Three-Dimensional Conformal Radiation Therapy Reduces Rectal Damage in Prostate Cancer Treatment

ST. LOUIS—Three-dimensional (3D) conformal radiation therapy is being widely used for treatment of prostate cancer and has been successful at reducing rectal toxicities. "Conformal radiotherapy has allowed dose escalation with acceptable or even reduced rates of severe morbidity," Jeff M. Michalski, MD, reported. He added, however, that "we have to start paying attention to the low-grade morbidity. Grade 1 and grade 2 toxicity may predict development of severe late complications." Dr. Michalski is assistant professor of radiology, Mallinckrodt Institute of Radiology, Washington University, St. Louis.

"The Radiation Therapy Oncology Group (RTOG) began a clinical trial of dose escalation using conformal radiation therapy in the early 1990s," he noted. "This was a classic dose-escalation study. We expected by the time we got to 79.2 Gy that we would have reached our limit of toxicity. Treatments were given at 1.8 Gy per day to a minimum planning target volume dose, which really means giving the center part of the prostate gland a dose of 71 or 77 Gy at this dose level. At 79.2 Gy, the center part of the gland is getting close to 82 Gy."

Patients were stratified into three groups: those who had little risk of seminal vesicle invasion; patients whose risk of seminal vesicle invasion exceeded 15%; and patients with T-3 disease. Institutions created 3D treatment plans and used a data exchange format to transmit it by the Internet to St. Louis, where it was reviewed and put into a searchable database.

"We had anticipated finishing our dose escalation trial at 79.2 Gy, but we did not see any toxicity early on and then opened it up to two additional dose levels. This time we lowered the total dose but increased the dose per fraction. Biologically these two doses are a little bit higher than in the 79.2 Gy arm. Data are still maturing, but to date we haven’t seen any toxicities to suggest that even these dose levels are intolerable," Dr. Michalski said.

Moving to Phase III

The RTOG investigators are proceeding to a Phase III randomized trial at the 79.2 Gy dose. "We feel that this represents a high enough dose escalation to show a difference compared to a standard dose arm of roughly 70 Gy in 39 fractions," Dr. Michalski said.

"With conformal radiation therapy we are able to reduce the rate of rectal toxicity compared to standard or older techniques of radiation therapy," Dr. Michalski said. Researchers from the Fox Chase Cancer Center had shown that as the central axis dose to the prostate gland increased, the probability of injury to the rectum rose steeply. This prompted them to add a block of the rectum at the final 10 Gy, which reduced the dose to the rectum and the risk of rectal toxicity.

Rectal toxicity appears to become a problem at the 75 to 77 Gy dose level. Factors that increase the risk of rectal toxicity include enclosure of the outer rectal wall contour by 50% isodose, greater volume of the rectal wall irradiated, older age of the patient, and a history of diabetes.

Freedom from Complications

A randomized trial at the University of Texas M.D. Anderson Cancer Center in Houston found that if no more than 25% of the rectum received more than 70 Gy, about 90% of patients were free from rectal complications, according to Dr. Michalski. If more than 25% of the rectum received more than 70 Gy, the freedom from complications was closer to 60%.

"Low-grade morbidity may be rising and should raise concern for higher rates of severe late complications. Dose-volume analyses are allowing physicians to predict which patients may have a high risk of mild-to-moderate morbidity, and we should be especially aware of comorbid factors that may increase the risk of late radiation sequelae," Dr. Michalski said.