James C. Andrews

The use of 3-D dose volume analysis to predict radiation hepatitis

Although it is well known that the tolerance of the liver to external beam irradiation depends on the volume of liver irradiated, few data exist which quantify this dependence. Therefore, a review was carried out of our clinical trial for the treatment of intrahepatic malignancies in which the dose of radiation delivered depended on the volume of normal liver treated. Three dimensional treatment planning using dose-volume histogram analysis of the normal liver was used for all patients. Nine of the 79 patients treated developed clinical radiation hepatitis. None of the patient related variables assessed were associated with radiation hepatitis. All patients who developed radiation hepatitis received whole liver irradiation, as all or part of their treatment, which produced a mean dose ≥ 37 Gy. Dose volume histograms were used to calculate normal tissue complication probabilities based on parameters derived from the literature. The risk of complication was greatly overestimated among patients receiving a high dose of radiation to part of the liver without whole liver treatment. An estimation of model parameters based on the clinical results indicated a larger magnitude for the “volume effect parameter” than the literature estimate (n = 0.69 ± 0.05 vs 0.32; p < 0.001). Computation of the normal tissue complication probabilities using the larger value of n produced a good description of the observed risk of radiation hepatitis. These findings suggest that dose volume histogram analysis can be used to quantify the tolerance of the liver to radiation. The predictive value of this parameterization of the normal tissue complication probability model will need to be tested with liver tolerance and dose volume histogram data from an independent clinical trial.

Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy.

PURPOSEnTo develop more effective regional therapy for patients with unresectable primary hepatobiliary cancer using concurrent conformal radiation therapy and intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd).nnnPATIENTS AND METHODSnTwenty-six patients with unresectable, nonmetastatic primary hepatobiliary cancer were treated with concurrent IAH FdUrd (0.2 mg/kg/d) and conformal hepatic radiation therapy (1.5 to 1.65 Gy per fraction twice per day). The total dose of radiation administered to the tumor depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for toxicity, hepatobiliary relapse, and survival; 17 patients were assessable for response (eight had cholangiocarcinoma not assessable by computed tomographic [CT] scan and one progressed distantly during treatment). The median potential follow-up duration was 27 months.nnnRESULTSnWhole-liver radiation was administered to six patients with diffuse hepatocellular carcinoma (HCC). Eleven patients with localized HCC and nine with cholangiocarcinoma received focal radiation to a dose of 48 to 72.6 Gy. An objective response for assessable patients was observed in 11 of 11 patients treated with focal radiation, but only one of six patients treated with whole-liver radiation. Whole-liver radiation accounted for five of seven patients with > or = grade 3 toxicity and four of six local treatment failures. Two patients had nonfatal radiation hepatitis. The median survival duration for patients with localized hepatobiliary cancer was 19 months, while patients with diffuse HCC had a median survival duration of 4 months. The rate of actuarial freedom from hepatobiliary progression in patients with localized disease was 72% at 24 months.nnnCONCLUSIONnThese findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer.

Long-term results of hepatic artery fluorodeoxyuridine and conformal radiation therapy for primary hepatobiliary cancers

PURPOSEnWe have previously shown that conformal radiation therapy (RT) combined with hepatic artery (HA) fluorodeoxyuridine (FdUrd) had encouraging hepatic control and survival rates for patients with nondiffuse primary hepatobiliary malignancies. With longer follow-up, we were particularly interested if long-term hepatic control and disease-free survival could be achieved, and if late hepatic complications due to radiation therapy were observed.nnnMETHODS AND MATERIALSnPatients with unresectable primary hepatobiliary cancer were treated with concurrent HA FdUrd (0.2 mg/kg/day) and conformal RT (1.5-1.65 Gy per fraction, twice a day), directed only to the liver abnormalities. Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of radiation (48 or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. Patients were followed routinely for response, patterns of failure, long-term toxicity, and survival. The median potential follow-up was 54 months.nnnRESULTSnA total of 22 patients (11 with hepatocellular carcinoma and 11 with cholangiocarcinoma) were treated. There were 10 objective responses in the 11 evaluable patients. The overall freedom from hepatic progression at more than 2 years was about 50%. The median survival was 16 months with an actuarial 4-year survival of about 20%. Gastrointestinal bleeding was the most common long-term toxicity. Late hepatic toxicity was not observed; in fact, hypertrophy of the untreated liver was seen.nnnCONCLUSIONSnCombined conformal RT and HA FdUrd can produce long-term freedom from hepatic progression and survival in patients with unresectable, nondiffuse primary hepatobiliary malignancies. There were no long-term liver complications observed.

