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Previous studies have shown that platinum-DNA adduct level in leukocyte DNA (measured by antibody methodology) is directly related to disease response in ovarian cancer and testicular cancer. To determine if this principle could be more broadly applied, platinum-DNA damage was studied in a blinded fashion in leukocyte DNA of 21 cancer patients who received carboplatin (day 1) and cisplatin (day 3) in a phase 1 clinical trial. Fifteen different tumor types were included in this cohort. Using atomic absorption spectrometry with Zeeman background correction, DNA-bound platinum was measured during cycles 1 (C1) and 2 (C2) of therapy for most patients. For each of two cycles of therapy, most patients developed measurable levels of adduct after carboplatin, and in most patients adduct levels increased further after cisplatin, often in a supra-additive fashion. Total mg dose levels varied by less than 2-fold, whereas individual patients differed by as much as 10(3) in their adduct measurements after C1 and after C2, and by 29-fold after the very first carboplatin dose. All patients had refractory disease at the initiation of therapy, and 19 patients were evaluable for disease response. Adduct determinations were made 24 h after the first dose of platinum therapy in 17 of these individuals. Mean adduct levels after the first dose of carboplatin were higher in six responders (50 fmol/micrograms DNA +/- 26) than in 11 non-responders (14 fmol/micrograms DNA +/- 10); Wilcoxon two sample test two-sided P = 0.0071. The six responders were patients with pleural mesothelioma (2), breast cancer, buccal mucosa cancer, esophageal cancer and ovarian cancer. Adduct levels were consistently higher in the group of responders on each day that adduct was measured, with a summary two-sided P value of 0.00011. We conclude that analysis of platinum-DNA adduct formation may help determine whether pharmacogenetics are important in cancer drug resistance; and may help to determine the relationship between DNA damage in the peripheral blood compartment and internal organ response to in vivo exposures to DNA-damaging agents.

The Testicular Cancer Center Intergroup Study entered surgically staged patients with nonseminomatous tumor and metastases limited to the regional lymph nodes into a previously reported cooperative trial of immediate versus delayed therapy for positive retroperitoneal node disease. Patients with negative nodes (stage I) were placed in an observation registry with specified treatment strategy upon relapse. Of 264 stage I cancer patients 27 (10.2%) had recurrence: 5 of these 27 patients died after recurrence of the testicular malignancies, while 4 other nontumor-related deaths have occurred. Pre-lymphadenectomy staging characteristics observed to predict significantly node positivity are the results of radiological examinations, presence of tumor invasion, vascular invasion and tumor histology. In a multiple logistic regression analysis with these variables, misclassification still occurs in more than a fourth of the patients. Future refinements in diagnosis may allow for better prediction of these patients at risk to have positive lymph nodes and ultimately recurrence. Presently, if assessment of nodal involvement is the objective, noninvasive procedures are not an adequate substitute for surgical staging with modified lymphadenectomy.

Adenocarcinoma of unknown primary (AUP) has generally a poor prognosis. Previous studies have suggested that Cisplatin and Etoposide have activity in AUP. The aim of this study was to determine if dose intensification of this combination would result in increased efficacy. Each 28 day cycle consisted of Cisplatin 100 mg/m2 given on Day 1 and 8 with Etoposide 80 mg/m2 given on day 1, 2, 8 and 9. Sixteen patients (Pts) with no prior chemotherapy were accrued to this study. Predominant sites of disease were lung, liver, and bone. BHCG and AFP were not elevated. One complete remission was seen in a patient with a mediastinal mass (duration of remission = 59 weeks). Two other patients had a partial response. Overall response rate was 19%. Moderate to severe renal toxicity was recorded in 8 patients, with neuro- and ototoxicities in 2 patients each. Severe granulocytopenia occurred in 8 patients, and one patient died of congestive heart failure on day 1 of cycle 2. This excessive toxicity, without enhanced efficacy does not encourage a more extensive empiric trial by this dose schedule in the treatment of AUP.

Carboplatin and cisplatin have similar antitumor activities but different toxicities. Combining these two analogs may be expected to balance the toxicities and allow higher doses of platinum compounds to be administered with tolerable toxicity. To test this concept, a Phase I trial of carboplatin in combination with cisplatin was performed. Thirty-three eligible patients received carboplatin doses ranging from 200-480 mg/m2 on day 1 and cisplatin doses ranging from 50-100 mg/m2 on day 3 of the 28 day cycle. A 2-day interval ensured no interference in renal excretion of carboplatin by cisplatin. Myelosuppression was the dose limiting toxicity. With the usual full dose of carboplatin, 480 mg/m2, patients tolerated 50 mg/m2 of cisplatin, without apparent additional toxicity. At 100 mg/m2 of cisplatin, non-hematologic as well as hematologic toxicities frequently precluded administration of more than 300 mg/m2 of carboplatin. Platinum-DNA adduct quantitation was done in leukocytes and buccal cells during cycle 1 in most patients. The adduct-specific immunosignal in buccal cells was always increased after carboplatin and in all but one after cisplatin. The level of adducts in buccal cells increased with increasing doses of carboplatin and cisplatin. In leukocytes, measurable levels of adducts were formed after carboplatin with further contribution made by cisplatin but not obviously in a dose dependent fashion. We conclude from the toxicities observed, that combinations of carboplatin with cisplatin may have advantages over either drug alone in certain clinical situations; and that further study of platinum-DNA adducts may shed light on platinum dose-response relationships.

Twenty-seven evaluable patients with advanced malignant melanoma received fludarabine phosphate in a daily x 5 injection. Initial dosing was based on the presence of previous radiation therapy. There was no response seen in these patients despite appropriate dose escalation. Myelosuppression occurred without significant sequelae.

The epipodophyllotoxin derivatives etoposide and teniposide have been evaluated intermittently for possible use in the treatment of ovarian cancer. Conflicting studies suggest that variables such as dose and prior treatment have a major influence on outcome. Response rates ranged from 0% to 40% in five series with teniposide, and from less than a 10% overall response rate to greater than a 10% complete response rate in nine studies with etoposide. One study documented activity with oral etoposide. However, because all patients had received various prior chemotherapies, firm conclusions regarding the activity of etoposide could not be drawn. These results, and the expectation of synergy with etoposide and cisplatin, led to several studies that combined etoposide with platin compounds by the systemic and intraperitoneal (IP) routes. Various studies have used intravenous drug combinations of these agents in both previously treated and untreated patients. One study, which used carboplatin instead of cisplatin, reported only seven failures among 26 previously untreated patients. Conversely, the prominent toxicities reported by another study were discouraging, and responses did not exceed what might be expected from cisplatin alone. Studies of analogous combinations administered IP are ongoing. A favorable experience, which was initially reported by the University of California (San Diego group), is being confirmed by other investigators. This has prompted the incorporation of etoposide into first-line strategies. The pharmacologic advantage of etoposide by the IP route (related to its high protein binding) may provide appropriate dose intensity against IP disease while sparing systemic toxicities. Finally, systemic dose intensity with autologous bone marrow support indicates some promise for etoposide in combination with high-dose alkylating drugs.