Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up.

BACKGROUND: Imatinib evaluated as a new treatment option in patients with recurrent or established progressive aggressive fibromatosis/desmoid tumor (AF/DT). PATIENTS AND METHODS: Forty patients with unresectable and progressive symptomatic AF/DT were treated with imatinib (400 mg/day for 1 year) in a Simon's optimal two-stage phase II study (P(0) = 10%, P(1) = 30%, α = 5%, ß = 10%). The primary end point was non-progressive at 3 months (RECIST). RESULTS: The study population consisted of 28 women and 12 men, with a mean age of 41 (range 20-72 years). Most of the primary sites were extra-abdominal (24, 54.5%). Familial adenomatous polyposis was observed in six (15%) cases. The median follow-up was 34 months. Imatinib toxicity was similar to that previously reported in literature. Tumor assessment was validated by a central independent radiology committee for 35 patients At 3 months, one (3%) complete and three (9%) partial confirmed responses were observed. The non-progression rates at 3, 6 and 12 months were, respectively, 91%, 80% and 67%. The 2-year progression-free and overall survival rates were 55% and 95%, respectively. Two patients with mesenteric AF/DT died from progressive disease. CONCLUSION: Imatinib is active in the treatment of recurrent and progressive AF/DT, providing objective response and long-term stable disease in a large proportion of patients.

Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper.

BACKGROUND: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first-line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly patients are at increased risk of this event and measures to reduce it should be considered. METHODS: A committee of experts in breast cancer and NHL met under the auspices of the International Society for Geriatric Oncology to review the literature and make recommendations, based on level of evidence, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines. RESULTS AND RECOMMENDATIONS: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative dose of anthracyclines and short infusion duration. The fact that cumulative and irreversible cardiotoxicity is likely to be greater in this population than among younger patients calls for effective pretreatment screening for risk factors, rigorous monitoring of cardiac function and early intervention. Use of liposomal anthracycline formulations, prolonging the infusion time for conventional anthracyclines and cardioprotective measures should be considered. However, when treatment is being given with curative intent, care should be taken to ensure reduced cardiotoxicity is not achieved at the expense of efficacy.

Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.

PURPOSE: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. METHODS: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. RESULTS: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. CONCLUSION: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

Primary chemotherapy or hormonotherapy for patients with breast cancer.

Scientific rationale for primary treatment of breast cancer relies on experimental data showing that the incidence and growth of disease correlate with the primary tumour mass and tumoral angiogenesis. Although the strategy may be applied to both chemotherapy and hormonotherapy, only the first was extensively explored for patients with locally advanced breast cancer in order to improve survival and to avoid mastectomy through the achievement of a downstaging of the tumour. Encouraging results obtained in this clinically advanced setting combined with renewed interest for tumoral angiogenesis brought clinicians to apply this strategy to smaller tumours. Despite high clinical and radiological response rates, only pathologic information, carefully assessed in both the primary and axillae lymph nodes, stands out as the major source of prognostic information on patients' outcome. Recent developments in chemotherapy (dose-intensity, new drugs) do not seem to influence these results, indicating the possible limitations of recent developments in chemotherapy. Of 6 published randomized trials comparing primary vs adjuvant chemotherapy, none showed any significant impact of primary chemotherapy on survival, with a trend towards delayed/less distant recurrences in patients treated by primary chemotherapy in some. Some recent reports suggest that local relapse rate might be increased after conservative treatment following induction chemotherapy in subgroups analyse and this should cause oncologists to revise and define the role for conservative surgery after primary medical treatment without calling into question the global strategy. Through sequential samplings, neoadjuvant medical treatment provides indeed the opportunity (a) to identify molecular mechanisms associated with pathologic response and (b) to study the possibility to guide the choices for induction treatment and patient populations submitted to primary medical treatment.

In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity.