Treatment of cancers involving the liver and porta hepatis with external beam irradiation and intraarterial hepatic fluorodeoxyuridine

A Phase I/II clinical trial was designed for patients with malignancies of the liver and porta hepatis. This protocol employed three concepts: a) boost treatment to gross tumor within the liver for selected patients, determined by the dose-volume histogram (DVH) of the normal liver that would be irradiated by boost treatment; b) concurrent use of intraarterial hepatic 5-fluorodeoxyuridine (FdUrd) as a radiosensitizer; and c) hyperfractionation (1.5 Gy fractions given bid greater than 4 hr apart). This report describes the results of treatment of the first 33 patients entered onto this study, with a minimum follow-up of 1 year. Twenty patients received only whole liver irradiation (33 Gy). Thirteen patients were treated with whole liver irradiation (30 Gy) plus a 15 Gy (6 patients) or 30 Gy (7 patients) boost (total 45 Gy and 60 Gy to the tumor, respectively). Forty-eight percent of the evaluable patients (14/29) had an objective response, based on CT scan. The median duration of response was 8 months. The chief toxicities were fatigue, nausea, gastritis, and diarrhea, which were less than or equal to grade 2 in severity. Two patients developed mild radiation hepatitis which was treated successfully with diuretics. These data suggest that the treatment of intrahepatic malignancies can be guided by the concept of DVH analysis of the normal liver to allow the safe administration of doses of radiation that are potentially tumoricidal and are well above those that would be predicted to be tolerable for the whole liver.

THE TREATMENT OF COLORECTAL LIVER METASTASES WITH CONFORMAL RADIATION THERAPY AND REGIONAL CHEMOTHERAPY

PURPOSEnWhole-liver radiation, with or without chemotherapy, has been of modest benefit in the treatment of unresectable hepatic metastases from colorectal cancer. A Phase I/II study combining escalating doses of conformally planned radiation therapy (RT) with intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd) was performed.nnnMETHODS AND MATERIALSnTwenty-two patients with unresectable hepatic metastases from colorectal cancer, 14 of whom had progressed after previous chemotherapy (2 with prior IAH FdUrd), were treated with concurrent IAH FdUrd (0.2 mg/kg/day) and conformal hepatic radiation therapy (1.5-1.65 Gy/fraction twice a day). The total dose of radiation given to the tumor (48-72.6 Gy) depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for response, toxicity, hepatobiliary relapse, and survival. Median potential follow-up was 42 months.nnnRESULTSnEleven of 22 patients demonstrated an objective response, with the remainder showing stable disease. Actuarial freedom from hepatic progression was 25% at 1 years. The most common acute toxicity was mild to moderate nausea and transient liver function test abnormalities. There were three patients with gastrointestinal bleeding (none requiring surgical intervention) after the completion of treatment. Overall median survival was 20 months. The presence of extrahepatic disease was associated with decreased survival (p < 0.01).nnnCONCLUSIONSnCombined conformal radiation therapy and IAH FdUrd can produce an objective response in 50% of patients with hepatic metastases from colorectal cancer. However, response was not durable, and hepatic progression was frequent. Improvements in hepatic tumor control for patients with metastatic colorectal cancer may require higher doses of conformal radiation and/or improved radiosensitization. In an effort to increase radiosensitization, we have recently initiated a clinical trial combining IAH bromode-oxyuridine, a thymidine analog radiosensitizer, with conformal high dose radiation therapy.

Effects of hepatic arterial yttrium 90 glass microspheres in dogs

A 22‐μm glass microsphere called TheraSphere (Theragenics Corp., Atlanta, GA) has been developed in which yttrium 89 oxide is incorporated into the glass matrix and is activated by neutron bombardment to form the beta‐emitting isotope yttrium 90 (Y 90) before using the spheres as radiotherapeutic vehicles. The injection of up to 12 times (on a liver weight basis) the anticipated human dose of nonradioactive TheraSphere into the hepatic arteries of dogs was well tolerated and produced clinically silent alterations within centrolobular areas. The hepatic arterial (HA) injection of radioactive TheraSphere also produced portal changes similar to those observed in humans after external beam therapy. While the extent of damage increased with the delivered dose, radiation exposures in excess of 30,000 cGy did not cause total hepatic necrosis and were compatible with survival. No microspheres distributed to the bone marrow and absolutely no myelosuppression was encountered in any animal. Proposed hepatic exposures to humans of 5000 to 10,000 cGy by means of these microspheres, therefore, would appear to be feasible and tolerable. Radiotherapeutic microsphere administration preceded by regional infusion of a radiosensitizing agent and/or immediately following the redistribution of blood flow toward intrahepatic tumor by vasoactive agents can potentially yield a synergistic, highly selective attack on tumors confined to the liver.

