. The median age of the patients was 57 years (range 33-71 years), their median performance status was 1 (0-3), and 27 (47%) had liver involvement, 17 (30%) lung involvement, 30 (53%) bone involvement and 15 (26%) skin/lymph node involvement. Toxicity was recorded in 295 cycles. This scheme was well tolerated, the dose-limiting toxicities being hematological and neurological. Grade 3/4 leukopenia was observed in 20% of patients at nadir, while grade 3 leukopenia was observed in 3% of patients at recycle. Only one patient experienced febrile neutropenia. Grade 2/3 neurotoxicity was observed in 26% of patients, leading to drug withdrawal in three. The treatment was given on an outpatient basis in all patients and the median relative dose intensity of 86.6 mg/m2 per week was 100% of the planned dose (range 75-100%). Three patients (5%) attained a complete clinical response and 12 (21%) a partial response for an overall response rate of 26% (95% confidence interval 18-38%), while 30 (53%) attained disease stabilization and 11 progressed (19%). Time to progression in responding patients was 10.3 months, and the median overall survival of the entire population was 15.4 months. To conclude, paclitaxel administration on days 1 and 8 every 21 days was active and manageable in advanced breast cancer patients previously treated with anthracyclines. The response obtained was durable.

Survival in patients with recurrent squamous cell head and neck carcinoma treated with bio-chemotherapy.

BACKGROUND: We have shown that rIL-2 administration in recurrent head and neck cancers induces a tumor-specific T-lymphocyte reactivity and tumor regression; in a pilot study we have shown a safe and effective administration of rIL2 after cisplatin + 5-fluorouracil. Long-term results are not known. METHODS: Thirty patients with recurrent-persistent head and neck cancer were treated with cisplatin (100 mg-m(2)) d.1,5-fluorouracil (1 gr-m(2)-d c.i. 96 h), and SQ rIL-2 (4.5 M IU day 8 to 12 and 15 to 19) every 3 weeks. RESULTS: The overall response rate was 53.3% (95% CI; 34.4-72.3%): 26.6% complete response (CR) (8 patients) and 26.6% partial response (PR) (8 patients); 6 patients had SD (20%), 8 had PD (26.6%). The median follow-up was 36 months (range, 28-44). The median CR duration is 16.2 months (8.5-39+); the median survival duration of this group has not been reached. The median PR duration was 7.2 months (3-10); the median survival was 13.3 months (10-26). The median overall survival was 14 months. CONCLUSIONS: The most impressive finding is the very long survival of CRs patients. This outcome has been reported in other cancer patients with a CR after IL-2 therapy.

Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies.

BACKGROUND: Some previous studies have shown that vinorelbine (VNB) is active in recurrent salivary gland tumors. METHODS: Between April 1993 and April 1997, 36 patients in a Phase II randomized trial received either cisplatin, 80 mg/m(2), on Day 1 plus VNB, 25 mg/m(2), on Days 1 and 8 (every 3 weeks) (for a minimum of 3 cycles (Arm A [16 patients]), or VNB, 30 mg/m(2)/week, (for a minimum of 9 wks) (Arm B [20 patients]). There were 23 males and 13 females with a median age of 59 years (range, 20-74 years) and a median Eastern Cooperative Oncology Group performance status of 1 (range, 0-2). Four patients had been treated with prior surgery (S) or radiotherapy (RT), 27 patients had been treated with S plus RT, and 5 patients had been treated with S plus RT plus mitoxantrone. Eighteen patients had major salivary gland tumors, and 18 patients had minor salivary gland tumors; 9 patients had adenocarcinoma, 22 patients had adenoid cystic carcinoma, 1 patient had a malignant mixed carcinoma, 3 patients had undifferentiated carcinoma, and 1 patient had a mucoepidermoid carcinoma. The site of recurrence was local in 16 patients, local plus metastatic in 5 patients, and metastatic only in 15 patients. These characteristics were well balanced between the 2 arms. RESULTS: In Arms A and B a complete response (CR) was noted in 3 patients (19%) and no patients, respectively; a partial response (PR) was noted in 4 patients (25%) and 4 patients (20%), respectively; no change was noted in 6 patients (37.5%) and 9 patients (45%), respectively; and progressive disease was noted in 3 patients (19%) and 7 patients (35%), respectively. The median duration of the CR was 15+ months (range, 6-27+ months) and for PR the median duration was 7.5 months (range, 3-11+ months) and 6 months (range, 3-9 months) in Arms A and B, respectively. Number of patients surviving > 12 months was 6 versus 1 in Arms A and B, respectively (P < 0.05). Grade 2-3 nausea and emesis was statistically higher (P < 0.001) in Arm A; there was no significant difference with regard to other side-effects between the two treatment arms. CONCLUSIONS: VNB is a drug with moderate activity in salivary gland malignancies. The combination of cisplatin plus VNB was found to be more active than VNB alone, with a good number of CRs and long-term survivors reported in the current study.

