Edward F. McClay

The importance of tamoxifen to a cisplatin‐containing regimen in the treatment of metastatic melanoma

The combination of dacarbazine (DTIC, 220 mg/m2) and cisplatin (DDP, 25 mg/m2) IV daily for 3 days every 3 weeks, carmustine (BCNU, 150 mg/m2) IV every 6 weeks, and tamoxifen (TAM, 10 mg orally twice daily) produced a 50% objective response rate in patients with metastatic melanoma. Associated with this treatment, there was a high incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE). In an effort to reduce this toxicity, this regimen minus TAM was studied, and the results are reported. Twenty of twenty patients are evaluable for response and toxicity. There was one complete response (CR) lasting 5+ months and one partial response (PR) lasting 4+ months for an overall response rate of 10% (95% confidence limits, 1.23% to 31.70%). Two patients exhibited a mixed response and three patients developed disease stabilization lasting 4 to 10 months. Toxicity was similar to the original study except that no patients developed DVT or PE. This statistically significant (Fishers exact test [two‐tail] P = 0.008) decrease in the response rate by comparison with that achieved with the TAM‐containing regimen may signal an essential role of TAM in this regimen. TAM may be acting in synergy with cisplatin through its calcium channel‐blocking properties. TAM should be included as described in the initial reports, and the patients should be carefully observed for vascular complications.

Phase I/pharmacokinetic study of high-dose progesterone and doxorubicin.

PURPOSE We developed a new formulation of progesterone that permits administration of up to 10 g of progesterone as a continuous intravenous infusion over 24 hours and conducted a phase I clinical trial to determine whether progesterone could modulate the in vivo cytotoxicity of the P-glycoprotein substrate doxorubicin. PATIENTS AND METHODS Thirty-four patients with advanced malignancies were treated with increasing doses of progesterone and a fixed dose of 60 mg/m2 of doxorubicin given as an intravenous bolus 2 hours after starting a 24-hour intravenous infusion of progesterone. RESULTS Progesterone enhanced doxorubicin-induced myelotoxicity in a dose-dependent fashion without altering the pharmacokinetics of doxorubicin. The steady-state plasma concentration of progesterone at a dose level of 4 g was 4.1 +/- 0.9 mumol/L, which was higher than the minimal concentration required to reverse multidrug resistance (MDR) in vitro. CONCLUSION Progesterone enhanced the hematologic toxicity of doxorubicin without altering its pharmacokinetics, suggesting that progesterone could modulate P-glycoprotein at the level of pluripotent hematopoietic stem cells. Adequate tissue concentrations of progesterone could be achieved in vivo to modulate doxorubicin toxicity in the bone marrow and thus potentially in tumor tissue as well. Selectivity may potentially be gained by using hematopoietic growth factors to offset the enhanced hematologic toxicity of doxorubicin while leaving the enhancement of toxicity to tumor cells unchanged.

Phase I and pharmacokinetic study of intraperitoneal topotecan

Objective. To determine the maximum tolerated dose and pharmacokinetics of topotecan when administered by the intraperitoneal route. Methods. A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusion over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. Results. Seventeen patients received a total of 43 cycles at 21-day intervals. The maximum tolerated dose was 4 mg/m2 and acute dose-limiting toxicity was neutropenia. Other toxicities included leukopenia, anemia, emesis, fever, and abdominal pain. Although no objective responses were achieved, five of ten patients with ascites had a decrease in fluid accumulation with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m2. Pharmacokinetic analysis performed at a dose of 3 mg/m2 demonstrated that elimination from the peritoneal cavity followed second-order kinetics with k1 = 1.6 hr-1, k2 = 0.3 hr-1 and first and second-phase half-lives of 0.49 and 2.7 hours, respectively. Plasma pharmacokinetic behavior was best described by first-order kinetics with k = 0.5 hr-1 and a half-life of 3.9 hours. The pharmacologic advantage, expressed as the peritoneal to plasma AUC ratio was 31.2. Conclusions. Intraperitoneal administration of topotecan at 3 mg/m2 results in a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure; this may be beneficial for the treatment of patients with ovarian cancer or intraperitoneal carcinomatosis.

A review: Intraperitoneal cisplatin in the management of patients with ovarian cancer

Since ovarian cancer remains confined to the peritoneal cavity for the majority of its natural history, it provides us with a unique opportunity to explore the possibility of administering chemotherapeutic agents in direct contact with the tumor. Sound pharmacologic principles have been developed that allow us to predict with accuracy agents that should be useful in this approach. The peritoneal pharmacokinetics of a number of active chemotherapeutic agents have been investigated and several effective agents have been identified. Cisplatin has been extensively investigated and has demonstrated excellent activity when used in this fashion. The recognition of sodium thiosulfate as a renal protective agent, against cisplatin-induced nephrotoxicity, has allowed for significant dose escalation of cisplatin. The favorable pharmacokinetic profile and clinical activity of cisplatin render it an important component of intraperitoneal chemotherapy regimens.

