James Raschko

Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study

Oral transmucosal fentanyl citrate (OTFC) is a novel opioid formulation in which the potent synthetic mu-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth. It is undergoing investigation as a treatment for cancer-related breakthrough pain, a prevalent phenomenon defined as a transitory flare of moderate to severe pain that interrupts otherwise controlled persistent pain. There have been no controlled trials of other treatments for this condition. To evaluate the safety and efficacy of ascending doses of OTFC, a novel controlled dose titration methodology was developed that applied blinding and randomization procedures to the evaluation of recurrent pains in the home environment. The study was a multicenter, randomized, double-blind dose titration study in ambulatory cancer patients. The sample comprised adult patients receiving a scheduled oral opioid regimen equivalent to 60-1000 mg oral morphine per day, who were experiencing at least one episode per day of breakthrough pain and had achieved at least partial relief of this pain by use of an oral opioid rescue dose. After collection of 2 days of baseline data concerning the efficacy of the usual rescue drug, patients were randomly treated with either 200 or 400 microg OTFC unit doses in double-blind fashion. Up to two breakthrough pains each day could be treated with up to four OTFC unit doses per pain. OTFC in unit doses containing 200, 400, 600, 800, 1200 or 1600 microg of fentanyl citrate were available for the study. The unit dose was titrated upward in steps until the patient had 2 consecutive days on which breakthrough pain could be treated with the single unit dose, titration was ineffective at a 1600 microg unit dose, or 20 days elapsed. To maintain the double-blind, orders to titrate up were ignored one-third of the time according to a pre-defined randomization schedule accessible only to an unblinded study pharmacist. Main outcome measures included, numeric or categorical measures of pain intensity, pain relief, and global assessment of drug performance. Dose response relationships were found suggesting that the methodology was sensitive to opioid effects. Seventy-four percent of patients were successfully titrated. There was no relationship between the total daily dose of the fixed schedule opioid regimen and the dose of OTFC required to manage the breakthrough pain. Although the study was not designed to provide a definitive comparison between OTFC and the usual rescue drug, exploratory analyses found that OTFC provided significantly greater analgesic effect at 15, 30 and 60 min, and a more rapid onset of effect, than the usual rescue drug. Adverse effects of the OTFC were typically opioid-related, specifically somnolence, nausea and dizziness. Very few adverse events were severe or serious. This study demonstrated the feasibility of controlled trial methodology in studies of breakthrough pain. OTFC appears to be a safe and effective therapy for breakthrough pain, and dose titration can usually identify a unit dose capable of providing adequate analgesia. If the lack of a relationship between the effective OTFC dose and fixed schedule opioid regimen is confirmed, dose titration may be needed in the clinical use of this formulation. Further investigation of OTFC as a specific treatment for breakthrough pain is warranted.

High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival.

PURPOSE To examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue. PATIENTS AND METHODS Between June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP). Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT. RESULTS With a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen. In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05). OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02). In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001). CONCLUSION HDCT in selected patients with HRBC is safe and warrants further evaluation. Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.

Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support.