Creation of Reentry Tears in Aortic Dissection by Means of Percutaneous Balloon Fenestration: Gross Anatomic and Histologic Considerations

PURPOSEnTo study the safety and efficacy of percutaneous fenestration in aortic dissection, transmural tears in canine and human aortae were created with conventional angioplasty balloons.nnnMATERIALS AND METHODSnTears created in the aortae of five living dogs were compared with tears created in postmortem specimens. Percutaneous fenestration was performed in a woman with acute type I dissection and ischemic hepatitis who died in multisystem failure, and the balloon tear was documented at autopsy. Additional tears in the human aorta were studied in necropsy specimens of normal, Marfanoid, atherosclerotic, and acutely and chronically dissected thoracic and abdominal aortae.nnnRESULTSnIn the canine aorta, transmural balloon tears resulted in rapid death of all five animals, and the tears were approximately 10% longer than tears created post mortem with the same balloon. In human aortic specimens, most transmural and all transseptal tears were linear and were oriented nearly perpendicular to the longitudinal axis of the aorta. Tears that were initiated near calcified plaques or large aortic branches extended in unpredictable directions. The transverse orientation of the tears coincided with the long axis of smooth muscle cells in the media of the intact aorta or the dissection septum.nnnCONCLUSIONnPercutaneous balloon fenestration, when performed in areas of the aorta relatively free of atherosclerosis, results in transverse tears in the aortic dissection septum. Percutaneous fenestration of the aortic dissection septum appears feasible and should be considered as a treatment option in carefully selected cases of aortic dissection with ischemic complications. A final conclusion regarding the safety and efficacy of percutaneous fenestration undertaken to relieve organ ischemia requires further clinical experience.

Percutaneous Transhepatic Embolization as Treatment for Bleeding Ileostomy Varices

We report two patients with bleeding stomal varices following total colectomy and ileostomy. The varices were demonstrated by superior mesenteric angiography and percutaneous transhepatic mesenteric venography; dilated ileal veins drained via the stomal varices into abdominal wall veins. Bleeding from the stomal varices was treated by transhepatic embolization. The first patient required three transhepatic embolizations after recurrent bleeding due to recanalization of the embolized ileal vein and the development of collaterals from the adjacent ileal veins over a one-year period. The second patient died of respiratory failure 1 week after embolization. Neither patient developed mesenteric or stomal ischemia.

Canine Model of Acute Aortic Rupture: Treatment with Percutaneous Delivery of a Covered Z Stent—Work in Progress☆

PURPOSEnTo develop a percutaneous treatment for aortic rupture with use of a covered intraluminal stent.nnnMATERIALS AND METHODSnA transmural tear was created percutaneously in the thoracic aorta in six dogs with use of a 4-mm angioplasty balloon. Gianturco Z stents were covered with polytetrafluoroethylene, loaded into a 14-F sheath, and advanced through the femoral artery to the site of injury. Within 2 minutes after initiation of the injury, the stent was deployed. Homologous canine blood was given during the procedure. Dogs that survived 24 hours were then killed.nnnRESULTSnThe first stent did not expand completely, and the dog died in 1 hour. At necropsy, the first two dogs (1-hour and 8-hour survival) had a large left hemothorax and extensive periaortic hematoma, indicating intrathoracic exsanguination. The next four dogs were treated with a modified stent and survived 2 hours (n = 1), 8 hours (n = 1), and 24 hours (n = 2). At necropsy hemothorax did not exceed 15 mL, and periaortic hematomas were small. The cause of death in the two early casualties with the modified stent is uncertain. There were no signs of spinal cord injury despite occlusion of three pairs of intercostal arteries.nnnCONCLUSIONnThe covered Z stent (in its modified form) tamponaded the aortic tear, preventing exsanguination. Long-term studies of biocompatibility of this device appear justified.

Design and Testing of a High-Flow Autoperfusion Catheter: An Experimental Study

An autoperfusion catheter is similar to an angioplasty balloon catheter with side holes in the guide-wire lumen proximal to the balloon. When the balloon of the autoperfusion catheter is deployed and inflated in an artery, the guide wire is removed, and the hub of the guide-wire lumen is capped. The catheter then allows passive distal perfusion by using ambient pressure to drive blood into the guide-wire lumen, through the balloon, and out the end hole. This article discusses the requirements and constraints of a high-flow autoperfusion catheter, summarizes attempts to modify standard angioplasty catheters for use as an autoperfusion catheter, and describes the design and testing of a custom autoperfusion catheter capable of delivering approximately 3 mL/sec at physiologic pressures. In a model of canine acute renal artery occlusion lasting 90 minutes, the custom autoperfusion catheter provided marked protection from acute tubular necrosis compared with conventional percutaneous transluminal angioplasty catheters. The authors conclude that the high-flow autoperfusion catheter may be useful as a temporary stent in cases of rupture, dissection, or penetrating wounds involving large arteries.