Selective arterial embolisation for bone tumours: experience of 454 cases.

PURPOSE: The authors present the experience of a single institution with selective arterial embolisation for primary and metastatic bone tumours. MATERIALS AND METHODS: A total of 365 patients were treated with 454 embolisation procedures from December 2002 to April 2010. Embolisation was the primary treatment for benign bone tumours, adjuvant treatment to surgery for benign and malignant bone tumours and palliative treatment for bone sarcomas and metastases. Indications for repeat embolisation included pain or imaging evidence of progressive disease: 105 patients had repeat embolisation at the same location at an interval of 1-3 months; 260 patients had one embolisation, 78 had two and 29 had three or more. In all patients, N-2-butyl cyanoacrylate (NBCA) in 33% lipiodol was the embolic agent used. RESULTS: A total of 419 of the 454 embolisations (93%) were technically successful. In 35 cases, embolisation was not feasible because of poor lesion vascularisation (21 patients with bone metastases and two with aneurysmal bone cysts), origin of the Adamkiewicz artery in the embolisation field (four patients with bone metastases and one with aneurysmal bone cyst), atheromatosis and arteriosclerosis (five patients with bone metastases) and anatomical and technical problems such as small-calibre vessels, many branches and acute vessel angles (two patients with bone metastases). A clinical response was achieved in 406 of the 419 procedures (97%), and no response in 13 procedures in patients with pelvis and sacrum tumours. Complications included postembolisation syndrome in 81 patients (22%), transient paraesthesias in 41 (11%), skin breakdown and subcutaneous necrosis at the shoulder and pelvis in five (1.4%) and paresis of the sciatic nerve in one (0.3%). CONCLUSIONS: We recommend embolisation as primary or palliative treatment or an adjunct to surgery for tumours of variable histology. Strict adherence to the principles of transcatheter embolisation is important. Arteries feeding the tumour and collaterals must be evaluated carefully and catheterised superselectively to protect the normal tissues. NBCA is considered the most appropriate embolic agent for small-vessel occlusion without major complications.

Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases.

BACKGROUND: This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin- and irinotecan-based systemic chemotherapy regimens. METHODS: Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2). RESULTS: Of 50 eligible patients, 38 (76%) had received > or =4 lines of chemotherapy. Most presented with synchronous disease (72%), >4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (>48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%. CONCLUSION: Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC.

Oxaliplatin plus raltitrexed in the treatment of patients with advanced colorectal cancer: a phase II study.

UNLABELLED: The combination of Oxaliplatin (OXA) and Raltitrexed (RTX) may represent a more convenient regimen as compared with OXA + 5-FU with Folinic acid (FA) modulation regimens. The present trial has been designed to explore the activity and tolerability of this combination in untreated and pretreated patients with advanced colorectal cancer (ACC). OXA and RTX were administered at the dose of 130 mg/m2 as i.v. 3-hour infusion and 3 mg/m2 over a 15-minute i.v. infusion, respectively, repeated every 21 days. Fifty patients were enrolled between February 1999 and March 2001. A total of 293 cycles were administered, with a median number of 6 cycles (range 1-14) per patient. The median dose intensity for OXA and RTX was 100% (50-100) and 86% (21-100), respectively. Reasons for RTX dose reduction were increases in transaminase serum levels and a reduction in creatinine clearance. Myelotoxicity was limited. A transaminase increase was observed in 74% of patients (14% grade 3 and 10% grade 4). Peripheral sensorial neurotoxicity was the most frequent side-effect (88%), although its intensity was mild in most patients (grade I 48%, grade II 24%, grade III 16%). Of 46 evaluable patients, 3 CR, 5 PR, 22 S and 16 P were observed. The CR + PR remission rate, according to the intention to treat analysis, was 16% with a 95% confidence limit of 7.2%-29.1%; in patients not pretreated for advanced disease the CR + PR rate was 26%, while only 2 out of 27 pretreated patients responded to the treatment (7%). The median time to progression was 5 months (2-11). The median survival was not reached after a median follow-up of 14 months. One-year survival is 60%. CONCLUSION: In this trial the OXA + RTX combination is confirmed to be active in ACC, although the level of activity seems to be lower than that of the other combination including OXA and 5-FU with or without FA modulation. The reasons for the low activity observed could at least in part be related to a reduction in the RTX dose intensity.

