The EORTC Cancer in the ElderlyTask Force (ETF) aims to develop, conduct, coordinate and stimulate research on elderly patients with cancer. Towards this goal, the ETF has established close interactions with disease-oriented EORTC groups by having representatives from most of these groups attend the ETF meetings. In addition, the ETF reviews every new protocol for elderly-specific questions within the protocol review process of the EORTC aiming to reduce ageism within study protocols. Since 2006, the ETF decided to focus on three aspects: open a discussion on specific methodology for clinical trials in the older population; create a common language for describing heterogeneity between older individuals, the EORTC minimal dataset for geriatric assessment in older cancer patients; and develop specific clinical trials in the older population. This article reports the achievements of the ETF in these three domains and discusses its future strategies.

Drug therapy studies imply that Pneumocystis carinii and Toxoplasma gondii possess the enzymes necessary for de novo folate synthesis. To verify this, incorporation of [3H]paraaminobenzoic acid [( 3H]PABA) into reduced folates by P. carinii and T. gondii was investigated. Both organisms synthesized tritiated reduced folates. In P. carinii, 10-formyltetrahydrofolate and tetrahydrofolate, and in T. gondii, 5-formyltetrahydrofolate were the major synthesized folates. P. carinii remained metabolically active in vitro for only a few days. Because current systems for screening antipneumocystis agents are cumbersome, the utility of this assay system for screening therapeutic agents was investigated. Sulfonamides and pentamidine efficiently inhibited de novo folate synthesis in P. carinii. Inhibitors of dihydrofolate reductase such as trimethoprim and trimetrexate were poor inhibitors for P. carinii but efficient inhibitors for T. gondii. This study demonstrates the first unambiguous evidence of metabolic activity in P. carinii, and provides a potential assay for efficiently screening antipneumocystis drugs in vitro.

Five patients with severe, treatment refractory rheumatoid arthritis were treated with high dose intravenous methotrexate (500 mg/m2) followed by leucovorin (50 mg/m2). Four courses of chemotherapy were given over a 2-month interval. At the end of the final course, there was a 50% or greater improvement in joint swelling and pain indices and morning stiffness in all patients. Clinical responses persisted for 6-14 weeks posttherapy. High dose methotrexate-leucovorin was associated with a significant reduction in DR antigen expression on peripheral Leu 2, Leu 3 and Leu 4 lymphocytes.

Trimetrexate is a lipid-soluble antifolate that has been shown in vitro to be a much more potent inhibitor of Pneumocystis carinii dihydrofolate reductase than the conventionally used inhibitor trimethoprim. To evaluate the in vivo efficacy of trimetrexate, steroid-treated rats which spontaneously develop P. carinii pneumonia were used. Rats treated with trimetrexate (25 mg/kg/d) plus sulfamethoxazole (250 mg/kg/d) orally responded at least as well as rats treated with trimethoprim (50 mg/kg/d) plus sulfamethoxazole. Trimetrexate alone administered orally was ineffective in treating P. carinii infection, but subcutaneous (sc) trimetrexate (7 mg/kg/d) significantly decreased the intensity of infection compared to controls. Trimetrexate is a potent antifolate that may provide an effective alternative to pentamidine and trimethoprim-sulfamethoxazole for treatment of P. carinii pneumonia in humans.

Tetrahydrouridine (THU), a potent inhibitor of cytidine deaminase, has been shown to increase the antitumor activity of 1-beta-D-arabinofuranosylcytosine (ara-C) both in vitro and in vivo. In initial studies, which examined the cerebrospinal fluid (CSF) pharmacokinetics of intrathecally (i.t.) administered THU, the drug was found to be slowly cleared from the CSF with alpha and beta half-lives of 1 and 8 hr, respectively. In subsequent experiments, both i.v. pretreatment with THU and concomitant i.t. injection of THU were found to retard the disappearance of i.t. ara-C from the CSF, although the effect of i.t. THU was more profound. ara-C given alone was cleared from CSF with alpha and beta half-lives of 27.5 +/- 6.7 and 115.6 +/- 0.4 (S.D.) min, respectively. Pretreatment with i.v. THU resulted in alpha and beta half-lives of 10.4 +/- 1.5 and 85.7 +/- 11.1, respectively, whereas concomitant administration of i.t. THU resulted in a single half-life of 96 +/- 0.7. The mean calculated clearance rates for ara-C alone, ara-C plus i.v. THU, and ara-C plus i.t. THU were 7.5, 6.2, and 4.2 ml/hr, respectively. This effect appeared to be primarily due to THU inhibition of ara-C deamination, since a decrease in formation of 1-beta-D-arabinofuranosyluracil in the CSF was observed when ara-C was given in the presence of THU (either i.t. or i.v.). No acute neurotoxicity was noted after administration of either i.t. THU alone or i.t. THU with ara-C. The ability of THU to alter CSF ara-C pharmacokinetics may have potential therapeutic value.

Plasma melatonin concentrations were determined over a period of 24 hours in 20 women with clinical stage I or II breast cancer. In ten of the patients, whose tumors were estrogen receptor positive, the nocturnal increase in plasma melatonin was much lower than that observed in eight control subjects. Women with the lowest peak concentration of melatonin had tumors with the highest concentrations of estrogen receptors. A significant correlation was found between the peak plasma melatonin concentration and the tumor estrogen receptor concentration in 19 of the patients. These data suggest that low nocturnal melatonin concentrations may indicate the presence of estrogen receptor positive breast cancer and could conceivably have etiologic significance.