Intraarterial iododeoxyuridine infusion combined with irradiation. A pilot study.

The halogenated pyrimidine, iododeoxyuridine (IUdR), enhances cytotoxicity of ionizing irradiation experimentally. Continuous intraarterial infusion of IUdR was combined with irradiation to maximize drug concentration in tumor and reduce potential systemic toxicity. Percutaneous tumor-specific artery catheterization was utilized in five patients, with delivery of IUdR (20 mg/kg/day) by continuous infusion 5 days prior to irradiation treatments and continued for 10-14 days. Infusion vessels included the internal mammary, the internal iliac, the renal, the common femoral, and the bronchial arteries. Conventional radiotherapy fields, fractionation, and total doses were utilized, and therapy was well tolerated. Low-grade leukopenia and thrombocytopenia was observed several weeks following infusion. A clinically nonsignificant skin reaction was observed within the irradiation fields 2-3 weeks after initiation of irradiation in several patients. No alopecia or stomatitis was observed. This study minimizes initial hepatic dehalogenation of IUdR when given by intraarterial administration. Two patients have been free of disease for over 20 years, with no long-term toxicity from IUdR therapy.

An evaluation of the effect of vincristine added to cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone in advanced breast cancer.

A multi-institutional randomized clinical trial was carried out to evaluate the effect of vincristine (V) added to cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) for the treatment of metastatic breast cancer. There were 427 patients entered into the study and randomly assigned to one of the two treatments, i.e. the five drug therapy CMFPV or the four drug therapy CMFP. The differences in patient survival and tumor response between the two treatment groups were not statistically significant. The data were also analyzed using multivariate procedures to determine those factors ascertained at entry into the study which were predictors of survival or predictors of response to therapy. The one factor that predicted both response and survival was performance status. An additional important predictor of survival was sites of metastatic involvement. Other significant predictors of response were menopausal age, BUN, and hematocrit.

Phase I-II studies of oral tegafur (ftorafur).

A total of 65 patients with advanced colorectal or breast cancer were given oral tegafur in the phase I study. Of these, 28 patients had accurately measurable lesions and were entered into the phase II study. Patients with liver metastasis, compromised bone marrow, or a decreased oral intake to less than 50% of their normal intake were given a poor-risk schedule consisting of 0.75 g/m2/day divided into 4 doses/day X 28 day unless early toxicity developed. In the absence of any of the above deficits, patients were given a good-risk schedule of 1.25 g/m2/day X 21 days if no toxicity appeared. The courses were followed by a 2-3-wk rest period depending upon the speed to recovery from all reactions and then repeated. Compared with 5-FU, nausea and vomiting occurred more frequently with tegafur while hematologic toxicity was less common and less severe. The paucity of significant hematologic toxicity permitted courses of this drug to be given safely on an outpatient basis even to the point of slight reaction for optimal dosing. No serious reactions occurred in any of the 65 patients. The clinical results showed partial regressions in 6 of 21 colorectal cancer patients and 3 of 7 breast cancer patients. Six of the 9 responses occurred in patients who had previous 5-FU trials. The average duration of regression in the colorectal cancer patients on oral tegafur was 9 mo with a significantly increased survival of the responders.

Clinical results with megestrol acetate in patients with advanced carcinoma of the breast.

Since it has been clearly established that multiple drug chemotherapy is more effective than the use of a single drug for advanced carcinoma of the breast, the latter is not commonly used today. However, upon failure of one of two combinations of drugs, if any of these drugs are then tried singly they are rarely useful, and valuable time is lost. It is at this point that megestrol acetate, a potent progestin, was found to be effective in 30 per cent of a series of 161 patients with advanced carcinoma of the breast. This drug was given orally, 40 milligrams, after each meal and at bedtime, without any toxicity or any undesirable reactions, except a weight gain--not fluid retention--in patients less than 55 years of age. The average duration of response was 8.1 months from onset of megestrol acetate therapy and for the group classified as unchanged, 5.2 months. This drug is at least as effective as any steroid or cytotoxic compound but has the advantage of not producing toxicity and, with the exception of weight gain in patients less than 55 years, no undesirable reactions of any kind, such as bone marrow depression, alopecia, nausea, vomiting or diarrhea. Hence, it can be properly administered by the patient's physician or surgeon. Since oncologists known that medroxyprogesterone therapy had not shown promising use for advanced carcinoma of the breast, it was assumed that megestrol acetate also had little activity, and hence, it was not used. However, those who did give it a trial found it a valuable compound in the management of advanced carcinoma of the breast, even after failure of all hormonal or cytotoxic combination trials. It proved to serve as an important addition to our armamentarium in the management of advanced carcinoma of the breast.

