Fred J. Ansfield

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 × 4, then 15 mg/kg/day × 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.

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.

Intrahepatic arterial infusion with 5-fluorouracil

Since 1964, 200 patients were treated with intra‐arterial 5‐FU infusion. Of them, 127 failed with intravenously injected 5‐FU, and 27 were unsuitable for such treatment as their involvement was so far advanced as to have jaundice due to extensive parenchymal involvement. In all but 12 patients, the catheter was placed percutaneously through the brachial artery. The criteria for improvement included at least a 6‐cm decrease in distance of the liver edge from the xiphoid or costal margin, a 50% decrease in the abnormal enzyme studies, a return of elevated bilirubin levels to normal so that jaundice disappeared, and all these responses continued for at least 2 months. Inpatients were treated with 5‐FU, 25 mg/kg/day × 4, then 15 mg/kg/day for 7 or 8 days. If no toxicity appeared, the 5‐FU was then increased to 20 mg/kg/day until the total infusion period was 21 days, and the catheter was removed. Outpatients received 500 mg daily in 140 ml 5% dextrose and 2,500 units heparin daily for 90 days, and then the catheter was removed. Following the termination of the infusion, the patient was given weekly intravenous doses of 5‐FU at 15 mg/kg. After several months, with reactivation of the disease, the intra‐arterial infusion was repeated. Minimal toxicity occurred, and there was one death from the procedure. Morbidity in the forms of infection and hemorrhage did occur, but, in the last 100 patients, there were only 2 minor infections. Of 113 study patients, 69 (61%) met our criteria of improvement and had a median survival of 8.7 months. Forty‐four (39%) failed, and their median survival was 2.5 months. This demonstrates a significantly increased survival in the responders.

Adenocarcinomas of stomach, pancreas, liver, and biliary tracts. Survival of 328 patients treated with fluoropyrimidine therapy

A series of 328 patients with advanced cancers of the stomach, pancreas, liver, and biliary tract were treated with intensive fluoropyrimidine therapy, including 5‐FU, 5‐FUDR, intra‐arterial infusions of 5‐FU, and 5‐FU plus radiotherapy. Survival patterns were analyzed with particular emphasis on survival over 1 year after treatment was begun. Patients with stomach cancer had median survivals of 5–7 1/2 months; over‐all survival of more than a year was seen in 22%. Radiation therapy plus 5‐FU was associated with slightly longer survival, as was prior resection of the primary tumor. Patients with pancreatic cancer survived four months median, with 12.5% surviving longer than 1 year. Survial was most dependent on extent of disease at the onset of therapy. Hepatobiliary cancer continued to present a very bleak prognosis. However, excellent responses occurred in 3/31 patients with liver cell or bile duct carcinoma. Intra‐arterial infusions for liver involvement in these patients appeared to contribute little benefit to over‐all survival, although dramatic responses were observed in two patients with primary liver tumors. It would appear that fluoropyrimidine therapy may modestly increase over‐all survival in advanced stomach cancer. Survival in pancreatic cancer does not seem to be favorably influenced by this therapy.

Triple drug therapy in testicular tumors

Thirty‐four patients with disseminated choriocarcinoma, embryonal cell carcinoma, and teratocarcinoma of the testis were treated with triple drug therapy—chlorambucil, methotrexate, and actinomycin D as employed by Li et al. Although two‐thirds of patients with measurable lesions had at least a 50% regression, reactivation usually occurred within 3 months. Four patients have complete regressions which are being maintained, the longest a seven and a half‐year complete remission for a patient with choriocarcinoma. It is recognized that there is a high recurrence rate following orchiectomy even in patients with negative nodes. This fact coupled with the responsiveness of these radioresistant tumors to triple therapy, and without life‐threatening toxicity, led us to employ this as adjuvant chemotherapy for one year in 13 patients following orchiectomy. There has been no recurrence in 11 of these patients, with the longest follow‐up five and one‐half years in a patient with choriocarcinoma. No patient in either series had x‐ray therapy.

Treatment of advanced cancer of the head and neck

The combination of radiation plus 5‐FU produced a significantly increased survival in patients with advanced tonsil and intra‐oral cancer compared to patients who received radiotherapy alone. There was no significant difference in survival between these 2 treatment modalities in advanced cancer of the nasopharynx, hypopharynx, extrinsic larynx, or primary unknown. Similarly, there was no significant difference in survival resulting from these 2 methods of treatment in patients with T1 and T2 as well as T4 head and neck cancers, but a highly significant difference in those with T3 lesions.

A clinical trial of megestrol acetate in advanced breast cancer

Megestrol acetate is a potent oral progestin with anti‐estrogenic activity. It was given in doses of 40‐mg tablets after each meal and at bedtime (160 mg daily) to 30 patients with progressing disseminated breast cancer. It was well tolerated; no toxic reactions were observed. Seven patients < 23.3%) met the criteria of improvement as employed by the Cooperative Breast Cancer Group, and had a mean objective remission of 5.5 months. Most of the seven responders to megestrol acetate had prior trials with a sex hormone, and one or more cytotoxic compounds; three had a modified Coopers five‐drug combination. The circumstance that this progestin has demonstrated utility late in the sequence of therapy bodes well for this compound having a useful role in the treatment of advanced breast cancer.

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

Gastric ulceration developed in eight patients during intrahepatic 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.

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.

Five‐drug therapy in advanced breast cancer. Factors Influencing Toxicity and Response

Seventy‐four women with advanced breast cancer were treated with a combination of continuous oral prednisone (45 mg/day × 2 wks, 30 mg/day × 2 wks, then 15 mg/day) and cyclophosphamide (100 mg/day), and weekly injections of 5‐fluorouracil, 500 mg; methotrexate, 25 mg; and vincristine, 1 mg. Thirtyone of 74 showed an objective response to therapy for a median length of 5 months. The responses were seen in soft tissue and visceral metastases. Definite recalcification of lytic bone lesions was seen in only 1 patient. Prior therapy decreased the number of responses to five‐drug therapy. With no prior cytotoxic therapy, 11/16 responded; with prior 5‐FU therapy 13/25 responded; with both prior 5‐FU and alkylating agent therapy, 7/33 responded. The median length of response was similar regardless of prior therapy. Toxicity was moderately severe; dosage modifications were necessary in the majority of patients, and there were seven drug contributory deaths during therapy. After failure of this combination, only 5/28 responded briefly to a variety of therapeutic measures. Comparable survival from first recurrence was seen whether response or failure occurred on five‐drug therapy. Trials of sequential vs. combination therapy will be necessary to define the role of combination therapy in advanced breast cancer.