Clinical and pharmacokinetic data of a docetaxel-epirubicin combination in metastatic breast cancer.

In order to explore activity and pharmacokinetic data of a docetaxel-epirubicin combination we analyzed a population of 60 metastatic breast cancer patients. All the patients had an ECOG performance status < 3; 41 patients (68%) had visceral metastases as dominant site of disease, including 33% with liver metastases. Three or more involved organs were present in 43% of patients; 35% had received prior hormonotherapy; 10% for metastatic disease. Twenty-five patients (42%) had received prior adjuvant chemotherapy; 15% a CAF regimen. Twenty per cent of patients had less than 12 months disease-free interval. Docetaxel and epirubicin were both given at a dose of 75 mg/m2 i.v. d. 1 every 3 weeks. After a median of six cycles we had 5 CR (8.3%), 40 PR (66.6%), 7 NC (11.6%), and 8 PD (13.3%). Response rates in patients with visceral and liver metastases were 78% and 55% respectively. Premenopausal status, < 1 year disease free survival and > 3 metastatic sites were associated with a lower response rate. After a median follow-up of 19 months (12-36), median disease-free survival is 11 months and median overall survival has not been reached. Grade 4 neutropenia was observed in 75% of courses but with febrile neutropenia in 6.2% of courses only. Non-hematologic toxicity wasn't clinically important. A NYHA class III reversible cardiac failure was observed in one patient (1.6%). The pharmacokinetic evaluation in 16 patients has shown that docetaxel transiently interfered with epirubicin plasma level when docetaxel was administered 1 h after epirubicin.

Low dose adriamycin and ifosfamide in the treatment of advanced adult soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are infrequent tumors (up to 1% of all neoplasms) in adult patients. Treatment of advanced disease is largely unsatisfactory. Only a few drugs are active agents and combination regimens offer limited and short-lived activity. High dose chemotherapy may be administered only to limited groups of patients. PATIENTS AND METHODS: We evaluated, in a phase II study, the adriamycin and ifosfamide combination regimen. The drugs were administered at 60 mg/sqm and 6 g/sqm dosage, respectively. The total number of treated patients was 42 of which 40 were evaluable. RESULTS: We observed 6 complete responses (14% response rate) and 6 partial responses (14%). The mean survival was 6 months (median 7.6 months). Toxicity was limited and reversible. CONCLUSION: While high dose chemotherapy may be reserved for selected groups of patients, an adriamycin and ifosfamide combination regimen at conventional doses can be administered to the great majority of patients with suboptimal performance status or with advanced age.

Paclitaxel and carboplatin for recurrent salivary gland malignancies.

