Derek Raghavan

Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase.These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search.Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t2 of 0.12h.We conclude that great caution is warranted in administering DENSPM on this schedule at doses of ≥ 83 mg/m2/day.

Intracellular glutathione and cytotoxicity of platinum complexes

Although there have been a number of reports correlating cellular GSH levels with cytotoxicity of platinum agents, none has examined the relationship between GSH concentrations and cytotoxicity. In this study, using a highly specific HPLC method for measuring GSH and expressing GSH as concentration and also per cell number, we evaluated the correlation between GSH levels and the cytotoxicity to five agents in ten human tumor cell lines. The five platinum agents included the platinum(II) complexes cisplatin, carboplatin and oxaliplatin and platinum(IV) complexes iproplatin and tetraplatin. The correlation between intracellular GSH concentration and cytotoxicity was highly significant only for iproplatin (P=0.002) followed by tetraplatin, which demonstrated a trend toward statistical significance (P=0.06). Cytotoxicity of the other platinum complexes showed no relation to GSH concentration, cisplatin itself showing aP-value of 0.09. In contrast, the GSH levels normalized to cell number showed a statistically significant correlation with the cytotoxicity of four of the five platinum agents, the exception being carboplatin; the strongest correlation observed was that for iproplatin and tetraplatin. Glutathione-S-transferase (GST) activity in these cell lines showed no correlation with cytotoxicity of any of the platinum complexes. Our results, from the analyses of both GSH concentration as well as GSH per cell number, suggest a significantly higher interaction between GSH and iproplatin compared with the other platinum agents. Moreover, our data suggest that relationships between cytotoxicity and GSH levels on a per-cell basis may not persist when differences in cell volume are taken into account.

Phase II trial of gemcitabine in patients with previously untreated metastatic cancer of the esophagus or gastroesophageal junction

BACKGROUNDnThere were approximately 12,500 cases of esophageal carcinoma diagnosed in the US in 1992 and 12,200 deaths. The impact of chemotherapy on patients with metastatic disease is marginal with a median survival of only five months. Gemcitabine (LY188011,2,2,-difluorodeoxycytidine: dFdC), an analog of cytosine arabinoside (ara-C), is a pyrimidine antimetabolite. Gemcitabine has shown interesting clinical activity in initial phase II clinical trials in a variety of malignancies, including the aerodigestive malignancies, squamous-cell carcinoma of the head/neck and both non-small-cell and small-cell lung cancer.nnnPATIENTS AND METHODSnA total of 21 patients with chemotherapy-naïve metastatic esophageal carcinoma were entered. Nineteen patients were evaluable for toxicity and seventeen patients were evaluable for response. Gemcitabine was administered intravenously at 1250 mg/m2 over 30-60 minutes on days 1, 8, and 15 followed by 1 week of rest. This four-week schedule defined a cycle of treatment. Patients may have received a maximum of six cycles.nnnRESULTSnGemcitabine was well tolerated with minimal non-hematologic toxicity and grade 3-4 anemia, granulocytopenia, and thrombocytopenia occurring in 10.5%, 21%, and 0% of patients, respectively. No responses were seen in the seventeen evaluable patients.nnnCONCLUSIONSnAt the dose and schedule studied it would appear that gemcitabine has no activity in patients with chemotherapy-naïve esophageal carcinoma.

Phase I and pharmacokinetic evaluation of floxuridine/leucovorin given on the Roswell Park weekly regimen

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly×6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with at1/2β of approximately 2 h. Plasma clearance was high (>200 l h−1). No correlation between pharmacokinetic parameters and toxicity could be identified.

Progress in the Management of Metastatic Bladder Cancer

BACKGROUNDnInadequate survival results from single agents in the management of advanced bladder cancer have prompted several trials involving multidrug combinations to increase response rates and survival.nnnMETHODSnSince the development of the MVAC regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) and the CMV regimen (cisplatin, methotrexate, and vinblastine), other regimens have been tested. We evaluate results from regimens that include cisplatin combined with gemcitabine, paclitaxel, or docetaxel, and paclitaxel combined with gemcitabine or carboplatin.nnnRESULTSnObjective results observed with various new combinations are promising. Objective response (OR) rates of 41%, 59%, and 71% are reported with a regimen of gemcitabine plus cisplatin. Paclitaxel plus cisplatin produced OR rates of 65% and 72%.nnnCONCLUSIONSnThe use of combination cytotoxic chemotherapy regimens in treating patients with metastatic bladder cancer has nearly doubled median survival to 12 months, with a 3-year survival of approximately 20% to 25%. Caution must be exercised in using some of the newer regimens as survival may be inferior compared with the MVAC regimen.

