Stephen Frytak

Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group.

One‐hundred‐ninety‐four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high‐dose (6000 rads) radiation therapy alone, to moderate‐dose (4000 rads) radiation + 5‐fluorouracil (5‐FU), and to high‐dose radiation plus 5‐FU. Median survival with radiation alone was only 51/2 months from date of diagnosis. Both 5‐FU‐containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Forty percent of patients treated with the combined regimens were still living at one year compared with 10% of patients treated with radiation only. Survival differences between 4000 rads plus 5‐FU and 6000 rads plus 5‐FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level.

Failure of High-Dose Vitamin C (Ascorbic Acid) Therapy to Benefit Patients with Advanced Cancer

One hundred and fifty patients with advanced cancer participated in a controlled double-blind study to evaluate the effects of high-dose vitamin C on symptoms and survival. Patients were divided randomly into a group that received vitamin C (10 g per day) and one that received a comparably flavored lactose placebo. Sixty evaluable patients received vitamin C and 63 received a placebo. Both groups were similar in age, sex, site of primary tumor, performance score, tumor grade and previous chemotherapy. The two groups showed no appreciable difference in changes in symptoms, performance status, appetite or weight. The median survival for all patients was about seven weeks, and the survival curves essentially overlapped. In this selected group of patients, we were unable to show a therapeutic benefit of high-dose vitamin C treatment.

Randomized Clinical Trial of Diethylstilbestrol versus Tamoxifen in Postmenopausal Women with Advanced Breast Cancer

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo.

The antiemetic activity and side-effects of delta-9-tetrahydrocannabinol (THC) were evaluated in 116 patients (median age 61 years) receiving combined 5-fluorouracil and semustine (methyl CCNU) therapy for gastrointestinal carcinoma. In a double-blind study, patients were randomized to receive THC, 15 mg orally three times a day, prochlorperazine, 10 mg orally three times a day, or placebo. The THC had superior antiemetic activity in comparison to placebo, but it showed no advantage over prochlorperazine. Central nervous system side-effects, however, were significantly more frequent and more severe with THC. With the dosage and schedule we used, and in our patient population of largely elderly adults, THC therapy resulted in an overall more unpleasant treatment experience than that noted with prochlorperazine or placebo. Although THC may have a role in preventing nausea and vomiting associated with cancer chemotherapy, this role must be more clearly defined before THC can be recommended for general use.

A phase I clinical trial of recombinant human tumor necrosis factor

We performed a Phase I assessment of recombinant human tumor necrosis factor (rTNF‐α) in 27 patients with advanced solid neoplasms. Therapy consisted of a 30‐minute intravenous (IV) infusion on days 1 through 5, every 2 to 3 weeks. Daily doses ranged from 5 μg/m2 to 200 μg/m2. Dose‐limiting sequelae were hypotension, rigors, and phlebitis. Transient fatigue and fever (median, 38°C) were not clearly dose‐related between 5 μg/m2/d and 150 μg/m2/d. Other reversible complications in three patients included transient leukopenia (leukocyte count, 1.3,1.2 × 103/μl in two patients) at a dose of 5 μg/m2/d and 150 μg/m2/d, respectively; and thrombocytopenia (leukocyte count, 73 × 103/μl) at 10 μg/m2/d. Among 22 patients with initial and subsequent differential counts, the median number of eosinophils at the commencement of therapy was 182 cells/μl compared with a subsequent median of 462 cells/μl. We also detected hypertriglyceridemia in all patients. The median baseline increased from 93 mg/dl (range, 56 to 219 mg/dl) to 203 mg/dl (range, 94 to 454 mg/dl). From our experience, a clinically manageable outpatient regimen for Phase II trials consists of rTNF‐α (150 μg/m2) followed by a 1‐hour IV infusion of 500 ml of normal saline to abrogate hypotension daily for 5 days every 2 weeks for four cycles, then every 3 weeks thereafter to facilitate recovery from constitutional sequelae.

Neurologic Toxicity Associated with High-Dose Metronidazole Therapy

Excerpt Special interest in hypoxic-cell radiation sensitizers and their potential application in the treatment of malignant tumors has been stimulated by the report of Urtasun and associates (1) o...

