Faculty Bibliography

Previous studies have shown that intraperitoneal (i.p.) floxuridine (FUDR) is tolerated at a dose of 3 g x 3 days given in 1.5-2 L of normal saline (NS). In a randomized phase II trial by the Southwest Oncology Group, this treatment was selected for further study because of a favorable 1-year progression-free survival. We have now evaluated ip FUDR in full doses combined with i.p. cisplatin given on the third day at a dose of 60 mg/m2 in 500 mL of NS. Intraperitoneal carboplatin was partially or fully substituted for i.p. cisplatin in patients with symptomatic neuropathies. All patients also received i.p. leucovorin, as previously piloted for fluoropyrimidine modulation. Seven patients with symptomatic ascites or measurable tumors were entered, as were 11 asymptomatic patients with minimal residual (< or = 1 cm) epithelial ovarian cancer. Six cycles of the combination of i.p. FUDR + cisplatin were completed in three patients; however, the combination of FUDR with both platinums was particularly well tolerated. Intraperitoneal FUDR + carboplatin (AUC of 5) was associated with some grade 3 and 4 thrombocytopenia and neutropenia. Eight of these 11 patients are alive, and 3 have been continuously with no evidence of disease exceeding 32 months. The regimen of i.p. FUDR + i.p. cisplatin (or i.p. FUDR with both platinums) is suitable for a phase III trial testing i.p. therapy either from the outset (e.g., i.p. up front) or after achieving clinical complete responses from initial treatment without intervening relapse (i.e., i.p. consolidation) in comparison to i.p. cisplatin.

A sensitive method has been developed for the determination of hydroxyurea in plasma and peritoneal fluid using reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection. Plasma or peritoneal fluid samples were treated with acetonitrile to precipitate proteins then injected to the HPLC. A C18 analytical column was used to separate hydroxyurea from interfering substances in the biological matrix. The mobile phase, consisting of 0.2 M sodium perchlorate-methanol (95:5, v/v) adjusted to pH 5.0, was delivered isocratically at a flow-rate of 1 ml/min and hydroxyurea was detected using a glassy-carbon electrode operating at an applied potential of +800 mV. Hydroxyurea eluted with a retention time of 3 min. The cycle time for analysis is short and the assay precision is acceptable (C.V. plasma=1.4-3.9%. C.V. peritoneal fluid=2.1-9.7%). The method has been validated and is linear from 25 to 400 ng/ml in plasma and 5 to 30 ng/ml in peritoneal fluid. The method has been shown to be applicable for pharmacokinetic studies.

Radiation therapy is the mainstay in treatment of locally advanced cervical carcinoma. Several chemotherapeutic agents have been used as radiation sensitizers in the treatment of cervical cancer in an effort to improve local response and survival. A prospective study was designed to evaluate carboplatin as a radiosensitizer in advanced cervical cancer. Standard radiotherapy techniques were used to treat patients with Stage IIA-IIIB cervical cancer. Intravenous carboplatin was administered twice weekly concurrent with external beam radiation. Of 22 evaluable patients, there were 19 complete responders of whom 15 remain alive: 11 patients were alive and disease free at last visit for a median duration of 15 months follow-up (range, 4-43 months) and 4 patients remain alive with disease for a median duration of 17 months (range, 3-55 months). Seven have died, one of whom was without evidence of disease. There were no treatment-related deaths and no grade 4 toxicity. The most significant adverse effect was hematologic resulting in four patients with grade 3 neutropenia or anemia. There were no fistulae or late gastrointestinal or genitourinary complications. This pilot study suggests that carboplatin administered with standard radiation is safe, well-tolerated, and thus may be useful as a radiation sensitizer in the treatment of locally advanced cervical cancer

PURPOSE: A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS: Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS: Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION: Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory patients

Estramustine phosphate (EMP) is thought to form a chemical link between estradiol and non-nitrogen mustard. An estramustine-binding protein has been isolated in prostate, breast, and brain cancers as well as in malignant melanoma cells. Estramustine phosphate's ability to bind to microtubular-associated proteins and to interfere with mdr-mediated drug efflux are thought to result in its enhancement of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) activity in cell lines and in its ability to affect hormone-resistant prostate cancer. This phase I study administered combined paclitaxel and EMP to 25 women with ovarian, breast, and other tumors and assessed efficacy and toxicity. Estramustine phosphate was administered at two dose levels, 900 or 1,200 mg/m2 daily on days 1, 2, and 3 in 3-week cycles. On day 3, paclitaxel (150, 180, 210, or 225 mg/m2) was given concomitantly by 3-hour infusion. Therapeutic effects were noted in all patients. Partial responses were noted in three of eight patients with breast cancer who had failed to improve on paclitaxel alone. Three other patients experienced prolonged stable disease. Only moderate toxicities were noted until EMP levels of 1,200 mg/m2 were reached. At these dose levels, gastrointestinal toxicities became more prominent. The addition of EMP to paclitaxel allowed patients to receive paclitaxel for longer periods, and may have enhanced the therapeutic effects of paclitaxel. If so, the mechanisms of such enhancement warrant investigation. The two drugs may work on different aspects of microtubular function, for example, or may reduce efflux of paclitaxel in P-glycoprotein overexpressed tumors.

There is an urgent need for more active and better tolerated chemotherapy regimens for the treatment of advanced breast and ovarian cancers. Current therapeutic strategies in these malignancies include the use of moderately effective initial regimens that are usually accepted by patients. Tolerability considerations are especially important in the development of palliative regimens: retreatment for persistent or hormone-resistant disease must include quality-of-life analyses. Pegylated liposomal doxorubicin (PLD) has demonstrated a better therapeutic index than free doxorubicin in murine solid tumours and human tumour xenografts in nude mice. In early clinical studies in patients with refractory ovarian cancer, PLD has produced high response rates (26%) and gratifyingly long response durations (8 to 21 + months after onset of therapy). Less mature data also suggest that PLD is active against breast cancer. Information from these same clinical studies confirms the marked reduction in several toxicities associated with free doxorubicin, including nausea and vomiting, myelosuppression and cardiotoxicity. Alopecia is also markedly diminished. On the other hand, mucosal and skin toxicities appear to be more common with PLD. PLD therefore offers the prospect of retaining activity, together with attenuated acute toxicity. In addition to facilitating the development of palliative regimens with better tolerability, the drug may lend itself to effective integration of chemotherapy with loco-regional therapies; utilisation in 'maintenance' regimens that are associated with an acceptable quality of life for the patient, and the avoidance of long term toxicities associated with treatment. Moreover, additional study of PLD in combination with other drugs and modalities may extend the use of the drug beyond palliation to the development of combination regimens with other drugs at conventional doses, and high doses with G-CSF support