PURPOSE To evaluate the activity of two cycles of high-dose ifosfamide, carboplatin, and etoposide (ICE) with autologous hematopoietic progenitor cell support (aHPCS) in patients with poor-prognosis, chemotherapeutically sensitive germ cell cancer. PATIENTS AND METHODS Twenty patients with germ cell tumor who had persistent disease or relapse from standard-risk or high-risk presentation were entered on this pilot study. The entry criteria included relapsed gonadal and extragonadal germ cell cancer unlikely to be cured by standard salvage therapy but without proven refractoriness to chemotherapy. Treatment consisted of two cycles of ICE chemotherapy with mesna uroprotection and aHPCS. On the first cycle, ifosfamide (IFX), 2 gm/m2; carboplatin, 400 mg/m2; and etoposide, 20 mg/kg, were administered on days -6, -5, and -4. On the second cycle, the doses and schedule of carboplatin and etoposide were identical, and patients with normal renal function received additional IFX, 2 g/m2 on day -3 and 1 g/ m2 on day -2. Mesna, 600 mg/m2 every 6 hours, was given until 24 hours following the final dose of IFX on each cycle, and autologous bone marrow and/or peripheral stem-cells were infused on day 0. RESULTS All twenty patients are assessable for toxicity and current disease status. Two patients received only one cycle of therapy, one because of the development of active hepatitis C following cycle 1, and one because of renal insufficiency. No patient died as a result of protocol therapy, and no patient developed debilitating peripheral neuropathy, symptomatic hearing loss, or severe renal insufficiency requiring dialysis. The median time to recovery of > or = 500 neutrophils/microL and platelets > or = 50,000/microL was day +11 and day +15, respectively. The median maximum creatinine was 1.6 mg/dL on each treatment cycle, and there was no other significant organ toxicity. With a median follow-up of 45 months, nine patients are alive and disease-free following protocol chemotherapy. One patient with embryonal cancer developed progressive pulmonary metastases 3 months after completing high-dose therapy, underwent complete resection of lung metastases, and remains disease-free at 63+ months. Eight patients are continuously disease free at 23+ to 70+ months after protocol therapy. Eleven patients died of progressive disease between 4 and 23 months following completion of treatment. CONCLUSION These results compare favorably to other studies in similarly selected patients undergoing salvage therapy with one or two cycles of chemotherapy containing high-dose carboplatin and etoposide with or without cyclophosphamide (CTX) or IFX. The excellent safety and tolerability profile of this regimen and its encouraging activity in poor-prognosis patients make it worthy of further study as part of initial therapy in randomized protocols for high-risk disease and early in the treatment of relapsed germ cell cancer.

Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis

Purpose: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. Methods: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200–1500 mg/m2, followed by a 23-h infusion of 800–6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. Results: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 μM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 ± 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 ± 41 ml/min per m2) versus without CNS disease (59 ± 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. Conclusion: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (>1 μM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.

High-dose doxorubicin, etoposide, and cyclophosphamide with stem cell reinfusion in patients with metastatic or high-risk primary breast cancer

Background. Chemotherapy with a doxorubicin‐containing regimen results in high overall response rates in the treatment of metastatic adenocarcinoma of the breast; the combination of doxorubicin, etoposide, and cyclophosphamide has produced a response rate of 84% in untreated patients with stage IV disease. Recent data suggest that selected groups of patients with metastatic disease treated with high‐dose chemotherapy and stem cell support may enjoy unmaintained, long‐term remission. This study was designed to establish the feasibility of administering the combination of high‐dose infusional doxorubicin, etoposide, and cyclophosphamide followed by autologous stem cell rescue in patients with responsive metastatic, or high‐risk primary breast cancer.

Mitomycin C and menadione for the treatment of lung cancer: a phase II trial

SummaryA phase II trial of menadione [2.5 gm/m2 as a continuous intravenous (iv) infusion over 48 hours] followed by mitomycin C (10–20 mg/m2 iv bolus) administered every 4 to 6 weeks was performed in 23 patients with advanced lung cancer. Menadione, a vitamin K analog which lowers intracellular pools of reduced glutathione (GSH), was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating agent chemotherapy. The median age of patients entered on this trial was 62 years; performance status ranged from 60–90%. Two of the 23 patients (9%; 95% confidence interval, 1% to 28%) had objective responses lasting 3.5 months and 13 months respectively, while 4 additional patients developed short unconfirmed responses (lacking follow-up response data to estimate response duration). Median survival for all patients was 5.5 months. Treatment with mitomycin C and menadione was well tolerated except for hematologic toxicity and cardiac events of unclear relationship to the study drugs. Thirty-one percent of treatment courses were complicated by grade 3 or 4 hematologic toxicity including one episode of hemolytic anemia. One patient developed interstitial pneumonitis. Two patients developed a decrease in left ventricular ejection fraction: one patient remained asymptomatic, but the other patient developed congestive heart failure. Although only 9% of patients had confirmed objective responses, 28% (5 of 18) of the patients with non-small cell lung cancer demonstrated biological activity (tumor regressions fulfilling the criteria for objective response on a single occasion but 3 patients lacking a follow-up measurement to document response duration) to this combination of mitomycin C and menadione. We conclude that further studies of chemomodulation in non-small cell lung cancer are appropriate.