A phase II trial of intraperitoneal high-dose carboplatin and etoposide with granulocyte macrophage-colony stimulating factor support in patients with ovarian carcinoma

Based upon results obtained in a Phase I study, we conducted a Phase II trial of high-dose CBDCA and etoposide administered via the intraperitoneal (IP) route in patients with ovarian cancer. CBDCA at a dose of 600 mg/m2 and etoposide at a dose of 400 mg/m2 were administered rapidly into the peritoneal cavity. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of D5W and administered intraperitoneally as rapidly as possible. On days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on day 4 as a subcutaneous injection at a dose of 500 μg/m2/day. A total 53 courses of treatment was administered to 18 patients; 9 of 13 patients (69%) with evaluable disease demonstrated evidence consistent with a partial response; however, the majority were response determined by a decrease in tumor marker (CA-125). One patient who had pathologic evidence of disease at second look laparotomy, but no measurable disease, was treated and shown at subsequent reexploration to have no further evidence of disease. This patient remains free of disease at 17+months. The toxicity encountered in this trial was formidable, resulting in the removal of 78% of the patients from the study prior to completing 6 cycles of therapy.

A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel

Purpose: The purpose of this study was to investigate the effect of high-dose progesterone, an inhibitor of P glycoprotein, on the pharmacokinetics and toxicity of paclitaxel. Patients and methods: A total of 29 patients with various tumors were treated with single-agent paclitaxel (125 mg/m2 administered over 3 h once every 3 weeks) until progression of disease, at which point high-dose progesterone (3 g administered i.v. over 24 h) was added to the paclitaxel treatment program in 20 patients (13 women, 7 men). Pharmacokinetic studies of paclitaxel administered alone and with progesterone were performed in eight patients. Results: The pharmacokinetic parameters of paclitaxel were highly variable. High-dose progesterone increased the peak plasma levels (3.00 ± 0.94 vs. 4.15 ± 1.63 M; P=0.029; mean ± SD) and the area under the curve (AUC; 14.3 ± 4.75 vs. 17.3 ± 5.59 M × h; P=0.006) of paclitaxel. The absolute neutrophil and platelet nadir counts did not differ significantly between the paclitaxel and the combined treatment cycles. Three of the 20 patients documented to have progressive disease on paclitaxel alone had partial responses when high-dose progesterone was added to the paclitaxel regimen. Conclusion: Progesterone had a statistically significant impact on the pharmacokinetics of paclitaxel. The addition of high-dose progesterone to paclitaxel is feasible, but the small number of patients prevents conclusions being drawn about the clinical efficacy of combined progesterone and paclitaxel.

Frequency of occult residual melanoma after excision of a clinically positive regional lymph node.

A retrospective study of the medical records of 102 patients with Stage II malignant melanoma was conducted to determine the frequency of occult residual melanoma after excision of a clinically positive regional lymph node. Twenty-one patients met the study criteria for evaluation. Fifteen of 22 dissections were positive for melanoma (68.1%). These results support definitive regional lymph node dissection if the results of excisional biopsy are abnormal. No conclusions can be drawn from these data regarding the survival advantage of therapeutic regional lymph node dissection.

Increase in tumor GADD153 mRNA level following treatment correlates with response to paclitaxel.

Purpose: We investigated the relationship between the basal and treatment-induced change in the tumor expression of the drug resistance gene MDR1 and the cellular injury response gene GADD153, and clinical response to paclitaxel treatment. Methods: MDR1 and GADD153 mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) in tumor samples obtained by fine needle aspiration biopsy from 14 patients before and 24 h after paclitaxel infusion. Results: There was no difference between responders and non-responders with respect to either the basal MDR1 mRNA level or the change in MDR1 mRNA level at 24 h after treatment (P = 0.464). Likewise, there was no difference in basal GADD153 mRNA level between responders and non-responders. However, there was a significantly greater increase in GADD153 mRNA at 24 h in responders compared with non-responders (P = 0.005). An increase in GADD153 mRNA level of 1.5-fold or higher predicted response with a sensitivity of 86% and a specificity of 100%. Conclusions: An increase in GADD153 mRNA level reflects chemotherapy-induced damage sufficient to be manifest as a clinically detectable reduction in tumor volume. Measurement of the change in GADD153 mRNA level successfully identified patients destined to respond as early as 24 h post-treatment.

Interruptions of once-daily thoracic radiotherapy do not correlate with outcomes in limited stage small cell lung cancer: analysis of CALGB phase III trial 9235.

PURPOSE Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study. MATERIAL AND METHODS This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes<1000/mm3 or platelets<75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration). RESULTS TRT interruptions > or =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (>70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration. CONCLUSION Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.

A phase I trial of intraperitoneal carboplatin and etoposide with granulocyte macrophage colony stimulating factor support in patients with intraabdominal malignancies

Background. Although somewhat controversial, there are data to suggest that patients with ovarian cancer may experience a survival advantage if the dose intensity of platinum‐containing regimens can be maximized. Administration of chemotherapeutic agents via the intraperitoneal route offers the opportunity to increase dose intensity of several chemotherapeutic agents.