In a presentation at the Third Annual Interdisciplinary Prostate Cancer Congress (IPCC), Howard M. Sandler, MD, MS, a Ronald H. Bloom Family Chair in Cancer Therapeutics and professor and chair of the Department of Radiation Oncology at Cedars Sinai Medical Center in Los Angeles,
In a presentation at the Third Annual Interdisciplinary Prostate Cancer Congress (IPCC), Howard M. Sandler, MD, MS, a Ronald H. Bloom Family Chair in Cancer Therapeutics and professor and chair of the Department of Radiation Oncology at Cedars Sinai Medical Center in Los Angeles, California, spoke on the latest technologies in radiation oncology. The IPCC was hosted by ArcMesa Educators in New York, New York, on March 27, for medical oncologists, urologists, radiation oncologists, and others who treat patients with prostate cancer.
IMRT versus 3D-CRT
Sandler noted that there have been many technological advances in radiation oncology centers in the use of intensity-modulated radiation therapy (IMRT). He compared IMRT to the older standard of 3D conformal radiotherapy (3D-CRT) to treat prostate cancer. “[3D-CRT] is not bad, but things have gotten better with IMRT,” he said. Sandler noted that the rectum is the primary organ at risk for radiation-related toxicity and that IMRT has lessened radiation exposure compared with 3D-CRT. According to Sandler, 3D-CRT delivers high doses to and around the prostate. “With IMRT, we get much more rounded, conformal dose distribution, where a high dose is delivered to the prostate and a relatively low dose to surrounding structures.” He singled out the rectal-prostate interphase as an area where IMRT affords a steep drop in the gradient of dose. “The difference in dose to the rectum between IMRT and 3D conformal type of distribution is clinically important,” said Sandler.
IMRT is more effective, Sandler said, because “lead leaves move in and out under computer control and create very structured radiation dose fields...instead of creating a beam of radiation, you break the beam up into small beamlets of about 1 cm x 1 cm.” He told the audience that they could get a sense of how intensity modulation directed at the prostate works by envisioning 200 penlights, each aimed at the prostate and each individually adjustable in intensity. The intensity modulation optimization program with IMRT, he explained, is smart enough to ensure that a beam coming through the prostate and exiting the rectum does not deliver too much radiation to the rectum. A dose-volume histogram (DVH) depicts the dose of radiation delivered to different organs. Sandler polled colleagues at several well-known radiation facilities and learned that everyone uses different spots on the DVH to optimize radiation delivery with IMRT.
Does hypofractionation work?
In Sandler’s poll, he asked his colleagues how they would treat someone with a diagnosis of intermediate risk prostate cancer and found that most institutions use overall doses ranging from 75 Gy to 80 Gy. “Radiation kills cells,” said Sandler. “Tumor and early-responding tissue, like mucosal, have an alpha- beta ratio of ~1 to 10, while late-reacting tissues, or prostate cancer, may have a different alpha-beta ratio than other cancers, at ~1 to 3.”
Investigators have been looking at whether giving higher daily doses of radiation in fewer fractions is as effective as standard radiation. This is known as hypofractionation, and Sandler said it should be equal to or better than standard radiation delivered with a lower dose but a greater number of fractions. “A hypofractionated regimen delivers a lower dose of radiation overall, and some studies suggest it is associated with fewer adverse effects,” he said.
Radiation Therapy Oncology Group (RTOG) 0415 is a phase III randomized study comparing hypofractionated 3D-CRT/ IMRT with conventionally fractionated 3D-CRT/IMRT. The trial has accrued 800 patients with stage T1c to 2a prostate cancer who have a Gleason score <7 and a PSA level <10 ng/mL. The endpoint of the study is 5-year biochemical failure. Sandler said preliminary data suggest a 70 Gy/28 fraction regimen is just as effective as a 73.8 Gy/41 fraction regimen. The study recently closed, and Sandler said he expects additional data to become available in about 3 years.
Fiducial markers to track prostate movement
One of the key concerns when using IMRT that Sandler honed in on is the potential of the prostate to move with respect to the pelvis. “A CT [computed tomography] scan with 3 metal fiducial markers showing where the prostate is, taken just before the patient is about to be treated, may not accurately indicate the location of the prostate,” he said. Various factors can cause the prostate to shift, such as a gas bubble or even breathing. For example, breathing moves the prostate about two-tenths of a millimeter, which may not seem like much but is important when administering radiation. Daily prostate localization, said Sandler, is critical when using IMRT or other highly conformal strategies.