Neoadjuvant chemotherapy in cervical carcinoma: regulators of cell cycle, apoptosis, and proliferation as determinants of response to therapy and disease outcome.

To evaluate whether cellular markers predict the responsiveness to neoadjuvant chemotherapy (NAC) in cervical cancer, 21 patients with stages I and II cervical carcinomas treated by NAC before surgery were followed up for a mean of 52.3 months. Pre-NAC biopsy and operative specimens were subjected to counting of apoptotic (AI/V) and mitotic (MI/V) indices, detection of human papillomavirus (HPV) DNA, and immunohistochemical analysis of cell cycle and proliferation markers (p21, p53, pRb, proliferating cell nuclear antigen [PCNA], Ki-67) and multidrug resistance gene (MDR1), as related to NAC response (RAC), recurrence-free (RFS), and overall (OS) survival. Adenosquamous histology and lymph node involvement were significant determinants of nonsurvival. All carcinomas contained HPV DNA. In univariate analysis, p21, pRb, and MDRI in the biopsy specimen and PCNA, Ki-67, and pRb in the surgical sample significantly predicted RAC, while age, AI/V number of lymph nodes removed, and MI/V predicted RFS. Highly significant predictors of OS were AI/V number of lymph nodes removed, post-NAC MDR1 expression, MI/V and recurrence. Multivariate analysis confirmed the strong post-NAC effects of histologic type, AI/V, and MDR1 expression for RFS, and recurrence, age, and Ki-67 expression for OS. NAC responders with slightly decreased AI/V and increased MI/V had a poor prognosis.

Oxaliplatin and protracted continuous 5-fluorouracil infusion in patients with pretreated advanced colorectal carcinoma.

BACKGROUND: Both OHP and 5-FU are clinically active as single agents in the treatment of metastatic colorectal cancer (MCRC). Clinical and laboratory studies suggest a synergistic interaction between these agents. This phase II study was performed to evaluate the activity of a schedule including OHP and protracted 5-FU infusion in 5-FU-resistant MCRC. PATIENTS AND METHODS: From October 1997 to January 2000, 50 patients with measurable progressive MCRC after one or more 5-FU-based regimens were treated. OHP (2-3-hour i.v. infusion) on day 1 and 5-FU (protracted i.v. infusion using elastomeric/electronic pump through a central venous catheter) on days 1-21 were administered every 3 weeks, at the following 4 dose levels: 1) OHP 100 mg/m2 + 5-FU 200 mg/m2 (21 patients); 2) OHP 100 mg/m2 + 5-FU 250 mg/m2 (3 patients); 3) OHP 130 mg/m2 + 5-FU 200 mg/m2 (10 patients); 4) OHP 130 mg/m2 + 5-FU 250 mg/m2 (6 patients). RESULTS: Objective responses were 1 (2%) CR; 10 (20%) PR, for a median duration of 8 months; 23 (46%) stable diseases, for a median duration of 6 months: 16 (32%) progressions. CR + PR was higher in patients who had previously received no more than one line of chemotherapy for metastatic disease as compared with patients who had received two or more lines of therapy (33% vs. 5%, P < 0.01). The median time to progression was four months (one to nine). All dose levels (313 cycles) were well tolerated with mild toxicity. Major toxicity (grade 3 WHO) included: anaemia in 1 patient (2%), nausea and vomiting in 1 patient (2%), diarrhoea in 4 patients (8%) and stomatitis in 1 patient (2%); grade I and 2 peripheral neuropathy were encountered, respectively, in 30 (60%) and 8 (16%) patients. The median survival was 13 months (9-17), with 32 patients still alive after a median follow-up of 8 months. CONCLUSIONS: This study suggests that 1) OHP plus protracted 5-FU infusion is an active combination in MCRC patients resistant to pre-treatment bolus 5-FU; 2) it has a good tolerability profile and 3) the optimum dose level is OHP 130 mg/m2 and 5-FU 250 mg/m2.