The Clinical Development of Paclitaxel and the Paclitaxel/Carboplatin Combination

Paclitaxel and carboplatin have nonoverlapping toxicities with a broad range of clinical activity. The combination of escalating dose paclitaxel and carboplatin dosed to a fixed area under the curve (AUC) was explored in a series of phase I studies. 76 patients were treated with paclitaxel over three hours followed by a 30 min carboplatin infusion, dosed by the Calvert formula to a target AUC of 4.0 or 4.5 mg/min/ml-1. The maximum tolerated dose of paclitaxel was 270 to 290 mg/m2, with a dose limiting toxicity of peripheral sensory neuropathy. Activity was seen in lung cancer, with a paclitaxel dose at or above 230 mg/m2. Neuropathy correlated with paclitaxel AUC due to nonlinear pharmacokinetics at higher doses. Ongoing studies include the use of amifostine as a neuroprotectant and phase II studies of the paclitaxel/carboplatin regimen in head and neck cancer, small cell lung cancer and sarcomas.

Reported family history of cancer in 1,271 prostate cancer cases and 1,909 controls

Prostate cancer risk has been associated with a family history of the disease. A two- to three-fold increase in risk has been observed in several studies. Details concerning modification of this risk by age, type of familial history of prostate cancer, and possible involvement of history of cancer at other sites have been less well documented. This case-control study of 1,271 prostate cancer patients and 1,909 control subjects admitted to Roswell Park Cancer Institute in Buffalo, NY, found age-adjusted increased risk associated with reporting a history of prostate cancer in a father (RR = 2.3, 95% Cl 1.4-3.3) or brother (RR = 2.5, 95% Cl 1.6-3.9). Subjects with both a father and brother affected had a 6.5-fold (95% Cl 1.4-30.5) increased risk of prostate cancer. Greater risk were observed at younger ages of diagnosis. Risks associated with reporting a father or a brother affected were not significantly elevated for patients over age 70 at diagnosis. No significant differences in patients reporting histories of cancer other than prostate cancer were observed regardless of relationship, age at diagnosis, or type of cancer examined. These observations from a large cancer patient population may be useful when making recommendations for cost-effective prostate cancer screening and for directing investigators to the potentially most informative subjects.

Progress in the treatment of invasive bladder cancer

Invasive bladder cancer has been associated with a 5-year survival rate of only 50–60% when treated by radiotherapy or chemotherapy alone. Attempts to improve this outcome have included the combination of cytotoxic chemotherapy with definitive local treatment in neoadjuvant, concurrent, or adjuvant regimens. To date, randomized clinical trials have failed to show a survival benefit from neoadjuvant or concurrent schedules but adjuvant chemotherapy is associated with a disease-free survival benefit. New cytotoxic agents, such as paclitaxel and gemcitabine, are active in the management of metastatic bladder cancer and may contribute to improved outcomes for patients with this disease.

Systemic Therapy for Invasive Bladder Cancer.

BACKGROUND: Bladder cancer is one of the most common malignancies in Western society. In the United States, approximately 10,000 of these patients present with invasive disease, and more progress from superficial bladder cancer. METHODS: The authors review the literature on systemic treatment for both localized and metastatic bladder cancer, and they include their experience in defining approaches to various stages of disease. RESULTS: Cisplatin-based combination chemotherapy is the most effective systemic approach for advanced bladder cancers, although few patients are cured. Neoadjuvant, perspective, and adjuvant trials, as well as concurrent chemoradiation studies, are in progress to attempt to demonstrate better outcomes. CONCLUSIONS: The combination of systemic chemotherapy and definitive local therapy may have a useful role in the management of locally advanced bladder cancers, but optimal schedules and true survival benefit have not been established.

Karyotypic analysis of a heterogeneous human transitional cell carcinoma of the bladder

The UCRU-BL-17 (BL-17) series of xenografts, tissue culture sublines, and cloned cell lines (Fig. 1) shows a range of heterogeneous growth characteristics both in vitro and in vivo (Table 1) and represents a model of human bladder cancer heterogeneity. Cytogenetic analysis was undertaken to determine if specific chromosome changes correlated with particular aspects of the heterogeneous phenotypes. The BL-17 sublines and cloned cell lines shared many common chromosome abnormalities. Indeed, the cloned cell lines showed nearly identical karyotypes despite their marked differences in growth characteristics. Karyotypic evolution with passage through the nude mice was apparent, however. This evolution occurred at the specific chromosome regions of 1p12, 3cen-3p21, and 6cen-6q21. Whether the heterogeneity of karyotype between the BL-17 cell lines resulted from the existence of multiple clones in the original patient tumor or from karyotypic instability through passage in nude mice is uncertain, but in either case the specificity of karyotypic evolution observed suggests that 1p12, 3cen-3p21, and 6cen-6q21 are hotspots for rearrangement in the BL-17 tumor. No specific correlations between chromosome abnormalities and biologic characteristics could be made, but several unique karyotypic features arose in the progression to two of the sublines, BL-17/23 alpha and BL-17/0/X2A, coinciding with a loss of anchorage-independent growth by BL-17/23 alpha and a change in growth in vivo from a solid tumor to a fluid-filled tumor by BL-17/0/X2A.