Sandler said an AC wireless magnetic tracking system such as the Calypso 4D can help improve the accuracy of radiation delivery to the prostate. Calypso is a continuous tumor-localization system that uses radiofrequency markers, or transponders, implanted in the prostate to assess the organ’s position to the submillimeter. A console delivers an electromagnetic pulse to the transponders, which respond by emitting radiofrequency waves. These are received at the console and used to show where the prostate is in real time—left, right, in and out, and up and down. “In a study we did at the University of Michigan,” said Sandler, “over a course of 7-minute treatment sessions over 10 days for a patient, we found that the prostate might move several millimeters during treatment.” He said the patient’s prostate sometimes moved out of the beam entirely, which could have resulted in under-dosing. “If you have this real-time information, you can quickly correct for intra-treatment prostate motion,” Sandler said. Implanted fiducials have become the standard of care, and Sandler said he asks his urologist to put them in all his patients before treatment. “It is safe and allows us to reduce the margins because we know where the prostate is all the time. It is also reimbursable as part of image-guided radiation therapy [IGRT].”
Should lymph nodes be treated?
On the question of whether to treat pelvic lymph nodes, Sandler said some evidence suggests it might be useful. The landmark RTOG 9413 study showed some benefit to treating pelvic lymph nodes with radiation. Sandler compared treating pelvic lymph nodes using 3D-CRT to IMRT, saying, “In the 3D-CRT era, we would treat a block in the pelvic area, including a loop of bowel that would be treated unnecessarily. With pelvic-nodal IMRT, we draw where the lymph nodes are, add a margin for uncertainty, and end up with significantly less bowel exposure.”
Radiation therapy technologies
Several other radiotherapy technologies exist or are in various stages of development. Radiation damage to the prostate can have serious adverse effects for the patient, including incontinence and impotence, which have a tremendous negative impact on quality of life. Researchers have devoted considerable resources to identifying strategies to treat prostate tumors in a way that kills the cancer cells but spares the healthy tissue—and, hopefully, prevents some of radiation’s worst effects.
RapidArc Radiotherapy. RapidArc radiotherapy is another IMRT technique. “This is a fast way to do IMRT, within 2 to 5 minutes instead of 15 minutes, making radiation therapy departments more efficient,” Sandler said. With RapidArc, treatment is delivered in an arc-like fashion, and the leaves aimed at the prostate move as the arc movies. RapidArc delivers a focused dose to the prostate, with scattered low doses of radiation landing outside the area.
TomoTherapy. TomoTherapy was first used to treat patients in 2002 at the University of Wisconsin. It combines integrated CT imaging with IMRT. A standard 6 MV linear accelerator is mounted on a ring gantry and rotates around the patient as he moves through the machine. “I consider TomoTherapy to be just another way of doing IMRT,” said Sandler. “It is not superior to any of the other techniques [and] has roughly the same RDV histogram as other methods.” TomoTherapy says its “beam on” times are comparable to normal radiation therapy, averaging 3 to 5 minutes for a common prostate treatment. It is currently being used in several countries to treat multiple solid tumor types, including lung cancer, malignancies of the head and neck, breast tumors, and prostate cancer.
CyberKnife. CyberKnife, another prostate cancer treatment whose use is increasing, is a stereotactic radiosurgery system that delivers high-energy IGRT. It consists of a 6 MV linear accelerator mounted on an industrial robot arm, which is computer controlled. “It has imaging devices and a panel that can take standard kilovoltage radiographs for monitoring where the tumor is while you are using it to treat a patient,” said Sandler. Unlike a Gamma Knife, the CyberKnife is not frame-based and can be used to treat tumors virtually anywhere in the body. Sandler discussed a 2007 study by Pawlicki and colleagues that showed that CyberKnife offered near real-time target tracking (q30-90 sec) and took approximately 40 minutes for prostate treatment. “CyberKnife allows a total prostate cancer treatment in 7.25 Gy/fractions for a total dose of 36.25 Gy, which may equal 8 weeks of treatment,” Sandler said. He added that it is unclear whether 1 week is equal in efficacy to 8 weeks and various studies are underway to determine this. “I am concerned about toxicity or under-dosing... there is very little data on this,” he said. Last year, the American Society for Therapeutic Radiology and Oncology (ASTRO) published a position paper describing this type of approach as investigational. As a result, Sandler said many insurers do not cover CyberKnife. “It would not surprise me...if CMS [the Centers for Medicare & Medicaid Services] stops covering this, as well,” he added.