Phase I study of mitomycin C and menadione in advanced solid tumors.

A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n=51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m2 over 48 h were associated with hemolysis, so subsequent dose levels of menadione ranged from 1.0 to 3.0 g/m2 with mitomycin C from 5 to 20 mg/m2. All three patients treated with menadione at 8.0 g/m2 and the single patient treated at 4.0 g/m2 with mitomycin C at 5 mg/m2 developed clinically significant hemolysis despite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1–2.5 g/m2 over 48 h with mitomycin C doses up to 20 mg/m2. Since the 3.0 g/m2 dose of menadione was associated with mild hemolysis in three of four patients, the maximum tolerated dose of menadione was established at 2.5 g/m2. All of the mitomycin dose levels were tolerated without unexpected toxicities attributable to the combination. Prolonged infusions of menadione at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by menadione-related redox cycling. There was no detectable deleterious effect of pre-exposure to menadione on mitomycin C tolerance. We recommend a combination of menadione at 2.5 g/m2 as a continuous intravenous infusion and mitomycin C at 15 mg/m2 for further study in solid tumors for which treatment with single-agent mitomycin C is appropriate.

Mitomycin C and menadione for the treatment of advanced gastrointestinal cancers: a phase II trial

A phase II trial of menadione (2.5 g/m2 as a continuous intravenous infusion over 48 h) followed by mitomycin C (10–20 mg/m2 i.v. bolus) administered every 4–6 weeks was performed in 43 patients with advanced gastrointestinal cancer. Menadione, a vitamin K analog that lowers intracellular pools of reduced glutathione, was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating-agent chemotherapy. The median age of patients entered on this trial was 58 years; performance status ranged from 60%–100%. None of the 43 evaluable patients obtained an objective response to this combination regimen. Median survival was 6.6 months. Treatment with menadione and mitomycin C was reasonably well tolerated except for hematological toxicity. A total of 27% of treatment courses were complicated by grade 3 or 4 hematological toxicity including one episode of hemolytic anemia and one episode of hemolytic uremic syndrome. One patient developed irreversible interstitial pneumonitis, and 1 patient had an asymptomatic decrease in the left0ventricular ejection fraction. Despite preclinical evidence indicating that menadione pretreatment enhances the cytotoxicity of mitomycin C, our study documents the resistance of advanced gastrointestinal cancers, particularly colorectal cancer, to mitomycin C modulated by menadione.

High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome.

We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with ≥ 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150–775 mg/m2infused over 24 hours, doxorubicin 165 mg/m2as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg–1. There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m2dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan–Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51–83%) and 77% (95% CI; 64–93%). Paclitaxel up to 725 mg/m2infused over 24 hours in combination with with doxorubicin 165 mg/m2and cyclophosphamide 100 mg kg–1is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing.

Predictors of long-term outcome following high-dose chemotherapy in high-risk primary breast cancer

We report on a predictive model of long-term outcome in 114 high-risk breast cancer patients treated with high-dose chemotherapy between 1989 and 1994. Paraffin-blocks from 90 of the 114 primaries were assessed for the presence of five risk factors: grade, mitotic index, protein expression of p53, HER2/neu, and oestrogen/progesterone receptor status; we could analyse the effect of risk factors in 84 of these 90 tumours. Seven-year relapse-free and overall survival was 58% (95% confidence interval 44–74%) and 82% (95% confidence interval 71–94%) vs 33% (95% confidence interval 21–52%) and 41% (95% confidence interval 28–60%) for patients whose primary tumours displayed ⩾3 risk factors vs patients with ⩽2 risk factors. For the entire group of 168 high-risk breast cancer patients, inflammatory stage IIIB disease and involved post-mastectomy margins were associated with decreased relapse-free survival and overall survival; patients treated with non-doxorubicin containing standard adjuvant therapy experienced worse overall survival (RR, 2.08; 95% confidence interval 1.04 to 4.16; P=0.04), while adjuvant tamoxifen improved overall survival (RR, 0.65; 95% confidence interval 0.41–1.01; P=0.054). Future trial designs and patient selection for studies specific for high-risk breast cancer patients should include appropriate prognostic models. Validation of such models could come from recently completed randomised, prospective trials.