The widely used anticancer prodrug cyclophosphamide (CPA) is activated in liver by a 4-hydroxylation reaction primarily catalyzed by cytochrome P-4502B and P-4502C enzymes. An alternative metabolic pathway involves CPA N-dechloroethylation to yield chloroacetaldehyde (CA), a P-4503A-catalyzed deactivation/neurotoxication reaction. The in vivo modulation of these alternative, competing pathways of P-450 metabolism was investigated in pharmacokinetic studies carried out in the rat model. Peak plasma concentrations (Cmax) for 4-OH-CPA and CA were increased by 3- to 4-fold, and apparent plasma half-lives of both metabolites were correspondingly shortened in rats pretreated with phenobarbital (PB), an inducer of P-4502B and P-4503A enzymes. However, PB had no net impact on the extent of drug activation or its partitioning between these alternative metabolic pathways, as judged from AUC values (area-under-the-plasma concentration x time curve) for 4-OH-CPA and CA. The P-4503A inhibitor troleandomycin (TAO) decreased plasma Cmax and AUC of CA (80-85% decrease) without changing the Cmax or AUC of 4-OH-CPA in uninduced rats. In PB-induced rats, TAO decreased AUCCA by 73%, whereas it increased AUC4-OH-CPA by 93%. TAO thus selectively suppresses CPA N-dechloroethylation, thereby increasing the availability of drug for P-450 activation via 4-hydroxylation. By contrast, dexamethasone, a P-4503A inducer and antiemetic widely used in patients with cancer, stimulated large, undesirable increases in the Cmax and AUC of CA (8- and 4-fold, respectively) while reducing the AUC of the 4-hydroxylation pathway by approximately 60%. Tumor excision/in vitro colony formation and tumor growth delay assays using an in vivo 9L gliosarcoma solid tumor model revealed that TAO suppression of CPA N-dechloroethylation could be achieved without compromising the antitumor effect of CPA. The combination of PB with TAO did not, however, enhance the antitumor activity of CPA, despite the approximately 2-fold increase in AUC4-OH-CPA, suggesting that other PB-inducible activities, such as aldehyde dehydrogenase, may counter this increase through enhanced deactivation of the 4-hydroxy metabolite. Together, these studies demonstrate that the P-4503A inhibitor TAO can be used to effectively modulate CPA metabolism and pharmacokinetics in vivo in a manner that decreases the formation of toxic metabolites that do not contribute to antitumor activity.

Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo.

The anti-cancer prodrug ifosfamide (IF) is metabolized by liver P450 enzymes by two alternative pathways. IF is activated to 4-hydroxy IF (4-OH-IF), which ultimately yields the alkylating mustard isophosphoramide, whereas IF N-dechlororethylation inactivates the drug and produces the neurotoxic metabolite chloroacetaldehyde (CA). Both reactions are catalysed by multiple liver P450 enzymes in vitro in isolated rat liver microsomes. The present pharmacokinetic study investigates the potential for modulation of these alternative pathways of IF metabolism in vivo using the adult male Fischer 344 rat model. Rats were treated with IF alone or in conjunction with various P450 inducers and inhibitors in an effort to improve the balance between drug activation and drug inactivation. Plasma concentrations, areas under the curve (AUC) and half-lives were calculated for 4-OH-IF and CA, allowing estimations of the extent of IF activation and deactivation/toxification. Induction of liver P450 2B enzymes by 4-day high-dose phenobarbital (PB) pretreatment significantly decreased the fraction of IF undergoing 4-hydroxylation (AUC(4-OH-IF)/AUC(4-OH-IF)+AUC(CA)), from 37% to 22% of total metabolism (P < 0.05), consistent with in vitro findings that the PB-inducible P450 enzyme 2B1 plays a major role in IF N-dechloroethylation. Pretreatment with the P450 3A inducer dexamethasone proportionally decreased the AUC for both IF metabolites, without any net impact on the fraction of IF undergoing metabolic activation. By contrast, the P450 2B1 inhibitor metyrapone preferentially increased the AUC for the 4-hydroxylation pathway in 3-day low-dose PB-induced rats, thereby increasing the total fraction of IF metabolized via the activation pathway from 36% to 54% (P < 0.05), whereas the P450 inhibitors orphenadrine and troleandomycin had no significant affect on AUC values. These findings demonstrate specific roles for P450 2B and 3A enzymes in catalysing these pathways of IF metabolism in vivo, and demonstrate the potential for modulation of IF's alternative metabolic pathways in a therapeutically useful manner. These studies also highlight several clinically relevant drug interactions that may occur during concomitant administration of IF with drugs and other compounds that modulate hepatic P450 enzyme levels.