Others. Sandler noted there are several manufacturers that make state-of-the-art commercial accelerators, including Siemens, Varian Triology, and Elekta Synergy. These typically have arms on the side that provide opportunities for imaging, he said, because locating the exact position of the tumor in real time is becoming increasingly important to radiologists. Other systems are the BrainLAB by ExacTrac and the Medical Intelligence Hexapod Couch. “Patients sit on these tables that go up and down and in and out. There has been an effort to try to make these tables more sophisticated and allow the tables to rotate to account for differences in patient positioning,” he explained.
SHARP. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP) is slightly different than IMRT and operates similarly to CyberKnife. SHARP delivers a highly focused beam of radiation that Sandler said is “extremely tight on the target.” In 2007, Madsen and colleagues reported results from a phase I/II trial that used SHARP to treat 40 men with localized prostate cancer. Investigators administered 33.5 Gy in 5 fractions, which the authors said was the biological equivalent to 78 Gy in 2 Gy fractions (alpha-beta ratio of 1.5 Gy). The median follow-up was 41 months. Grade 1-2 acute toxicity was 48.5% genitourinary (GU) and 39% gastrointestinal (GI). The study reported one case of grade 3 GU toxicity but no late toxicity of grade 3 or higher was reported. Of the 26 patients who were potent prior to therapy, 6 (23%) developed impotence. The median time to PSA nadir was 18 months, with most nadirs <1.0 ng/mL. The authors concluded that dose escalation should be possible. Radiation oncologists at Virginia Mason advertise SHARP and say it reduces treatment time from the standard 8 weeks to 5 days.
In discussing particle therapy, Sandler explained the differences between conventional photon (X-ray) therapy and proton therapy. A cyclotron whips the protons around very quickly using powerful magnets, then uses additional magnets to direct a beam of protons out of the cyclotron. “When you administer proton therapy...the beam [of protons] comes in with a low dose, remains at a low dose, and then near the end of the range of the proton, it deposits most of its energy,” he said. This burst of energy that the protons release at the end of their journey—generally at the tumor site—is known as the Bragg peak. The total dosage of radiation is referred to as the spread-out Bragg peak (SOBP). Controlling the speed of the proton allows the precise depth at which it expels its energy to be manipulated. This potentially helps deliver a higher dose to targets deeper inside the patient and spares more healthy tissue. Tissues behind the tumor or deeper than the tumor receive little radiation exposure, and the dosage to tissue in front of the tumor or not as deep as the tumor is determined by the SOBP.
In contrast, photon therapy directs electromagnetic waves (or X-rays) through the skin, which deliver a continuous dose until they exit. Unlike protons, X-rays lack charge and mass. They always deliver substantial doses of radiation anterior and posterior to the tumor. The biological effects of proton therapy, Sandler said, do not differ fundamentally from those associated with photon therapy. “When we use X-ray (or photon) therapy, we activate electrons that hit DNA or turn water into [free] radicals that damage DNA. Proton therapy activates those same electrons, and it is the electrons that do the damage.” Proton therapy does not directly interfere with DNA. Sandler said because proton therapy conducts more of the dose to the tumor, it might afford increased tumor control and reduce treatment-related toxicities, such as tissue damage and second cancers, which he noted is especially important for pediatric patients.
“Is there scientific evidence for doing proton therapy?” Sandler asked hypothetically. A few articles were published in the Journal of Clinical Oncology in 2007, he said, that found little evidence to support the use of proton therapy. Brada and associates reviewed data from 36 published studies on proton therapy, only 2 of which were phase III. The studies involved patients with chordomas, chondrosarcomas, ocular tumors, prostate cancer, and head and neck cancer. The authors found that patients with chondrosarcomas had a 5-year local PFS of 95%, which was no better than PFS associated with conventional therapy. Compared with photon radiotherapy, none of the studies using proton therapy in localized prostate cancer demonstrated improved tumor control or increased survival, nor was there clear evidence that proton therapy resulted in less toxicity. The authors concluded, “Proton and other particle therapies need to be explored as potentially more effective and less toxic radiotherapy techniques.”