Gastric ulceration in patients receiving intrahepatic infusion of 5-fluorouracil.

Gastric ulceration developed in eight patients during intrahpeatic arterial infusion of 5-FU. Bleeding occurred in four instances and perforation in one. In all cases the catheter tip had been dislodged and was proximal to its correct position, allowing the stomach to be directly infused with 5-FU. No duodenal ulcers were noted. All patients were symptomatic for several days before the diagnosis was made. Of 20 patients with catheter dislodgement, five had documented ulcers, three had upper gastrointestinal bleeding of undetermined etiology, eight had epigastric pain or vomiting and only four were asymptomatic. Prompt determination of catheter position is necessary in patients receiving intrahepatic arterial infusion of 5-FU if symptoms consistent with gastric ulceration occur. Gastric ulcers should be vigorously treated because of the high rate of complications in patients receiving chemotherapy.

Diethylstilbestrol: recommended dosages for different categories of breast cancer patients. Report of the Cooperative Breast Cancer Group.

A total of 523 postmenopausal breast cancer patients with progressive disease were entered in a radomized, double-blind study of four dosages of diethylstibestrol (DES): 1.5, 15, 150, OR 1,500 MG/DAY. Higher dosages produced significantly (p less than .05) higher regression rates: 21% for the 1,500 mg dosage, 17% for the 150 mg dosage, 15% for the 15 mg dosage, and 10% for 1.5 mg dosage. Durations of regressions were similar regardless of the dosages used to induce them. Although the highest dosage produced the highest regression rate overall, selecting the best dosage or treatment of choice for each type of patient based on menopausal age and on dominant metastatic site would result in more regressions.

Review of local soft tissue recurrence of breast cancer irradiated with and without actinomycin-D.

Between 1962 and 1973, regionally recurrent breast cancer was treated in 156 patients by irradiation alone or irradiation with concurrent actinomycin-D. Thirty-two patients were entered into a randomized trial, and 124 patients were retrospectively reviewed. Local control with irradiation alone was achieved in 48 of 80 patients (60%) and in 60 of 76 patients (79%) treated with irradiation and actinomycin-D (p less than .05). Results were remarkably similar in the randomized and retrospective series.

Megace and no diabetes mellitus.

PIP: For the past 4 years this author has treated almost 300 patients with Megace (megestrol acetate) for periods ranging from 6 weeks to 18 months and, in a few instances, longer. Most of the patients received Megace alone, with the remaining group receiving it in combination with 4 other compounds. The development of diabetes mellitus as described in the paper by J.C. Bottino and C.K. Tashima was not observed in any patients. The majority of patients had SMA 12/60 profiles at 6-week intervals during the 1st several months on therapy and later at about 2-month intervals including blood sugars. The several patients who had controlled adult diabetes when placed on Megace therapy alone or in combination developed no exacerbation of their diabetes while on this steroid. All of the patients received 40 mg 4 times daily throughout the period they were on Megace. It is this author's opinion that in the case described by Bottino and Tashima the development of diabetes mellitus was simply coincidental. This opinion is based on the treatment of a large number of patients with this compound.^ieng

A phase III study comparing the clinical utility of four regimens of 5-fluorouracil: a preliminary report.

A clinical trial involving 462 colon, rectum, and breast cancer patients randomized among four different dosage regimens of 5-FU (an intravenous loading course, a weekly intravenous schedule, a nontoxic schedule, and an oral schedule) has shown a significantly better response among colon-rectum cancer patients for the intravenous loading course. In addition, duration of response and time to progression are also significantly better. Overall survival is approaching significance for the colon rectum group (p value .082). In contrast, breast cancer patients show little difference between treatments. Toxicity is somewhat higher for the loading course.

