SAN DIEGO - Technological innovations and new techniques to deliver radiation therapy (RT) are being developed at such a fast pace that some state-of-the-art treatments as of a few years ago have already become obsolete. Nowhere is the rapid pace of change more evident than at this week's American Society for Radiation Oncology (ASTRO) meeting.
In the ASTRO show's opening session on Sunday, a series of speakers looked hard at the challenges their profession faces in utilizing innovative technologies while testing their efficacy. ASTRO president Anthony Zietman, MD, a radiation oncologist at Massachusetts General Hospital in Boston and associate director of its Harvard University School of Medicine radiation oncology resident program, described the balancing act that radiation oncologists face while prescribing new and established treatments for their patients, observing outcomes, and assimilating practice-changing findings of clinical trials.
Defining "evidence" in such a complex milieu of patients and protocols is no easy task, pointed out another speaker, W. Robert Lee, MD, a radiation oncologist at Duke University School of Medicine in Durham, NC. Additionally, radiation oncologists must deal with opinionated patients in this Internet-enabled world of instant access to medical information.
"Consumers -- your patients and their families -- have the opinion that new, more costly treatments produce better results," he said. "Consumers revolt if they are told that the newest treatments may be comparable to well-established ones with respect to curative outcomes. They think that they are being denied the best treatment to survive. We need to improve our effective communication skills, and we need to translate evidence-based medicine into concepts and actions."
Assessing new technologies and how well they work is a never-ending challenge. Outcomes of clinical cancer trials take years to produce results, at which time the technologies or treatment protocols for which they are being tested may no longer be commonly used or may be obsolete. The challenges of implementing clinical trials at a time of limited research funding are considerable, and many are never completed because they don't reach enrollment requirements.
Then there's the matter of reimbursement, a topic tackled by Michael Steinberg, MD, professor of radiation oncology at the University of California, Los Angeles. The Obama administration has introduced an era of comparative effectiveness research in the U.S., where the cost of radiation oncology treatment has outstripped the rest of healthcare costs by 50%. Accountability and justification for new treatments and use of new technologies is going to become increasingly complex, Steinberg warned.
"We are going to need to show proof," he said. "There has been a dramatic rise in the use of intensity-modulated radiation therapy [IMRT]. We know how well it delivers radiation dose. But level 1 evidence to prove its effectiveness as compared to other technologies for many of the treatments where it is utilized does not exist. For technologies like IMRT and proton therapy, society is going to demand that we find a way to pay for the research and development needed to develop proof of efficacy and effectiveness."
Assessing IGRT
Image-guided radiation therapy (IGRT) is on the upswing, with a steadily increasing number of modalities and software available to provide this capability. But is it new? And exactly how will it improve outcomes?
IGRT isn't new, and no one knows how it will affect outcomes, according to Eli Glatstein, MD, professor of radiation oncology at the University of Pennsylvania School of Medicine in Philadelphia. Simulation began to be used in the 1950s for radiation therapy treatment. Today, many types of imaging can be integrated with linear accelerators and performed in the treatment room itself.
Imaging is used to precisely define target volumes, to qualify and quantify geometric uncertainties and errors, and to correct and compensate for uncertainties and errors. In the process, it can prove reliability and reproduce the radiation therapy treatment process.
"IGRT has gone Madison Avenue," Glatstein said. "How much benefit does the patient get? We know that using IGRT is easier for the radiation oncology team. But it is not easy to determine how much benefit a patient really gets."
Volumes greater than the tumor volume are irradiated to compensate for both setup and target outline errors. But the margins around the masses have been tightened to seek subcentimeter dimensions, which is essential for dose escalation delivered by hypofractionization and stereotactic radiation therapy. "What is the benefit of dose escalation beyond a certain point? What is enough?" Glatstein asked.
"The case to use IGRT largely rests on the basis of delivering radiation to reduced subcentimeter margins," he said. "If a surgeon excises a tumor with a margin less than 5 mm, we generally consider that inadequate surgery for a malignant tumor. When we use subcentimeter margins for tumors, aren't we doing exactly the same thing?"
"We generally have to select a target volume that not only reflects where the tumor was, but also where the surgeon has been," he said. "I have a principle that I've been telling our residents for years regarding the treatment of irradiating sarcoma: When you think you have an adequate margin around your target volume, double it."
In addition to evaluating the value of dose escalation, "marginal" miss must be assessed, along with the frequency of imaging errors. "Do you trust imaging 100%? I sure don't!" Glatstein said. He cited examples of finding tumors that weren't seen on imaging, as well as artifacts that were.
