Faculty Bibliography

Nine patients with cancers of gynecologic or peritoneal origin were treated with a combination of gemcitabine, amifostine and cisplatin (GAP). The rationale of including amifostine was primarily related to the amount of prior cisplatin the patients had received and the need to protect against additional neurotoxicity. After encouraging activity and tolerance had been noted, entry of three patients with severely compromised bone marrow was also allowed. These three patients required dose reductions and did not tolerate treatment more often than every other week, but nevertheless, one of them experienced a partial response lasting 9 months. Another two of the nine patients had CA125 decreases fulfilling Rustin's definition of response and one had elimination of ascites. Future studies of this combination are warranted

BACKGROUND: Cancer patients treated with the anticancer drug, paclitaxel (Taxol) often experience mild to severe hypersensitivity reactions. It is not known how these reactions are induced and whether the inducer is paclitaxel or its vehicle (i.e., Cremophor EL in 50% ethanol). Molecules present in Cremophor EL are similar in structure to certain nonionic block copolymers that activate complement proteins (i.e., proteins involved in various immune processes). To explore the role of complement in the observed hypersensitivity reactions, we studied the effects of paclitaxel and Cremophor EL plus ethanol on human complement in vitro. METHODS: Serum specimens from healthy individuals and cancer patients were incubated with paclitaxel or with relevant control compounds (Cremophor EL with ethanol, ethanol only, docetaxel, and cyclosporine), and markers of complement activation (SC5b-9 and Bb) were measured by enzyme-linked immunosorbent assay. Similar incubations were performed in the presence of inhibitors of complement activation (i.e., EGTA/Mg2+ and soluble complement receptor type 1 [sCR1]). RESULTS: Paclitaxel in Cremophor EL plus ethanol caused increased formation of SC5b-9 in serum specimens from 10 of 10 healthy control subjects and from five of 10 cancer patients. Experiments with one or more individual sera indicated the above effect was due to Cremophor EL plus ethanol, that increased formation of Bb also occurred, that the drug-induced rise in SC5b-9 was inhibited by sCR1, and that EGTA/Mg2+ partially inhibited SC5b-9 formation and stimulated Bb formation. IMPLICATION: The role of complement activation in hypersensitivity reactions associated with administration of paclitaxel in Cremophor EL plus ethanol should be studied in vivo.

Paclitaxel (Taxol) is a diterpene originally obtained from the bark of the Pacific Yew Tree, Taxus Brevifolia. Its mechanism of action is unique. It stabilizes microtubule polymerization, thus blocking cells in the G2/M phase of the cell cycle. In breast cancer, initial studies using paclitaxel demonstrated high activity. The first study was reported in 1991 by Holmes et al who gave paclitaxel as a 24-hour infusion at 250 mg/m2 to 25 patients with metastatic breast cancer following only one prior chemotherapy regimen--they achieved a 56% response rate. Since then, numerous studies have confirmed the effectiveness of paclitaxel in patients with metastatic disease. A second taxane, docetaxel (Taxotere), has also demonstrated excellent activity. Clinical research is now focused on integrating the taxanes into combination drug regimens and into neoadjuvant and adjuvant schedules for patients with early stage breast cancer, as well as looking at the biologic determinants of response and resistance to taxanes. This article will review developments in the use of taxanes in the adjuvant and neoadjuvant settings and it will review the information on possible molecular markers that may be useful in predicting tumor responsiveness to taxanes

PURPOSE: Tomudex is a second-generation folate analogue that when polyglutamated is a potent inhibitor of thymidylate synthase (TS). METHODS: Based on indications of antitumor activity in phase I trials, the Gynecologic Oncology Group initiated a phase II study of Tomudex 3 mg/m2 intravenously every 3 weeks in patients with epithelial ovarian cancer, who had been pretreated with platinum drugs, and had subsequently recurred more than 6 months following such treatment. RESULTS: Of 30 patients entered into the trial, 2 were pathologically ineligible, leaving 28 fully evaluable. In this patient population, Tomudex was generally well tolerated, but only three objective (partial) responses were documented. CONCLUSIONS: With the level of activity seen, the drug was not considered for further clinical development in ovarian cancer by the Gynecologic Oncology Group. However, it may be worthwhile to explore whether quantitation of TS could lead to selection of patients more likely to respond to this TS inhibitor