BACKGROUND: The use of chemotherapy for recurrent salivary gland carcinomas is under investigation. PATIENTS AND METHODS: Fourteen patients (10 males, 4 females; median age 55 years, range 20-70) with recurrent carcinomas of major (9 patients) and minor (5 patients) salivary gland origin (histology: 1 adenocarcinoma, 10 adenoid cystic carcinoma, 2 undifferentiated carcinoma, 1 mucoepidermoid carcinoma) were treated with carboplatin AUC 5.5 + paclitaxel 175 mg/m2 (3-hour infusion) on day 1 (interval = 3 weeks). All patients had been previously treated with surgery + radiotherapy and 8 with a cisplatin combination. One patient had a local lesion, 7 locoregional recurrence and metastases and 6 patients had metastases only. RESULTS: Overall 65 courses were given (median 5; range 2-6). Responses were: PR in 2 patients (14%) lasting 5 and 12 months; 7 NC (50%) with a median duration of 8.5 months (5-12); and 5 PD (36%). The median survival time was 13.5 months for PR/NC patients, 6 months for non responders; median overall survival was 12.5 months (3-17+). CONCLUSION: This combination had a moderate activity; the treatment was well tolerated and toxicity was manageable.

Docetaxel in combination with epirubicin in metastatic breast cancer: pharmacokinetic interactions.

Epirubicin (75 mg/m2) and docetaxel (75 mg/m2) were administered to 16 patients affected by metastatic breast cancer following two different schedules: (1) docetaxel as infusion administered 1 h after epirubicin administration (schedule A); and (2) docetaxel as infusion immediately (10 min) after the end of epirubicin i.v. bolus administration (schedule B). Experimental non-compartmental analyses such as AUC and Css, were affected very little by the drug combination, irrespective of whether the administration of docetaxel was immediately after the epirubicin bolus (10 min) or delayed (1 h). However, serum levels showed evidence of transient drug interaction: in schedule A, docetaxel infusion was associated with a transient increase of plasma epirubicin in correspondence with Cssmax of docetaxel. Bi-compartmental analysis showed a significant difference in epirubicin clearance between protocols A and B. It is suggested that polysorbate 80, used in minimal amounts to formulate docetaxel, may interfere with epirubicin plasma level.

Vinorelbine treatment of recurrent salivary gland carcinomas.

Twenty patients (13 males, 7 females, median age 61 years, range 27-74) with recurrent adenocarcinoma-like tumors of major (10 patients) and minor (10 patients) salivary gland origin (13 adenoid cystic carcinoma, 5 adenocarcinoma, 1 malignant mixed tumor, 1 undifferentiated carcinoma) were treated with vinorelbine at the dose of 30 mg/m2 i.v. weekly. Sixteen patients had been previously treated with surgery + radiation, 3 with surgery + radiotherapy + Novantrone and 1 with radiotherapy alone. Nine patients had local recurrence, 2 local relapse + metastasis and 9 metastasis alone. Site of metastases are: lung (7), bone (1), lung + bone (2), lung + bone + lymph-node + skin (1). Overall 174 courses were given (median 9, range 6-19). Responses were: PR in 4 patients (20%) with a median duration of 6 months (3-9), 9 NC (45%) with a median duration of 3.5 months and 7 PD (35%). The median survival time was 10 months for PR/NC patients, 4 months for non-responders. Median overall survival was 7 months. Vinorelbine has a moderate activity in these very advanced cases.

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.

Pharmacokinetics of ifosfamide administered according to three different schedules in metastatic soft tissue and bone sarcomas.

Ifosfamide is a leading drug in soft tissue sarcoma therapy. Recently high dose therapy (>9 g/m2) has been introduced in different schemes to obtain a higher response rate. All these higher doses can be administered following two different schedules: continuous infusion 24 hours a day for 4-5 days or bolus administration for 5 consecutive days. In this study we compare the differences in the pharmacokinetic profile between the two schedules. In both schemes we saw a very important autoinduction phenomenon, with a corresponding half-life decrease and total body clearance increase during the days of therapy. The clearances were not directly correlated with the administered dose. We can conclude that ifosfamide continuous infusion therapy is equivalent to fractionated administration, at least from a pharmacokinetic point of view. Short-term infusion is subjectively better tolerated and is therefore preferred.