Michael D. Green

Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast

In order to test the possible cardiac-sparing effect of doxorubicin administered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall in resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m2 was 0.06 (p less than 0.005); at 301 to 449 mg/m2 it was 0.09 (p less than 0.0005); and at 450 mg/m2 or greater it was 0.15 (p less than 0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the normal range (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 nM. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to include deteriorations in function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage.

The disposition of carboplatin in ovarian cancer patients

SummaryCarboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170–500 mg/m2. The ages, weights, and creatinine clearances (Clcr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Clcr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t1/2α of 1.6 h and a t1/2β of 3.0 h. The mean (±SD) residence time, total body clearance, and apparent volume of distribution were 3.5±0.4 h, 4.4±0.85 l/h, and 16±31l, respectively. Cmax and AUCinf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m2. No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Clcr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12–16 h. All of the platinum in 24-h urine was carboplatin, and only 2%–3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Clcr of less than about 60 ml/min exhibited dose-disproportional increases in AUCinf and MRT values. The latter were inversely related to Clcr (r=-0.98). Over a dose range of 300–500 mg/m2, carboplatin exhibited linear, dose-independent pharmaco-kinetics in patients with a Clcr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.

Lethal and sublethal effects of the combination of doxorubicin and the bisdioxopiperazine, (+)-1,2,-bis (3-5-dioxopiperazinyl-1-yl) propane (ICRF 187), on murine sarcoma S180 in vitro

Doxorubicin and the bisdioxopiperazine, ICRF 187, synergistically inhibit proliferation of murine sarcoma S180 cells in vitro. Cell cycle analysis was employed to help discriminate cytokinetic from lethal effects of the drug combination. Twenty-four-hour incubation with either agent produced dose-dependent partial G2M arrest. At high doses, ICRF 187 produced partial G2M arrest, inhibition of cell division, and continued DNA synthesis at a higher ploidy, resulting in a second G2M arrest of an 8n population. The addition of ICRF 187 to doxorubicin resulted in enhancement of cell cycle blockade at G2M. The combination also produced enhanced lethality as measured by reduced colony-forming efficiency of drug-treated S180 cells. Measurement of [14C]doxorubicin accumulation in, and effux from, ICRF 187 pretreated cells failed to reveal an effect of pretreatment with the bisdioxopiperazine on anthracycline disposition by S180 cells, suggesting that the enhanced cytotoxic and cytostatic effects do not result from increased intracellular concentrations of doxorubicin. The positive interaction between the two drugs may represent site-specific enhancement of the anthracycline effect by ICRF 187 at an intracellular target site.

Oral 4-demethoxydaunorubicin (idarubicin) in bronchogenic lung cancer; Phase II trial

Eighteen patients with non-small cell lung cancer were entered into a phase II protocol of oral 4-demethoxy-daunorubicin. All were evaluable for toxicity and 17 for response. The major toxicity was hematologic with eight patients developing an ECOG grade 3 or 4 toxicity. There were no responses to the treatment.

Phase II trial of ICRF-187 in patients with acquired immune deficiency related Kaposi's Sarcoma (AIDS-KS)

SummaryThirteen patients with AIDS related Kaposis Sarcoma were entered on a phase II trial of ICRF-187, 1000 mg/m2 IV daily for 3 days every 3 weeks. Eight patients had received prior chemotherapy for AIDS-KS. Six patients had prior opportunistic infection. There were no complete responses; one partial response lasting six months was seen. Toxicity was significant, and of the first 5 patients treated, 3 out of 5 had grade III or IV neutropenia. Because of this, subsequent patients received 800 mg/m2 IV days 1–3 if previously untreated or 600 mg/m2 if previously treated. Overall 4 of 13 patients had Grade IV neutropenia and 5 of 13 had Grade III neutropenia. One patient had Grade IV thrombocytopenia. ICRF-187 at a daily × 3 schedule has some efficacy in the treatment of AIDS related KS, future trials should evaluate lower doses or alternate schedules of administration.

New Chemotherapeutic Agents in Liver Cancer

Therapeutic concepts in hepatocellular carcinoma and bile duct carcinoma are undergoing considerable change. Technologic advances have stimulated the use of investigational approaches including resection, embolization, intra-arterial cytotoxic therapy, radiation, and a combination of these, as well as the trial of new and standard drugs or combination regimens by the systemic route. Pharmacologic studies are becoming more frequent and are essential for the proper evaluation. The interpretation of results is difficult because of the paucity of information on natural history or any large series of adequately staged and similarly treated patients. In the review of data on single drugs, it should be kept in mind that there is often inadequate therapeutic information and an inadequate description of prognostic factors. Data on bile duct carcinoma are not available beyond some small experience with 5-fluorouracil (5-FU) or 5-FU combinations [1,2,3, and chapter 15].

Phase I/II Trial of Thymostimulin in Opportunistic Infections of the Acquired Immune Deficiency Syndrome

Fifteen patients with acquired immune deficiency syndrome (AIDS) and opportunistic infection, were randomized to receive treatment with either thymostimulin (TP-1) at 1 mg/kg for 14 days then weekly for 12 weeks or placebo. The objectives of this study were to evaluate the toxicity of TP-1 in this patient population and to make observations on clinical response as measured by time to second opportunistic infection (OI) and changes in laboratory parameters of immune function. The study demonstrates that TP-1 can be administered safely. There were no differences, however, in time to second OI or overall survival between patient groups. In addition, no change in the immune function could be detected in patients receiving thymostimulin.

Phase II study of esorubicin (4 ′ deoxydoxorubicin) in anthracycline naive patients with ovarian cancer

SummarySixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4′ deoxydoxorubicin at a dose of 30 mg/m2 intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4′ deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease.

New antiviral compounds and impact in management of neoplastic disease and AIDS

The majority of viruses are associated with acute limited diseases in healthy hosts. For this reason, the development of safe and effective antiviral agents has until recently been slow.