CD44 isoform 6 (CD44v6) is a prognostic indicator of the response to neoadjuvant chemotherapy in cervical carcinoma.

OBJECTIVE: Theclinical efficacy of neoadjuvant chemotherapy (NAC) in distinct groups of cervical cancer patients has been well documented, but parameters at the cellular level regulating the different responsiveness to this treatment have not been adequately explored. METHOD: A series of 21 patients with stage Ib and IIa bulky cervical carcinomas were treated by preoperative NAC with three courses of cisplatin, epirubicin, etoposide, and bleomycin prior to radical hysterectomy, and subsequently followed up for a mean of 52.3 months. Biopsies taken prior to NAC and operative specimens were subjected to immunohistochemical (IHC) staining for alpha-catenin, beta-catenin, E-cadherin, and CD44 isoform 6 (CD44v6), to uncover the role of adhesion molecules as determinants of the response to NAC and disease outcome. RESULTS: Seven of the twenty-one (33.3%) women died of the disease; adenosquamous (n = 4 cases) histology (RR 4.50, 95% CI 1.85-10.68) and lymph node involvement (RR 6.00, 95% CI 0.42-85.26) were significant determinants of nonsurvival. All 21 carcinomas were human papillomavirus DNA positive. The factors predicting the response to NAC in univariate analysis were: CD44v6 expression in the pre-NAC and post-NAC samples (P = 0.00056 and P = 0.00336, respectively). In multiple logistic regression analysis, the factors with independent predictive value for response to NAC were CD44v6 expression prior to (P = 0.0099) and after (P = 0.0470) NAC. In univariate survival analysis, the most significant (P < 0. 001) predictors of recurrence-free survival (RFS) were age and number of lymph nodes removed. In multivariate survival analysis, the independent predictor for RFS was only histological type (P = 0. 0064). Overall survival (OS) was predicted in a Cox model by recurrence (P = 0.0033), CD44v6 expression after NAC (P = 0.013), and patient's age (P = 0.039). CONCLUSIONS: These data indicate that CD44v6 is involved in the response to NAC, and eventually in disease outcome. This implicates that the assessment of CD44v6 expression might help in selecting patients who are likely to respond to NAC, i. e., women with significantly reduced CD44v6 expression in their tumors before treatment. Noteworthy, the response to NAC did not predict a favorable disease outcome.

Pilot study on induction chemotherapy with cisplatin, epirubicin, etoposide and bleomycin in cervical cancer stage Ib, IIa and IIb.

METHODS: Induction chemotherapy, consisting of 3 courses of cisplatin (30 mg/m2/i.v. 1st and 2nd day), epirubicin (30 mg/m2/i.v. 1st and 2nd day), etoposide (75 mg/m2/i.v. 1st and 2nd day) and bleomycin (15 mg/i.v. 1st and 2nd day), prior to radical hysterectomy and lymph nodes resection, was used in the primary treatment of 34 consecutive patients (pts) with cervical carcinoma: 8 stage Ib < 4 cm, 11 stage Ib > 4 cm, 13 stage IIa, 2 stage IIb. Median age was 55 years (range 32-75) and median Karnofsky performance status was 90% (range 70-100%). RESULTS: Among the 34 evaluable patients (pts), the overall clinical response rate was 53%, which included a complete response in 9 pts (26.5%) and a partial response in 9 subjects (26.5%). Fifteen stable diseases and one progression were also observed. All the pts were operated on and no invasive residual tumor was found in the surgical specimens obtained from 6/9 clinical complete responders. Lymph-node metastases were found after chemotherapy in 16% (5/32) of the pts with stable disease. Eight pts presented disease recurrence, four had isolated pelvic recurrences, two had pelvic and distant failure, and two had isolated distant metastases. Until now, 9 pts have died. The most frequent toxic effects were: alopecia 100%, nausea-vomiting 73% (25/34), leukopenia 65% (22/34). CONCLUSION: The results suggest that the administration of induction chemotherapy prior to surgery is effective in reducing the tumor volume and results in tolerable toxicity. However, the impact on survival is questionable and randomized trials for conventional treatment are needed.

