April 7 , 2008

Improving Accuracy — Stereotactic Body Radiation Therapy for Non–Small-Cell Lung Cancer Treatment
By Kathy Hardy
Radiology Today
Vol. 9 No.7 P. 10

German philosopher Friedrich Nietzsche’s famous quote—“That which does not kill us makes us stronger”—is applicable to what a patient experiences when undergoing conventional cancer treatment. The physical toll that radiation therapy takes on a cancer patient is at times more than his or her body can tolerate. In addition, the cancer can render the body too weak for surgery, another standard option for the removal of cancerous tumors.

Ironically, hope for a more powerful, as well as gentler, cancer treatment could come from clinical trials that involve high-dosage stereotactic body radiation therapy (SBRT), particularly for the treatment of non–small-cell lung cancer (NSCLC). SBRT is external radiation therapy that uses image guidance and computer control to precisely deliver intense doses of radiation directly to tumors. While imaging assists with precision mapping of the tumor, a stereotactic body frame immobilizes the patient, decreasing the effects of lung and other organ movement that would cause the target—in this case a cancerous tumor—to move.

Radiation used with SBRT is divided into higher doses than traditional radiation treatments and is more tightly focused on the tumor site, sparing healthy surrounding tissue. Because of the high radiation doses to the tumor, the treatment time is shorter than with traditional radiation treatments—one to five treatments over no more than two to three weeks. The result is less damage to surrounding tissue and organs and a more concentrated dose of radiation with a better chance of eradicating the tumor.

“In the end, we try to help the patient get the cancer treatment and get healthier at the same time. This is a foreign concept for most conventional cancer treatment options,” says Robert Timmerman, MD, a professor and the vice chair of radiation oncology at the University of Texas Southwestern Medical Center in Dallas. Timmerman has been the principal investigator or coinvestigator on several prospective trials involving SBRT.

Narrowing Treatment Focus
SBRT has a high eradication rate because it is so accurate, coming within millimeters of the tumor. Despite the fact that the treatment is considerably more potent, SBRT is no more toxic than conventional radiation and perhaps even less. Measuring local control of the radiation is important, explains Benjamin Movsas, MD, chairman of the radiation oncology department at the Henry Ford Health System in Detroit. He compares the focus of the radiation beam to that of a flashlight: The wider the beam of light, the more area you cover. In the case of radiation, the broader the target means more damage is potentially caused to normal surrounding structures.

“The more you can focus the treatment, the more you can improve the quality of life,” Movsas says. “More focused radiation treatment means less damaged normal tissue and a shorter recovery time between treatments. With the treatments lasting two weeks rather than six to seven weeks, the overall process is shorter and less disruptive to daily life. SBRT is an improvement over the global shotgun approach to radiation treatment.”
According to the American Cancer Society, lung cancer is the leading cause of cancer deaths. An estimated 215,000 new lung cancer cases will be diagnosed in 2008, and about 161,840 people will die of lung cancer this year. Of the cases of lung cancer, 85% are NSCLC.

“From a practical point of view, lung cancer is killing more people than any other type of cancer,” Timmerman says. “It’s costly to treat conventionally. It behooves us to stop this trend.”

Timmerman and Movsas agree that the gold standard treatment for early-stage NSCLC to date is surgery. Movsas says this is particularly true with peripheral “coin-shaped” lesions in the lung. Beyond surgery, there is conventional radiotherapy. The standard dose of radiation used in conventional radiotherapy calls for a total of roughly 60 to 70 Grays given in increments of 2 units per day, five days per week over a period of six to seven weeks. The radiation field often includes the primary tumor and neighboring lymph nodes, which is what Timmerman calls a “swath” of the patient’s body. This treatment typically leaves patients with serious side effects.

“If the entire conventional treatment process is followed, 30% to 40% of patients would have success,” he says. “Here we have a patient population where there is room for improvement but also a group where more could go wrong.”

Radiation oncologists believe SBRT could play a role as a viable alternative for NSCLC patients who are poor candidates for surgery, either because of the stage of the disease at diagnosis or other health issues. Many patients are unable to tolerate the rigors of surgery or the postoperative recovery period due to such medical conditions as impaired breathing, cardiac problems, diabetes, vascular disease, or general frailty due to advanced age. Some of these patients are treated with a less radical wedge resection, removing just a triangle-sized area that includes the tumor. Other patients undergo conventional radiotherapy.

However, before SBRT use could increase, physicians needed to deal with the issue of stability. With radiosurgery for brain tumors, where SBRT got its start, it’s easier to stabilize the head with a frame and target the tumor with concentrated radiation in its fixed position. “Inside the skull, nothing moves, allowing for accuracy in targeting the tumor,” Timmerman says.

When trying to apply the same procedure to nonrigid parts of the body, the challenge of a moving target makes the process more difficult. “You cannot secure a frame to the flexible rib cage and soft tissue,” he says. “Movement is also a factor. Whether it’s the heart beating or bowels digesting, any movement could cause the radiation to miss the target.”

Innovations in image guidance have enhanced the ability to stabilize the patient and better focus on the tumor. “When we’re in the treatment planning process, we can confidently use very small beams of radiation without missing the target,” Timmerman says. “We don’t expose a swath of tissue as is the case with conventional radiotherapy.”