Further clinical studies with megestrol acetate in advanced breast cancer.

A previous study showed activity of megestrol acetate in advanced breast cancer; as a result the study was expanded. Of 101 patients treated with this compound, 26 (26%) met our criteria of improvement. The drug was well tolerated and produced no toxicity and, as opposed to androgens and estrogens, no endocrine effects were observed. Prior hormonal or cytotoxic compounds, including alkylating agents, did not appear to reduce the subsequent responsiveness to this potent progestational compound. We now include it, often as the initial hormonal trial in postmenopausal patients, in our sequential treatment of disseminated breast cancer because of its favorable therapeutic ratio.

Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study.

In 1961, a randomized study was begun at the University of Wisconsin Medical Center in which the treatment of advanced squamous cell carcinoma of the head and neck with radiation therapy was compared with combined treatment with radiation therapy and 5-Fluorouracil. One hundred and thirty-six patients with primary lesions in the oral cavity, the base of the tongue, and the oropharynx were analyzed. Both local control and survival were better in the combined treatment group than in the group with radiation therapy alone. However, in only the oral cavity patient population was the difference statistically significant. Both acute and late complications were also increased in this group of patients who received combined treatment.

Further clinical studies with intrahepatic arterial infusion with 5-fluorouracil.

A total of 419 patients with progressive liver disease, in nearly all cases metastatic from gastrointestinal primaries, were treated by intrahepatic arterial infusion with 5-FU. Three-fourths of these patients had had prior trials with intravenous 5-FU for 1 or 2 months to several years and had been switched to the infusion upon the development of progression. Catheters were placed percutaneously and the patients infused with 5-FU at a dose of 20 to 30 mg/kg/day X 4, then 15 mg/kg/day X 17, at which point the catheter was removed and the patient sent home on weekly i.v. doses at 15 mg/kg. Toxicity, morbidity, and mortality were minimal with the intrahepatic arterial infusion treatment and the rigid criteria of improvement were met by 55% of the study cases. The survival rate of those patients who responded to the treatment was greater than the survival rate of those who failed to respond.

Combined intra-arterial actinomycin D and radiation therapy for surgically unresectable hypernephroma.

One primary goal of preoperative radiotherapy for hypernephroma is to reduce the volume of tumor and, therefore, improve the possibility of resection. It is important that this goal be accomplished promptly so that 4 to 6 weeks after radiation therapy nephrectomy can be attempted. A longer waiting period may allow fibrosis of the normal surrounding tissues and make surgery more difficult. In addition, longer waiting periods could theoretically increase the probability of metastasis. Therefore, we plan to continue clinical investigation on the use of combined intra-arterial actinomycin D and radiotherapy as a possible useful means of improving the possibility of prompt surgical resection, since theoretically this regimen may be a method of increasing the effective radiation dose to the hypernephroma without increasing the effective radiation dose to surrounding normal tissue, such as bowel. The method may also have merit as an improved means of palliating selected patients with metastases who are symptomatic from a bulky primary hypernephroma.

Clinical and theoretical aspects of the treatment of surgically unresectable retroperitoneal malignancy with combined intra-arterial actinomycin-D and radiotherapy.

A small pilot series (eight patients) of surgically unresectable retroperitoneal tumors treated with radiotherapy and a selective, prolonged, continuous intra-arterial infusion of actinomycin-D is discussed, in addition to the possible theoretical advantages for this therapy. For such tumors, there is a very low probability of obtaining local control with conventional radiotherapy alone. However, on the basis of recent knowledge from radiobiology and molecular biology, the technique is a rational attempt to improve the local control probability. Geographic miss with radiotherapy portals is another major cause for local failure with such tumors. We also emphasize the importance of detailed tumor localization procedures. The local responses, some of the local controls, the palliation achieved, and the lack of significant morbidity with this technique have been encouraging. We therefore consider it worthy of further clinical investigation.