Comparative crossover trial of two intravenous doses of granisetron (1 mg vs 3 mg) + dexamethasone in the prevention of acute cis-platinum-induced emesis.

BACKGROUND: The 5HT3 receptor antagonist Granisetron (GRA) is available on the market as a 1 mg vial in USA and as a 3 mg vial in Europe. This study aimed to compare the two i.v. doses of GRA (3 mg vs 1 mg), both of which combined with Dexamethasone (DEX) (20 mg) in the prevention of acute Cisplatinum (CP)-induced emesis. PATIENTS AND METHODS: One hundred and ninety-eight consecutive chemotherapy-naive cancer patients, mainly suffering from lung and bladder cancer, were randomized at their first cycle to receive either GRA 1 mg + DEX or GRA 3 mg + DEX as i.v. bolus prior to chemotherapy and crossed-over to another GRA dose at the second cycle. The cytotoxic treatment included different multi-drug regimens containing CP (median dose 60 mg/m2, range 50-70) administered on day 1 and repeated every 21-28 days. RESULTS: Of the 192 evaluable patients complete protection from acute emesis with GRA 1 and GRA 3, was observed after the 1st + 2nd cycles as follows: nausea 70% and 74%, vomiting 90% and 94%, nausea and vomiting 67% and 74% respectively (no statistically significant difference). No carry-over effect was observed on the complete protection from emesis. The crossover analysis comprising 156 patients confirmed there were no differences between the two antiemetic treatments. Twenty-seven per cent of patients preferred GRA 1, 31% preferred GRA 3, while 42% expressed no preference (P = 0.75). Nor was any difference observed for tolerability, the only reported side-effects being mild headache (16% vs 17%) and constipation (18% vs 25%). CONCLUSION: This study shows that, under the above conditions, the 1 mg and 3 mg i.v. GRA doses are comparably effective when combined with DEX 20 mg in the prevention of acute CP-induced emesis.

Chemotherapy of advanced ovarian cancer.

Majority of ovarian cancer patients have advanced disease (stage III or IV) at diagnosis and the prognosis of these patients is poor in spite of aggressive surgery. Therefore chemotherapy has gained a fundamental role in the therapeutic approach of ovarian cancer. Platinum compounds in combination with alkylating agents and taxoids have the higher antitumor activity in ovarian cancer, while the role of anthracyclines remains controversial. Our 10-year experience with cisplatinum-based polychemotherapy in 196 advanced ovarian cancer patients previously untreated with chemotherapy is reported. 74 patients were treated with the combination cis-platinum and anthracyclines; 53 patients received the combination cis-platinum plus epirubicin alternated to cyclophosphamide plus 5-fluorouracil; 48 patients were treated with cis-platinum plus cyclophosphamide plus epirubicin and 21 patients were treated with the same combination with intraperitoneal administration of cisplatin. Our data confirm literature results of 55% remission rate, with 29% showing complete remissions. The median survival was 79 weeks and the overall 10-year survival was 13%. Complete responders had a median survival of 263 weeks and a 30% survival at 10 years. The main prognostic factors in our retrospective analysis were the objective remission, the size of residual tumor, the performance status and the stage. With the combination carboplatin (300-400 mg/sm) and cyclophosphamide (600 mg/sm) we observed 80% objective responses (23% complete responses) in 53 advanced ovarian cancer patients. The median overall survival in this group was 140 weeks. We carried out a phase II, non-randomized study of taxol in 54 ovarian cancer patients pretreated with platinum-compounds. The overall tolerability was good and an objective remission was observed in 47% of cases (8% complete remissions). The median survival was 68 weeks. As a consequence of our previous experience, a phase I dose-finding study with the combination carboplatin and taxol was started in our Division in 1994. Up to now, 22 chemotherapy untreated patients entered the study and the 5th dose level (taxol 175 mg/sm and carboplatin 350 mg/sm) has been completed without reaching the maximum tolerated dose. Our preliminary data suggest that the combination taxol-carboplatin is very active as the first-line chemotherapy in advanced ovarian cancer (73% objective remissions in 15 evaluated patients).