PURPOSE: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally > or =5 microM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. METHODS: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. RESULTS: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) microM and 9.8 (+/- 4.4) microM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. CONCLUSIONS: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

PURPOSE/OBJECTIVE: 1) To test feasibility of preoperative continuous infusion (c.i.) 5-Fluorouracil (5-FU) and radiation (RT) in locally advanced breast cancer. 2) To study clinical and pathological response rates of 5-FU and radiation. 3) To attempt preliminary correlations between biological probes and pathological response. METHODS AND MATERIALS: Previously untreated, locally advanced breast cancer patients were eligible: only patients who presented with T3/T4 tumors that could not be resected with primary wound closure were eligible, while inflammatory breast cancer patients were excluded. The protocol consisted of preoperative c.i. infusion 5-FU, 200 mg/m2/day with radiotherapy, 50 Gy at 2 Gy fractions to the breast and regional nodes. At mastectomy, pathological findings were classified based on persistence of invasive cancer: pathological complete response (pCR) = no residual invasive cells in the breast and axillary contents; pathological partial response (pPR) = presence of microscopic foci of invasive cells in either the breast or nodal specimens; no pathological response (pNR) = pathological persistence of tumor. For each patient pretreatment breast cancer biopsies were analyzed by immunohistochemistry for nuclear grade, ER/PR hormonal receptors, her2/neu and p53 overexpression. RESULTS: Thirty-five women have completed the protocol and are available for analysis. 5-FU was interrupted during radiation in 10 of 35 patients because of oral mucositis in 8 patients, cellulitis in 1, and patient choice in another. Objective clinical response rate before mastectomy was 71% (25 of 35 patients): 4 CR, 21 PR. However, in all 35 patients tumor response was sufficient to make them resectable with primary wound closure. Accordingly, all patients underwent modified radical mastectomy: primary wound closure was achieved in all patients. At mastectomy there were 7 pCR (20%), 5 pPR (14%) and the remaining 23 patients (66%) had pathological persistence of cancer (pNR). Variables analyzed as potential predictors for pathological response (pPR and pCR) were: initial TNM clinical stage, clinical response, nuclear grade, hormonal receptor status, p53 overexpression, and Her2/neu overexpression in the pretreatment tumor biopsy. Only initial p53 status (lack of overexpression at immunohistochemistry) significantly correlated with achievement of a pathological response to this regimen (p = 0.010). CONCLUSION: The combination of c.i. 5-FU and radiation was well tolerated and generated objective clinical responses in 71% of the patients. With the limitation of the small sample size, the complete pathological response achieved (20%) compares favorably with that reported in other series of neoadjuvant therapy for similar stage breast cancer. These preliminary data suggest that initial p53 status predicts for pathological response (pPR and pCR) to the combination of c.i. 5-FU and radiotherapy in locally advanced breast cancer

The object of this study was to define the toxicity and maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered on a biweekly schedule, without and with granulocyte colony-stimulating factor support. Eligible patients had a diagnosis of recurrent or metastatic carcinoma and had received no more than one prior chemotherapy regimen. Patients were treated with paclitaxel administered as a 3-hour infusion. Entry dose level was 150/mg/m2. Subsequent dose levels were 175, 200, and 225 mg/m2. Granulocyte colony-stimulating factor was added at the two highest dose levels beginning on day 4, until absolute neutrophil count was above 10 x 10(9)/L. Forty-six patients were entered. Up to 175 mg/m2 could be safely administered every 2 weeks. Previously treated patients experienced severe dose-limiting neutropenia at 200 mg/m2, and at 225 mg/m2 all patients experienced treatment delays due to grade 3/4 neutropenia. Dose intensity was maintained in all patients due to the addition of granulocyte colony-stimulating factor. Escalation to 250 mg/m2 does not appear desirable, due to neurotoxicity