Improved Tools
Technology innovations play a significant role in adapting SBRT to parts of the body other than the brain. At some centers, respiratory motion is inhibited by breath holding or compression of the abdomen. Also, gating and chasing techniques are helpful in successfully targeting the tumor with a high dose of radiation. With gating, a breathing pattern is observed and markers are used to designate the tumor’s location, and the radiation is delivered only when the tumor is within the specified area. With chasing, different imaging modalities are used to determine the tumor’s location as it moves, and the computer-controlled radiation beam tracks the moving target.

Researchers in Sweden were the first to address the issue of SBRT for areas of the body other than the brain. In the early 1990s, they developed a frame for stabilizing patients with chest and abdomen tumors and focused larger, more targeted doses of radiation for shorter periods of time. Doses ranged from 20 Grays at one time to up to 45 Grays over three times. CT scans showed the disappearance of tumors in 35% of patients, tumor reduction in 41% of patients, no change in 18% of the patients, and only one patient whose tumor grew larger.

Indiana University Medical Center picked up the ball with a phase 1 dose escalation protocol for the treatment of 37 medically inoperable patients with stage 1 lung cancer. In this study, toxicity levels were measured, with patients categorized into separate dose escalations according to tumor volume. Timmerman was with the department of radiation oncology at the medical center at that time, where much of the work on SBRT for NSCLC in the United States originated.

“Results of these prospective trials, using more radiation with concentrated doses, show high tumor control rates and low toxicity levels,” Timmerman says. “We had a surprising success story. In these patients, there was a local tumor control of 80% to 90%. Conventional radiotherapy usually results in side effects in 20% to 50% of patients but with SBRT, we were seeing side effects in 5% to 20% of patients. We never thought that a more potent dosage of radiation would be less toxic.”

Based on this study, the same group completed a larger phase 2 study in 2006 funded by the National Institutes of Health, which included 70 medically inoperable patients with stage 1 or 2 NSCLC. Stage 1 patients received 20 to 22 Grays for each of three treatments while larger tumors received the larger dose.

With some success in treating inoperable patients came the belief that SBRT should be tested in operable patients, which is how researchers, including Timmerman, began the first pilot study involving operable patients in December 2007. The Radiation Therapy Oncology Group 0618 phase 2 clinical trial of SBRT is for patients with operable early-stage NSCLC, and Timmerman is the principal investigator.

“This is a big deal,” he says. “Typically, these patients would be treated with surgery. While surgery is very good at curing cancer, surgery is not a perfect treatment. Some patients struggle to recover. This trial is raising eyebrows.”

SBRT works because of biology, Timmerman adds. The high radiation dosage overwhelms the tumor’s ability to repair itself. Because it is focused in a concentrated area, it leaves only a small area of injured tissue, and a smaller area is easier to heal than the larger area associated with conventional radiotherapy.

“With radical treatments such as surgery, conventional radiotherapy, and chemotherapy, we’re throwing the kitchen sink at people,” he says.

Movsas says treatments at Henry Ford are now beginning to focus on combining the best of biologic strategies with the cutting-edge physics of radiation technology involved with SBRT to attack cancerous tumors with a “double bang” from two fronts. “Cancer is, at its core, a biologic disease of cells that are dividing out of control,” he says. “Ultimately, part of the cure needs to address the underlying biology at the level of the DNA, or the command center of the cell.”

For example, Movsas says doctors can sensitize the tumor to the radiation therapy by incorporating gene therapy and SBRT into the treatment. In theory, radiation damages the DNA and prevents the tumor from growing. However, that doesn’t always work due to the nature of how cells repair themselves from radiation injury, even if the injury has occurred to a potentially deadly tumor.

“With gene therapy, you can attack the tumor’s DNA … from a different front,” he says. “You can inject a gene right into the tumor, which sensitizes the tumor to the radiation by further preventing the tumor from repairing the DNA damage.”

Expanding Applications
While the clinical trial on operable early-stage NSCLC patients is just beginning, Movsas is already thinking about a larger group of patients who could benefit from SBRT: stage 3 NSCLC patients who present with bulkier, centrally located lesions. To date, studies have focused on peripheral tumors located farther away from the more sensitive central area of the lungs where higher concentrations of radiation could damage the trachea and other critical structures.

“Treatment plans need to be even more precise at this stage,” he says. “The radiation oncologist needs to analyze the exact dose and volume of radiation to key central structures, such as the main airways, the swallowing pipe, the spinal cord, and the heart.”
One method that could be applied in these cases is a “stereotactic boost,” Movsas says, where a patient undergoing 3D conformal radiation therapy would periodically receive an increased dosage of focused stereotactic radiation as a boost throughout the course of his or her regular treatment.

“There is emerging sufficient data available to suggest that for this group of stage 3 patients, escalating the dose of radiation should increase their chance of survival,” he says. “The technology is there to make this possible but it has to be done very carefully.”

When it comes to cancer treatments, advancements may come in small percentages but can measure greatly in what they add not only to the quantity but also the quality of life for cancer patients. Movsas, who also chairs the national Quality of Life committee for the Radiation Therapy Oncology Group, tells the story of treating a 90-year-old woman who presented with a cancerous coin lesion in the lung. She was not a candidate for surgery due to her advanced age and medical condition. He says she was eager to take part in a clinical trial for SBRT at Henry Ford. Today, 24 months after she began treatment, the lesion has disappeared, and her CT scan shows only a faint residual scar.

“She looks great and feels great, with no side effects of the treatment,” he says. “My hope is that with SBRT, we can start curing more people with cancer, even stage 3 patients. SBRT is here to stay.”

— Kathy Hardy is a freelance writer based in Phoenixville, Pa.