An open randomised cross-over study on granisetron versus ondansetron in the prevention of acute emesis induced by moderate dose cisplatin-containing regimens.

The aim of the study was to compare granisetron (GRA) with ondansetron (OND) in the prevention of acute emesis in consecutive chemotherapy-naive patients admitted to our department to receive a cytotoxic treatment containing cisplatinum (CP) at a dose > or = 50 mg/m2. Eligible patients were randomised at their first cycle to receive either OND or GRA with cross-over of the anti-emetic treatment on the second cycle. The cytotoxic treatments included five different multidrug regimens containing CP (median dose 60 mg/m2, range 50-70 mg/m2) administered on day 1 and repeated every 21-28 days. OND was administered at the dose of 8 mg x 3 i.v. on day 1 and 8 mg x 2 orally on day 2. GRA was always administered at the dose of 3 mg i.v. on day 1. 124 patients entered the study. 58 patients received OND at their first cycle and 66 received GRA. Complete protection of acute emesis with OND and GRA was observed, with the first and second cycles combined as follows: nausea 53 and 60%, vomiting 68 and 71%, respectively (no statistically significant difference). The cross-over analysis comprising 101 patients confirmed no difference between the two anti-emetic treatments. 21 patients (19%) on OND and 14 patients (12%) on GRA suffered headaches (P = 0.15). 25 (25%) patients preferred OND, 45 (45%) preferred GRA, while 31 (30%) expressed no preference (P = 0.003). However, these differences also depended on the sequence of anti-emetics in the cross-over. In conclusion, in this study, a single dose of GRA is demonstrated to be as effective as multiple doses of OND in the prevention of acute emesis.

A phase II study of carboplatin and cyclophosphamide in advanced ovarian carcinoma.

Forty-two patients affected by either stage III and IV ovarian cancer with residual tumor after surgery or recurrent ovarian cancer entered a phase II study of the combination carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2 every 28 days. Thirty-eight patients were evaluable for response and of these 27 obtained complete or partial remission with a 71% overall remission (clinical complete remission 45%; partial remission 26%). Treatment tolerability was on the whole good. The most frequent side effects were leukopenia (76%), anemia (67%) and nausea/vomiting (60%). Thrombocytopenia was present in 31% of the patients, but nearly always to a mild degree except for one grade 4 case. No other grade 4 side effect was observed. We did not observe any cases of nephrotoxicity and only two patients complained of paresthesia. This carboplatin-cyclophosphamide combination in advanced ovarian carcinoma produces comparable results, in terms of objective responses, to those obtained with standard cisplatin-based regimens, with suggestion of a better toxicological profile.

Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study.