Outlining the advantages and disadvantages of 13 different types of imaging used for image guidance, Glatstein emphasized that IGRT is appropriate when there are good reasons to use it. These include for adaptive changes, when change in tumor volume may alter dose distribution, when tumor volume changes rapidly, for proton therapy and stereotactic treatments, and for bladder cancer, where normal tissue volume or locations may change.
"The value of IGRT is largely inversely proportional to the size of the target margin," he said. "But then if IGRT is deemed appropriate, the question becomes how often should it be utilized? Weekly? Several times a week? Daily? IGRT is here to stay, but can we access its real value? And if so, how?"
Glatstein said that randomized clinical trials comparing patients with a mediastinal lymphoma or small cell carcinoma who received IGRT as part of their radiation therapy with patients who received adaptive simulation and two simulations might offer the evidence needed. But he suggested that what could be obtained now are data about partial organ tolerance and dose constraints.
"An objective assessment of value is probably no longer practical today," Glatstein concluded.
Assessing proton therapy
Joel Tepper, MD, professor of radiation oncology at the University of North Carolina in Chapel Hill, tackled the subject of the appropriateness of proton therapy treatment. Tepper has been a radiation oncology pioneer in proton therapy's development, starting in the early 1970s.
"Some evidence of enhanced efficacy should be present before an expensive medical device is used widely," he said. "Evidence can be clinical, such as an increased cure rate, decreased morbidity, improved therapeutic treatment, or effective palliative care. The medical device may be less expensive, more expensive but decrease cost of treatment, provide more efficient resource utilization, or allow wider access to a therapeutic approach."
Pointing out that technological changes are often more evolutionary than revolutionary, Tepper believes that proton therapy reflects an intermediate position in this spectrum. Some clinical situations require the need for clinical trials to prove the efficacy of proton therapy, while other situations need less formal evidence.
Very few randomized clinical trials of proton therapy have been conducted since it was first used for radiation therapy in the 1960s. But formal technology assessment of protons cannot be conducted now, as there is little useful data for such an analysis, according to Tepper.
"Protons offer exciting potential benefits in specific clinical situations when compared to standard photon therapy," Tepper said. "Depending upon the clinical application of proton therapy, formal clinical trials may or may not be appropriate."
Clinical trials are neither needed nor feasible to assess proton therapy use with pediatric brain tumors. Though the actual clinical benefit of administering proton therapy compared to another radiation therapy treatment is still unknown, Tepper stated that assumption of its potential value was entirely based on the presumed decrease in normal tissue toxicity.
Irradiation of the brain has the potential to produce severe neurocognitive defects, endocrine effects, and second cancer malignancies. More adverse effects occur with higher radiation and irradiation to larger volumes. While the magnitude of a radiation dose and volume effects are specifically known with respect to a pediatric patient, decreasing the dose to normal tissue is a worthwhile goal to attempt to decrease normal tissue toxicity.
Because proton therapy treatment decreases the radiation dose to normal tissue to low and intermediate levels, it is logical to assume that its use will produce some improvement in normal tissue injury compared to photon therapy. Interim results of several clinical trials indicate that pediatric patients are experiencing few neurocognitive changes, and they are experiencing comparable outcomes as pediatric patients who received photon radiation therapy.
But this is not enough: Thorough prospective, nonrandomized data must be collected and analyzed, Tepper said. Stronger estimates are needed of normal tissue sparing, and tumor control statistics must be confirmed. Subsets of pediatric patients with brain tumors must be identified with respect to whether proton therapy treatment will be beneficial.
There is a theoretical advantage to using proton therapy to treat lung cancer because the radiation dose to the lung will be reduced. However, it is still unclear whether proton therapy treatments have a clinical advantage in either decreasing toxicity or improving local control and survival.
Sparing normal tissue could result in inferior tumor control. Obtaining the certainty of treatment could result in increased toxicity. To determine the effectiveness of prescribing proton therapy treatment for lung cancer, randomized trials are needed to determine if an advantage exists, according to Tepper. This is also the case for prostate cancer.
Tepper concluded by referencing the appropriateness criteria for proton therapy that he, Zietman, and colleagues recommended in an article published in the Journal of Clinical Oncology (2010, Vol. 28:27, pp 4275-4279), covering:
- When conventional treatments cause significant side effects
- When normal tissues of organs that should not be irradiated will also receive significant levels of radiation from conventional treatments
- When the risk of late comorbidities could be reduced with proton therapy
- When the size of the target volume is large, and/or geometric interrelationship of a tumor and normal tissue make adequate dose to the tumor difficult or impossible
- When local control of the tumor needs improvement and conventional therapy is at the limit of tolerance
By Cynthia E. Keen
AuntMinnie.com staff writer
November 1, 2010
Related Reading
Patient safety symposium draws crowds at AAPM, July 22, 2010
SPIE: Is MRI-guidance the next step for IGRT? May 21, 2010
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