Phase II trial of gemcitabine in advanced sarcomas

Care for patients with advanced sarcomas is mainly palliative. Gemcitabine, a nucleoside antimetabolite, is an analog of deoxycytidine that has shown antitumor activity in several tumors. The aim of the current study was to determine the clinical activity of gemcitabine in patients with sarcomas.

Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy.

PURPOSE This analysis was performed to determine the most appropriate volume that should be encompassed by thoracic radiation treatments (TRTs) for patients with limited-stage small-cell lung cancer (LSSCLC) who have responded to initial chemotherapy. PATIENTS AND METHODS A retrospective review of all patients (N = 67) with LSSCLC who were not entered onto a research protocol and were treated at our institution between the years of 1982 and 1990 was performed. Fifty-nine of 67 patients had adequate information regarding the size of the tumor before the start of chemotherapy (computed tomographic [CT] scan of chest or chest x-ray), the size of the tumor before TRT, and the TRT field size based on a simulation radiography. All 59 patients were treated with cyclophosphamide-based chemotherapy, and TRT was generally delivered concomitantly with chemotherapy following two to three cycles of chemotherapy alone. RESULTS Of 59 patients, 28 were treated with TRT field sizes that encompassed postchemotherapy tumor volumes, and 31 patients were treated with TRT field sizes that encompassed prechemotherapy tumor volumes (defined as a volume that included at least a 1.5-cm margin on the prechemotherapy tumor volume). Nineteen patients had an intrathoracic recurrence of disease as the first site of recurrent small-cell carcinoma: 10 of 31 patients treated with TRT fields that encompassed prechemotherapy tumor volumes and nine of 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes. For the 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes, the greatest distance that the prechemotherapy tumor volume (without margins) extended beyond the edge of the TRT field was 0.5 to 5.0 cm, with a median of 2.5 cm. All 19 of the intrathoracic recurrences were in-field failures, although two patients (one prechemotherapy volume and one postchemotherapy volume) did have concurrent pleural effusions. CONCLUSION These results indicate that the use of TRT fields that encompass postchemotherapy tumor volumes does not increase the risk of marginal failures or intrathoracic failures outside the TRT field.

Leukoencephalopathy in small cell lung cancer patients receiving prophylactic cranial irradiation

The cases of 283 small cell lung cancer patients who received treatment with combination chemotherapy with or without prophylactic cranial irradiation (PCI) were reviewed to determine the incidence of leukoencephalopathy. The overall incidence was 10%. Of all patients receiving PCI, 17% developed neurotoxicity, and of those receiving PCI and surviving ≥ 1.5 years, 37% suffered neurologic sequelae. In those receiving PCI but surviving<1.5 years, the incidence of neurotoxicity was 4%. The mean time interval between the end of PCI and the onset of neurotoxicity was 17 months (range 2–63 months). The PCI dose ranged from 2600–3600 cGy. None of the patients not receiving PCI developed neurotoxicity. The incidence of neurotoxicity in long-term survivors (≥1.5 years) with respect to PCI dose was ≤3000 cGy (25%), 3200 cGy (56%), 3600 cGy (36%). Almost all of the patients getting PCI also received lomustine, an agent associated with DNA repair inhibition and synergism with DNA damaging agents such as ionizing radiation or alkylating agents. Under the conditions of our study, PCI was associated with an unacceptable risk of neurotoxicity. Until further information is forthcoming, one should proceed with caution when using PCI in conjunction with lomustine.

Randomized phase II clinical trial of adriamycin, methotrexate, and actinomycin-d in advanced measurable pancreatic carcinoma. A gastrointestinal tumor study group report

Sixty‐six patients with advanced pancreatic carcinoma were randomized to receive single agent chemotherapy with either adriamycin, methotrexate, or actinomycin‐D using conventional dose, route and schedule of administration. All patients had measurable lesions which were used for objective assessment of response. For adriamycin, 2 of 25 patients (8%) evidenced a partial response (2 of 15 (13%) previously untreated patients). One of 25 patients treated with methotrexate and one of 28 who received actinomycin‐D responded. The duration of responses ranged from 43–64 days for those patients with no chemotherapy prior to study entry. The median survival of patients who received adriamycin as initial treatment was 12 weeks compared to 8 weeks for methotrexate and 6 weeks for actinomycin‐D therapy.