The pharmacokinetics and metabolism of doxorubicin (DX) and epirubicin (epiDX) were investigated in eight cancer patients who received 60 mg/m2 of both drugs independently by intravenous (i.v.) bolus at 3-week intervals according to a balanced cross-over design. Unchanged DX and epiDX plasma levels followed a triexponential decay. Half-lives (t/2) of the three decay phases were longer for DX (t/2 alpha: 4.8 vs. 3 min; t/2 beta 2.57 h vs. 1.09 h; t/2 gamma 48.4 vs. 31.2 h). According to a model-independent analysis, the different plasma disposition kinetics of the two compounds appears to be related to a higher plasma clearance (PlCl) and to a lower mean residence time (MRT) of epiDX (PlCl: 75.0 l/h, range: 35.6-133.4 l/h; MRT: 31.6 h, range: 7.0-41.5 h;) compared to DX (PlCl: 56.8 l/h, range: 24.4-119.5; MRT: 45.6 h, range: 26.0-83.1 h). No statistically significant differences could be detected for the volume of distribution at steady state (Vss) (epiDX, 31.8 l/kg; DX, 33.3 l/kg). Metabolites common to both compounds were detected in plasma: the 13-dihydro derivatives doxorubicinol (DXol) and epirubicinol (epiDXol), together with minor amounts of four aglycones (7-deoxy adriamycinone, adriamycinone, 7-deoxy 13-dihydro adriamycinone, and 13-dihydro adriamycinone). Following epiDX administration, two additional major metabolites were detected: the glucuronic acid conjugates of epiDX (4'-O-beta-D-glucuronyl-4'-epiDX) and epiDXol (4'-O-beta-D-glucuronyl 13-dihydro-4'-epiDX). This additional detoxication route appears to account for the more efficient and faster elimination of epiDX than of DX. In the urine collected in the 6 days after treatment, 12.2% of the DX and 11.9% of the epiDX dose was excreted as unchanged drug and fluorescent metabolites. A comparable renal clearance was calculated for DX (4.7 l/h, range 1.4-7.0 l/h) and epiDX (4.4 l/h, range 1.7-7.0 l/h). One patient with hepatic metastases and abnormal bilirubin serum level had percutaneous biliary drainage because of extrahepatic obstruction. The elimination of both drugs was significantly impaired in this patient; nevertheless, elimination of epiDX was still more efficient and faster than that of DX (PlCl: 35.6 vs. 24.4 l/h; MRT: 39.0 vs. 83.1 h; t/2 gamma: 47 vs. 74 h). This patient's biliary excretion accounted for 35.4% of the epiDX dose and 18.2% of the DX dose.

Intrahepatic arterial administration of 4'epidoxorubicin (epirubicin) in advanced cancer patients. A pharmacokinetic study.

Epirubicin (epiDX) pharmacokinetics was followed in 10 advanced cancer patients with hepatic metastases from colorectal carcinoma or primary liver tumor after single bolus administration (20-40 mg) in the hepatic artery, through a surgically implanted catheter and subcutaneous access port. EpiDX plasma and whole blood concentrations follow a triphasic decay qualitatively similar to that observed after IV administration. Blood levels are consistently higher than plasma levels. Plasma clearance (nine patients, mean: 93.4 l/hr; range: 69.3-129.5 l/hr) is higher than the corresponding parameter determined in patients with hepatic metastases after intravenous therapy. The remaining patient is characterised by an abnormally low plasma clearance (13.6 l/hr), due to a hepato-pulmonary shunt. The subjects in this study were exposed to very low drug concentrations, and therefore experienced no relevant adverse side-effects.

Biliary excretion and pharmacokinetics of 4'epidoxorubicin (epirubicin) in advanced cancer patients.

