From OncoLog, September 2006, Vol. 51, No. 9

Zeroing In on a Moving Target

by Dawn Chalaire

Like many patients with liver tumors, Carter Lee had run out of options. Then Sunil Krishnan, M.D., an assistant professor in the Department of Radiation Oncology at The University of Texas M. D. Anderson Cancer Center, offered him a chance to enroll in a pilot study of image-guided radiation therapy using implanted gold fiducial markers to track the liver’s precise location.

“My doctor recommended it, and I don’t have anything to lose,” Mr. Lee said. “I mean, I have cancer, so I’ve got to do something. If they can help me and extend my life, I’m all for it.”

Mr. Lee is the fourth patient to be treated on the pilot study, which uses four-dimensional (4-D) computed tomography (CT) treatment planning and respiratory gating to tackle the problem of liver tumor movement during breathing. So far, this method of treatment delivery has shown astounding accuracy in pinpointing the location of liver tumors. Investigators hope that by perfecting the art of hitting a moving target, they will be able to deliver higher doses of radiation with less damage to normal liver tissues.

Liver tumors are relatively rare in the United States, but their incidence is rising, mainly because of an increase in hepatitis B and C infections. Treatment for primary (mainly hepatocellular carcinoma) and metastatic liver tumors is largely ineffective. Liver transplantation has the highest 5-year survival rate (50% to 71%), but it is limited by a shortage of livers for transplant. Among other treatments, surgery is the most effective, with a 5-year survival rate of 31% to 56%. However, fewer than 15% of patients with hepatocellular carcinoma are candidates for surgery or transplantation.

The remaining 85% of patients with unresectable liver tumors have few potentially curative treatment options. Systemic chemotherapy results in response rates of less than 20% and has no effect on survival. Treatment with locally ablative therapies, such as percutaneous ethanol injection and radiofrequency ablation, can be successful, but only in tumors smaller than 5 cm.

For many years, radiation therapy was not considered a viable option for treating liver tumors because the maximum tolerated dose for whole-liver irradiation, 30 Gy, is much lower than therapeutic levels. Although the liver has the ability to regenerate after resection, it is unable to do so after radiation therapy and is easily damaged by radiation. Also, radiation-induced liver disease can occur if too much of the normal liver tissues are irradiated.

More precise imaging techniques

The outlook for the treatment of liver tumors with radiation began to change in the early 1980s when radiation oncologists started using threedimensional conformal and intensitymodulated radiation therapy to escalate the dose to liver tumors focally and limit the dose to normal liver tissue. This shift toward more targeted radiation therapy has been made possible by more precise imaging techniques, including three-dimensional CT. The standard imaging technique used for conformal radiation therapy is to take simulation CT scans for treatment planning a few days before radiation is delivered. Marks made on the patient’s body are aligned with the internal anatomy and treatment beams. Then, marks on the patient’s body are aligned with lasers in the radiation treatment room to reproduce the positioning during simulation.

“This works really well for static tumors,” Dr. Krishnan said, “but the liver is assumed to have an up and down motion due to breathing.”

This type of organ motion during radiation treatment delivery, which is known as intrafraction movement, can cause the radiation beam to miss its target. Twenty years ago, radiation oncologists accounted for the intrafraction movement of liver tumors by expanding the treatment margin around the tumor to encompass the entire estimated range of motion, plus a wide margin, which resulted in exposure of a large volume of normal liver tissue to radiation.

Refining the state-of-the-art

Today, 4-D CT, which involves taking CT scans of the tumor at each of 10 designated phases in the respiration cycle, is the standard of care for radiation treatment planning at M. D. Anderson, but investigators are working to improve the accuracy even further. In a pilot study initiated by Dr. Krishnan and his colleagues Drs. Sam Beddar and Tina Briere in the Department of Radiation Physics, 4-D CT is being combined with intravenous contrast to obtain pretreatment images of the liver during the entire respiratory cycle. “I think we’re the only group in the country that is routinely using 4-D scanning with intravenous contrast for imaging liver tumors,” Dr. Krishnan said.

Once 4-D CT scans are obtained, the standard approach is to define an internal treatment volume that encompasses the tumor in all 10 phases of the respiratory cycle. Treatment is then delivered via three-dimensional conformal or intensitymodulated radiation therapy. Although this technique is state of the art, Dr. Krishnan and his colleagues are working to refine it. In their pilot study, they are using a different technique to account for intrafraction motion—respiratory gating.

In gated radiation therapy, the linear accelerator is triggered to begin delivering radiation at a specific point in the respiratory cycle. At another specified point, radiation delivery is halted. In standard gated treatment delivery, a small box is placed on the patient’s stomach as a standard of reference, and its location throughout respiration is recorded by a camera. The motion of the box, or external fiducial, is used to track the motion of the tumor internally, but there is no guarantee that the correlation between the external fiducial and the tumor is consistent. The two objects move differently, and that, combined with residual movement of the tumor during gating, can cause significant errors in treatment delivery. “The box is an external surrogate for what’s going on inside, but we felt that an internal surrogate would be more accurate,” Dr. Krishnan said.

To track the movement of the tumor internally, investigators are using three gold fiducials implanted inside the liver. In consultation with Dr. Krishnan, Ravi Murthy, M.D., an associate professor in the Department of Diagnostic Radiology, inserts the fiducials, spacing them three-dimensionally 2 to 3 cm apart, preferably outside the tumor itself. After the fiducials have had 2 to 3 days to settle into their permanent positions in the liver, 4-D CT with intravenous contrast is used to obtain treatment-planning images. The patient is then taken to the combined CT-linear accelerator treatment room, where an electronic portal imaging device is used to test whether the external fiducial consistently tracks the movement of the internal fiducials. If a reliable correlation cannot be found, the patient will receive 4-D CT–based conventional radiation therapy.

“So far, though, the study results have far exceeded our expectations of how accurate we could be,” said Dr. Krishnan. “The positioning accuracy is unparalleled. For a moving target, 2- to 3-mm accuracy is an amazing degree of accuracy.”

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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