H. Haynes

All-trans retinoic acid and interferon-α-2a in patients with metastatic or recurrent carcinoma of the uterine cervix : Clinical and pharmacokinetic studies

BACKGROUND Recent clinical trials with a combination of interferon (IFN alpha) and 13 cis-retinoic acid resulted in high response rates among women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha. METHODS Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFN alpha in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFN alpha was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m2 orally 3 times per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug. RESULTS Fourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUC) was significantly different between the two groups. The average AUC on Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28. CONCLUSIONS The combination of tRA + IFN alpha was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.amplify these observations by employing the isomer of 13 cis-retinoic acid, allRonalde Rameau, M.D. trans retinoic acid (tRA), in combination with IFNa. Astrid Quish, M.D. METHODS. Sequential clinical trials were initiated by the New York Gynecologic John Mandeli, M.D. Oncology Group to test the combination of tRA and IFNa in women with metastatic Robert Gallagher, M.D. or recurrent carcinoma of the cervix who had failed primary therapy. IFNa was Steven Hallam, B.S. administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was Abbie Fields, M.D. administered at 50 mg/m orally 3 times per day on a daily schedule (daily regiGary Goldberg, M.D. men), whereas in the second trial, tRA was administered at the same dose 3 times Frances McGill, M.D. per day, but only on Days 1–3 each week (intermittent schedule). Clinical outcomes Scott Jennings, M.D. included response to therapy and survival. Plasma pharmacokinetic studies of tRA Robert C. Wallach, M.D. were performed in both trials to assess the effects of different schedules on plasma Carolyn D. Runowicz, M.D. levels of the drug. for the New York Gynecologic RESULTS. Fourteen women with metastatic or recurrent squamous cell carcinoma Oncology Group of the cervix were enrolled in the daily trial and 12 women in the intermittent trial.

A phase I clinical trial of prolonged infusion of hydroxyurea in combination with hyperfractionated, accelerated, external radiation therapy in patients with advanced squamous cell cancer of the head and neck

Background: Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was initiated to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck.Methods: Patients were required to have histologically-documented and radiographically-staged locally advanced SCC of the hypopharynx (AJC stages II, III or IV), oropharynx (AJC stage IV), or oral cavity (AJC stage IV) not amenable to reasonable surgical resection. Eligible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, accelerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minimum interfraction interval) on weekdays and 1.2 Gy delivered daily on the weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydroxyurea (CHU) was administered at 0.25–0.375 mg/m2/min as a continuous intravenous infusion daily for 5 days with weekends days off for the duration of the radiation therapy. The dose of HU was increased by 0.125 mg/m2/min between dose levels until DLT was reached in 2/6 patients. If the primary had a complete clinical response and biopsies were negative, planned neck dissections were performed.Results: Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m2/min was tolerated by 3/3 patients. At 0.375 mg/m2/min, 3/6 patients experienced grade 3–4 infections, with one patient having a non-fatal, subendocardial infarction. At 0.313 mg/m2/min, no patient experienced DLT.Conclusion: The MTD for CHU-CHRT was 0.313 mg/m2/min. The toxicities were primarily mucosal and a phase II study is in progress.

PHASE I CLINICAL TRIAL OF PARENTERAL HYDROXYUREA IN COMBINATION WITH PELVIC AND PARA-AORTIC EXTERNAL RADIATION AND BRACHYTHERAPY FOR PATIENTS WITH ADVANCED SQUAMOUS CELL CANCER OF THE UTERINE CERVIX

PURPOSE Oral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix. METHODS This Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity. RESULTS At dose level 1 (0.25 mg/m(2)/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m(2)/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m(2)/min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU. CONCLUSIONS The maximal tolerated dose of parenteral HU was 0.375 mg/m(2)/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.

Phase II trial of chemotherapy, external and intraluminal radiation plus surgery for oesophageal cancer

A pilot study was performed to assess the feasibility of combining 5-fluorouracil, recombinant alpha-2b-interferon, external radiation therapy and intraluminal high dose rate brachytherapy with surgery in patients with locally advanced esophageal carcinoma. 5-fluorouracil, 750 mg m−2, was administered via continuous 5-day infusion beginning day 1 and weekly thereafter; interferon, 10 mu subcutaneously, was administered three times per week beginning day 1 and sargramostin, 5µg kg−1, was administered on days without 5-fluorouracil. External radiation began on day one using 1.5 daily fractions to 55.5 Gy. Intraluminal brachytherapy was delivered concomitantly once each week for 5 fractions of 4 Gy. None of the first eight patients went to surgery. The external radiation was changed to 1.5 Gy BID to 45 Gy followed by BID intraluminal radiation to 15 Gy. Of the last four patients, there was one case of radiation myelitis. It was found that successful surgery was not possible and excessive toxicities, including radiation myelitis, occurred with this aggressive regimen.