Plasma pharmacokinetics and biliary and urinary excretion of the new doxorubicin analogue, epirubicin, have been studied in three patients with extrahepatic obstruction and percutaneous biliary drainage. At variance with the reported observations concerning doxorubicin metabolism, conjugation of epirubicin and 13-dihydroepirubicin with glucuronic acid takes place, and corresponding amounts of 4'-o-beta-D-glucuronyl-4'-epidoxorubicin and 4'-o-beta-D-glucuronyl-13-dihydro-4'-epidoxorubicin can be found in the bile and urine. The total amount of unaltered drug and metabolites excreted in the bile in the first 4 days after treatment accounts for the 37%, 27%, and 40% of the administered dose; urinary excretion accounts for 19%, 16%, and 26%. Biliary clearance of epiDX (32.5, 8.1 and 21.6 l/h) is higher than renal clearance (15.2, 3.3 and 9.41 l/h). The relevance of the biliary disposition of epirubicin suggest prudent dose reduction in patients with impaired biliary drainage.

Low dose oral administration of 4-demethoxydaunorubicin (idarubicin) in advanced cancer patients. A pharmacokinetic study.

Data relating to 4-demethoxydaunorubicin (DMDR) pharmacokinetics after oral administration (10-15 mg/m2 per day for 3 days) were collected in a total of 12 patients with advanced breast cancer and melanoma. Drug absorption took place in the first 2-4 h after administration. Plasma levels of the reduced metabolite DMDRol were higher than those of the parent compound: Peak levels were 4-10 ng/ml for DMDR and 15-40 ng/ml for DMDRol. The dose-corrected area under the time-concentration curve (AUC) was consequently higher for DMDRol (12.3-74.7, mean 32.6 vs 2.4-7.4, mean 4.6 ng/ml.mg for DMDR). Apparent plasma terminal half-lives after the last dose administered were in the range of 13-36 (mean 23.7) h for DMDR and 30-81 (mean 58.9) h for DMDRol. Drug and the reduced metabolite accumulated in the blood cells; the ratio of AUC (blood) to AUC (plasma) was 1.40-3.75 (mean 2.80) for DMDR and 1.29-3.50 (mean 2.16) for DMDRol. The biliary excretion of the drug and of the fluorescent metabolites was studied in two additional patients with extrahepatic obstruction and percutaneous biliary drainage. In the first 7 days of therapy, biliary excretion (DMDR + DMDRol) accounted for 3.7%-4% of the administered dose. In contrast to our observations with doxorubicin and epirubicin, urinary excretion seems very likely to be more important for this drug than biliary excretion. In these patients urinary excretions were 2.2, 2.9 times (for DMDR) and 1.2, 3.4 times (for DMDRol) the biliary excretion.

Epirubicin pharmacokinetics after intrahepatic arterial and intraperitoneal administration.

The high hepatic clearance of the new doxorubicin analogue epirubicin (4'-epidoxorubicin, epiDX) suggests a possible use of this drug in local and regional therapy where a first pass through the liver is required before the drug can reach systemic circulation. EpiDX pharmacokinetics was followed in advanced cancer patients with liver metastases or a primary tumour after single bolus administration in the hepatic artery, through a surgically implanted catheter and subcutaneous access port. The first-pass effect through the liver was appreciable and only a relatively low fraction of the drug reached systemic circulation. Mild leucopenia and alopecia were observed only in a patient with a hepatopulmonary shunt; this subject was actually exposed to higher epiDX plasma levels. Low intraperitoneal doses of epiDX were administered in a weekly schedule to advanced cancer patients with peritoneal metastases and ascites. Drug concentrations were monitored in the ascitic effusion and in plasma. A high concentration gradient was present between the peritoneal cavity and peripheral circulation. No relevant local or systemic toxicity was observed.

Epirubicin plasma and blood pharmacokinetics after single i.v. bolus in advanced cancer patients.

