George W. Wirtanen

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.

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.

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.

Accuracy of bipedal lymphangiography in testicular tumors

The accuracy of bipedal lymphangiography to evaluate nodal metastases in patients with testicular malignancies is discussed. A total of 108 patients were evaluated. Histologic correlation was available in 45 cases. The over-all accuracy was 89% which compares favorably with other large series.

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 intraarterial 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.

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.

Percutaneous lymph node aspiration in patients with gynecologic tumors

Sixty-one patients with gynecologic malignancies had percutaneous transperitoneal lymph node aspiration performed by a flexible 8-inch needle guided to the nodes under monoplanar fluoroscopy. Of the patients who had malignant cells aspirated from pelvic and periaortic lymph nodes, 64% died or are alive with disease. Only 30% who had negative cytologic testing died or are alive with disease. Of the patients who had malignant cells aspirated from periaortic nodes, 69% died or are alive with disease whereas only 8% with negative cytologic testing died or are alive with disease. We believe that therapy such as extended field irradiation can be given on the basis of these results.

Primary anterior mediastinal malignant teratoma. A case report with long‐term survival

Primary anterior mediastinal malignant teratoma is an uncommon tumor. A 17‐year‐old girl presented with an advanced tumor extending parasternally. Therapy consisted of intraarterial iododeoxyuridine and irradiation followed by surgical resection after failing multidrug therapy. The patient is without evidence of disease 23 years after therapy.

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.

Utilization of Special Computerized Tomography and Nuclear Medicine Techniques for Quality Control and for the Optimization of Combined Precision Chemotherapy and Precision Radiation Therapy

We have previously reported the use of a combination of precision (selective, intra-arterial) chemotherapy and precision radiotherapy for advanced pancreatic, biliary tract, and sarcomatous malignancies. There were some remarkable responses, but also a few poor responses and even some morbidity. Accordingly, we are attempting to develop methods of pre-selecting those patients whose tumors are likely to respond to such therapy, as well as methods for improving the therapeutic ratio by the rational optimization of combined therapy. Specifically, clinical tumor blood flow characteristics (which we monitor with nuclear medicine techniques) may provide useful criteria for such selection. Also, we qualitatively evaluate the drug distribution or exposure space with specialized color-coded computerized tomography images, which demonstrate spatially dependent enhancement of intra-arterial contrast in tumor and in adjacent normal tissues. Such clinical data, we suggest could improve the quality control aspects of intra-arterial chemotherapy administration, as well as the possibility of achievement of a significant therapeutic ratio by the integration of precision chemotherapy and precision radiation therapy.