Structure-activity relationships within a series of C(7)-substitutedoxyiminocephalosporins containing the C(3)-methylaminopyridiniumthiomethyl substituent. Synthesis and biological properties of BRL 57342 and some close analogues.

(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-[(Z)-[(S)-carboxy(3,4- dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(1-methylaminopyri dinium-4-thiomethyl)ceph-3-em-4-carboxylate sodium salt (BRL 57342, 1f) combines excellent in vitro antibacterial potency against Gram-positive and Gram-negative bacteria, including P. aeruginosa and Acinetobacter spp., with excellent stability to extended spectrum beta-lactamases. This potency is reflected in in vivo efficacy studies.

Synthesis and biological activity of 3-(N-substituted pyridinium-4-thiomethyl)-7 alpha-formamido cephalosporins.

The synthesis and antibacterial activity of a series of 3-(1-substituted pyridinium-4-thiomethyl)-7 alpha-formamido cephalosporins is described. All the derivatives showed good potency and stability to bacterial beta-lactamases. The antibacterial efficacy seen with the N-alkyl pyridinium substituents was enhanced by the introduction of a catecholic side chain at C-7 and by preparation of N-(substituted amino)pyridinium derivatives.

Synthesis and biological properties of some 3-[(N-substituted-amino)pyridinium-4-thiomethyl]-7-[2-(2-amino-thiazol- 4-yl)-2-(Z)-(methoxyimino)acetamido]ceph-3-em-4-carboxylates.

The synthesis and antibacterial activity of a series of beta-lactamase stable, broad spectrum 7-[2-(2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-cephalo sporins, characterised by a C-3-[N-(substituted-amino)pyridinium-4-thiomethyl] group, is described. Gram-positive and Gram-negative bacteria including extended spectrum beta-lactamase-producing strains were most susceptible to the N-amino- and N-methylamino derivatives (3a) and (3b); with the exception of Pseudomonas aeruginosa, (3b) was more active in vitro and in vivo than cefpirome or ceftazidime.

Erythromycin A oxime 11,12-carbonate and its oxime ethers.

Erythromycin A oxime 11,12-carbonate (5a) and its oxime ethers 5b approximately 5p have been prepared and their antibacterial activities compared with those of erythromycin A (1) and its 11,12-carbonate 2. The oxime 5a and many of its oxime ether derivatives showed good activity in vitro against Gram-positive and the more permeable Gram-negative organisms, in some cases being even more active than the carbonate 2.

Structure--activity relationships in cephalosporins prepared from penicillins. 1. 7beta-Acylamino derivatives of 3-benzyl- and 3-(3-pyridylmethyl)ceph-3-em-4-carboxylic acids.

tert-Butyl 7beta-aminoceph-3-em-4-carboxylates carrying either benzyl or 3-pyridylmethyl substituents at position 3 have been prepared by a multistep modification of the penicillin nucleus. Acylation of either amine, followed by deprotection, gave a range of new cephalosporins. The relationship between structure and antibacterial activity is discussed. D-Phenylglycine proved to be a preferred side chain in both series.

Structure--activity relationships in cephalosporins prepared from penicillins. 2. Analogues of cephalexin substituted in the 3-methyl group.

A previously outlined general procedure for preparing various 3-substituted cephalosporins from the penicillin nucleus has been used, with modifications where required, to prepare a series of analogues of cephalexin with various substituents in the 3-methyl group. The 3-substituents most conducive to broad-spectrum antibacterial activity were 3-pyridylmethyl and m- or p-carboxybenzyl. The compounds were only poorly absorbed by the oral route in mice, but the 3-(carboxybenzyl) compounds gave more prolonged useful serum levels than the usual cephalosporins.