Plasma and whole blood pharmacokinetics of epirubicin (4'-epidoxorubicin, epiDX), a new doxorubicin (DX) analogue with an improved spectrum of activity and lower toxicity, were investigated in advanced cancer patients after i.v. bolus administration. Drug decay is triphasic, with a long terminal half-life. Plasma and blood levels of the C-13 reduced epiDX metabolite, epirubicinol (epiDXol), are lower than those of the parent compound. Glucuronides of epiDX and epiDXol are also present in plasma, bile and urine; similar compounds are not described in the literature among the metabolites of DX. EpiDX plasma clearance is consistently higher and mean residence time lower than the corresponding DX parameters, thus indicating a more efficient disposition of the new drug. This behaviour is also reflected in a faster elimination of epiDXol with respect to the corresponding Dx metabolite, doxorubicinol. After an initial induction period, epiDX concentration is higher in whole blood than in plasma. Blood clearance is lower than plasma clearance; volume of distribution at steady state Vss is lower if blood concentration data are used in the pharmacokinetic analysis. Mean Residence Time is similar in plasma and blood. A statistically significant reduction of clearance parameters is observed in patients with liver metastases, even in the absence of altered bilirubin levels. Drug clearance problems induced by renal dysfunction become relevant only in severe renal failure.

The effect of high dose medroxyprogesterone acetate on water and salt metabolism in advanced cancer patients.

Ten advanced cancer patients (both with hormone-sensitive and non-hormone sensitive tumors) were treated with high dose medroxyprogesterone acetate (MAP, greater than 500 mg/day). We determined body weight, lean body mass, blood pressure, sodium blood level, urinary excretion, and exchangeable sodium pool by the 22Na method before and after treatment. These data seem to exclude a fluid retentive effect for high-dose MAP.

A new six-drug antiblastic regimen (R 14) at low doses (micropolychemotherapy) compared to CMF in the treatment of metastatic breast cancer: phase III study.

Two groups of 23 patients each, having advanced breast cancer, entered this prospective and randomized study. One group was treated with the conventional schedule of CMF (cyclophosphamide 100 mg/m2/po from the first to the 14th day, methotrexate 40 mg/m2/iv the first and the 8th day, 5-fluorouracil 600 mg/m2/iv the first and the 8th day), and the other was treated with a new six-drug regimen, administered at low doses (R 14: cyclophosphamide 2 mg/kg/iv, vincristine 0.01 mg/kg/iv, vinblastine 0.1 mg/kg/iv, the first day and 5-fluorouracil 5 mg/kg/iv, methotrexate 0.7 mg/kg/iv, adriamycin 0.5 mg/kg/iv the 2nd day every 21 days). The remission rate was 35% (8/23) and 39% (9/23) for CMF and R 14 respectively. The median duration of objective remission was 6 months for CMF and 5 months for R 14 regimen. The median survival time of responding patients was 18 months for CMF and 14 months for R 14. This study shows that the new six-drug regimen at low doses is effective (regarding subjective, objective response and survival rate), and its toxicity is no higher than that of CMF (the incidence of leukopenia was significantly lower during the first course). Therefore, R 14 should be considered an alternative regimen to CMF in the treatment of advanced and, possibly, early breast cancer. The advantages for using R 14 are: 1) it is less toxic (a single dose is a very small amount of medicine compared to what is usually administered), 2) an iv administration always follows a therapeutic program (while in a CMF schedule cyclophosphamide is self-administered by the patient).

The anabolic effect of high dose medroxyprogesterone acetate in oncology.

Ten advanced cancer patients not amendable to conventional therapy were treated with high dose (greater than 500 mg/day, for 30 days) Medroxyprogesterone Acetate (MAP) both orally and intramuscularly, in order to evaluate a possible anabolic effect of this hormone. During the treatment, mean protein intake increased from 37.2 gr/day to 58.8 gr/day (p less than 0.01), nitrogen intake from 5.8 to 9.4 gr/day (p less than 0.01) and caloric intake from 1407.9 to 2075 Kcal/day (p less than 0.01). Nitrogen balance also showed a significant increase (p less than 0.05), as well as elementary strength (p less than 0.02). Lean body mass and body weight did not show significant variations. The above data confirms what was already been documented by us in animals and proposed in man-that MAP has an anabolic effect.