In a study at Massachusetts General Hospital in Boston that compared IMRT to proton therapy, Trofimov and associates found that proton therapy might produce less low-dose exposure outside the tumor area, possibly reducing the risk of second cancers. “In the high-dose area, I don’t see much of an advantage, if any,” Sandler said. In looking at medulloblastoma, proton therapy was found to give “exquisite protection” to a child’s organs. “For pediatric patients, proton therapy may be the treatment of choice. For a 70-year-old man who has a small risk of a radiation-induced cancer, it is hard to justify proton therapy,” he said. Sandler concluded that the evidence for proton therapy in prostate cancer is not well established and more research is needed to determine which patients are likely to benefit from proton technology.
“Assuming that you can give higher doses with proton therapy and that it is more effective, it is still not cost-effective,” he said. A 2007 study by Konski and colleagues compared a dose of 91.8 Gy for proton therapy versus 81 Gy for IMRT and found proton therapy to be more expensive. According to the authors, proton therapy cost $63,500 per quality- adjusted life year (QALY) for a 70-year-old man and $55,700 per QALY for a 60-year-old man, whereas the commonly accepted standard for cost-effectiveness in radiotherapy for prostate cancer is $50,000 per QALY.
In addition to being the most expensive radiation treatment to administer to prostate cancer patients, proton therapy is also the most expensive when it comes to building and running a proton treatment facility, though Sandler said some centers might consider it worthwhile from a business perspective. “Any big radiation facility is either buying protons or they’re talking about buying protons,” he noted. In the United States, active proton facilities exist at Loma Linda, Indiana University, University of Texas MD Anderson, University of Florida at Jacksonville, Massachusetts General Hospital, Oklahoma City, and the University of Pennsylvania. Many others are planned, including one at Hampton University in Virginia and one at the Cancer Alliance in Seattle. “Once you have an expensive cyclotron, you can steer the beam into multiple rooms,” Sandler said, “and treat several patients at once.” These rooms are called gantry rooms, and each room is equipped with a system to modulate the energy of the proton beam according to the patient’s needs. Given the cost-benefit ratio for proton therapy, said Sandler, establishing regional centers makes better sense for very expensive technologies like these.
Cancer centers that offer proton therapy frequently advertise the service on the radio, Sandler said, touting its benefits as a prostate cancer treatment and convincing men with the disease to seek proton therapy. He pointed to a press release from the Website of the Loma Linda University Medical Center’s proton facility that said patients with prostate cancer are more likely than patients with any other cancer to receive proton therapy and “a vast majority” of the men self-refer themselves.
As a counterstrategy to MD Anderson’s successful advertising of its proton facility, the University of Texas Southwestern is looking into carbon ion therapy. Sandler called carbon ion therapy “the next escalation in the technology war.” Because a carbon nucleus weighs 12 times as much as a proton, a much larger cyclotron is needed to accelerate it. “It has interesting biological differences,” Sandler said, and he noted that there are currently no carbon ion facilities in the United States.
MEDCAC reviews radiation therapy for localized
Given the cost of proton therapy, when Sandler saw that the Medical Evidence Development & Coverage Advisory Committee (MEDCAC) had scheduled a meeting on April 21 on “radiation therapy for localized prostate cancer,” he assumed that CMS might be looking for a way to deny coverage for the therapy. He was surprised to see instead that the topic on the agenda was whether MEDCAC was confident there was adequate evidence to determine whether radiation therapy to treat localized prostate cancer improves mortality and functional outcomes, with manageable adverse events. CMS also said it wanted to compare radiation therapy to a strategy of watchful waiting, which Sandler said “shows that CMS does not even understand the field very well, because ‘watchful waiting’ is not the correct term of art for this.” The agenda also singled out stereotactic body radiotherapy and CyberKnife for extra scrutiny.
CMS created MEDCAC several years ago to advise the agency on what Medicare should or should not cover based on the adequacy of scientific evidence. Sandler said MEDCAC comprises approximately 100 members and is an important committee whose recommendations often affect radiation oncologists. “I think with healthcare reform it is going to become even more important,” he added. Sandler identified MEDCAC as the group that suggested CMS no longer cover CT colonoscopy, a recommendation CMS adopted. He expressed concern and said he and others in the field of radiation oncology would be speaking at the meeting. To learn more about MEDCAC and watch for updates on this important meeting, visit www3.cms.gov/FACA/02_MEDCAC.asp.
The full IPCC conference included discussions on a range of issues related to prostate cancer, including prevention, treatment, diagnosis and immunotherapy. Watch for coverage of these sessions in Oncology & Biotech News and Contemporary Oncology. In addition, videos from the conference will be posted soon at the ArcMesa Educators Website.