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Fertile Genomic Ground Leads to Growth of Technology, Knowledge

Laberta, Valerie

doi: 10.1097/01.COT.0000482914.77195.4c
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As medical oncology harvests the advantages of this fertile genomic age, so do the associated therapies that benefit cancer patients. Radiation oncology has sprouted some new opportunities for improved patient care and outcomes, now ripening with the help of technology and research.

Adam Dicker, MD, PhD, Professor and Chair of the Department of Radiation Oncology at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, offers some insights into specific areas in which radiation oncology is seeing fresh growth.

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The Heft of Genomics

“Genomics and molecular signatures are beginning to impact systemic therapies with the use of radiation,” Dicker told OT. He used the example of prostate cancer to clarify his assertion. “In the world of prostate cancer there are companies ... that are seeking or already have FDA approval for genomic tests and the technologies built on each company's ‘signature.’” These signatures are keyed to determining something specific, such as which patient has a more-aggressive disease or a less-aggressive disease, or will develop metastasis in five years, etc., he explained.

Dicker and colleagues at Jefferson have been working with GenomeDx (whose signature addresses the five-year probability of metastasis) on a controversial topic that taps into this new genomic enlightenment.

“When men with advanced diseases have positive margins or other adverse features following surgery, there's a debate as to whether they should receive adjuvant radiation therapy after they have healed,” Dicker explained. “Our group, led by Robert B. Den, MD, working with scientists at GenomeDx (whose prostate cancer test is FDA-approved and approved for reimbursement by CMS), took the metastasis signature and applied it by asking the question, ‘Can this help us determine who benefits from radiation therapy and who doesn't benefit from radiation?’ It turns out that, yes, we can determine a group of men who, based on their genomic signature, will benefit from radiation therapy (PLoS One 2015 Apr 2;10(3):e0116866. doi: 10.1371/journal.pone.0116866.) And then we asked, ‘Can we use this to determine who benefits from immediate adjuvant radiation therapy or determine patients who can wait until their PSA goes up just a little bit after surgery (termed ‘salvage’)? And again, the answer is yes; the signature can help with that as well (J Clin Oncol 2015 Mar 10;33(8):944-51).”

Dicker said their research data, which has been validated with data from investigators at Johns Hopkins, Mayo Clinic, and Duke University, lead them to a clear belief that there is a group of men who, based on genomics, can be advised as to whether they can wait for, delay, or avoid radiation therapy, as well as those who need it sooner. “This is just one example where the intersection of genomics and radiation will allow more selective use of radiation,” said Dicker.

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Important Identifiers

Genomics are also being utilized to assess benefits of systemic therapies and how various drugs work in concert with—or without—radiation therapy. “There are drugs—whether molecularly targeted or hormonal therapies—that work better with radiation. Now we are trying to figure out who is going to benefit, how much magnitude of benefit there is, and how best to counsel patients as to whether it is worthwhile to have this therapy,” said Dicker.

“This is a harbinger of how all future drug approval will happen,” he commented. “In the older days, when a drug was approved, we never knew if it was going to benefit the patients in front of us. But now there is a trend to see if we can a priori identify the patients who will benefit the most from a particular therapy.” This approach has a financial implication on drug and technology development, an impact on reimbursement approval, as well as an emotional import on patients seeking therapies with real benefits and minimal toxicity.

Because genomic testing now allows for scanning tens of thousands of genes at a time, medical science is able to take a macro view, said Dicker, commenting, “There are some things we know about and yet a lot of things we don't know about. Closing that gap will be the next phase in the evolution of understanding.”

A “hot topic” among researchers is what Dicker called the current Holy Grail in molecular testing—immune oncology. “We don't understand why some patients have an unprecedented, robust, durable response to immunotherapy and other patients don't respond at all,” he noted. “What we do know is that in certain genetic circumstances, patients who have a particular type of colon cancer relating to a high mutation range have a better response to immunotherapy. But in general—for melanoma and lung cancer for which immunotherapies are currently approved—we don't understand why some people respond better and others have zero response.” There is a great deal of research effort focused on trying to find signatures for those patients, Dicker said. He explained there are isolated examples of “incredible responses” when radiation therapy is used with immunotherapy. “The challenge is to make those exceptional responses more common. No one has really cracked the code on how to do that yet,” he said. “Interrogating molecular signatures with a focus on the immune system is a very active area of investigation.”

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Better Imaging, Greater Precision

Another sprouting area of advancement in radiation oncology is found in image-guided therapy as it progresses to MRI-based radiation therapy.

“When radiation oncologists plan their beams for a course of radiation therapy, the goal is always to maximize the treatment to the tumor and minimize it to normal surrounding tissue. The usual entry level information for radiation treatment planning software is a CT scan,” said Dicker. Once a plan is developed, quality assurance checks follow. “But once a patient is on the table of a linear accelerator, all that is available to verify the region of interest—a particular tumor—is a CT scan, before, during, or after treatment,” said Dicker.

However, he said there are issues that would suggest CT scans are inadequate for this purpose. “A CT scan for soft tissue will never be as good as an MRI,” he said. Exactly that industry-wide realization prompted a search for a better method. “We all knew that tumors in the lung or liver and various other places in the body move, and we recognized a need to be able to image a moving tumor and still be able to deliver radiation therapy. That led to a combination of an MRI scanner with a linear accelerator (or some other device that delivers radiation).”

This newer imaging option has allowed radiation oncologists to hone in on cancer cells with greater dexterity and precision. It also offered a surprising new awareness. “We used to treat margins beyond the tumor because of the uncertainty of the set up and to take into account organ motion, breathing, etc. But when people started to use MRI-based radiation therapy, they realized that sometimes the tumor really wasn't being treated, or only a portion of the tumor was in the treatment field,” said Dicker. “It really opened up our eyes as to what was truly going on: some of the tumor was being missed or, in overcompensation to include the tumor, normal tissue was being compromised.”

Certain companies and a number of academic medical centers are driving development of real-time MRI-guided external beam delivery systems recently put into use in the U.S. These and other companies have already entered the market in Europe and Scandinavia.

“We don't know yet if, with more accurate delineation of tumor, there will be improvements in tumor control, tumor cure rates, and/or a decrease in normal tissue damage. But I think we can make reasonable assumptions,” said a hopeful Dicker. “It remains to be seen, but now with established groups of users obtaining clinical information, we can start to address those concerns.”

An additional ripening of precision lies in the evolving field of proton therapy, and its capability to penetrate a tumor then stop short—leaving no exit trail of radiation in normal tissue.

However, Dicker points out that a degree of planning uncertainty was inherent in the first generations of proton beam therapy. “When protons encounter bone or a gas bubble or air, whether it was in the rectum or the lung, the beam gets perturbed a great deal,” said Dicker. “A common approach in passive scattering proton therapy is to ‘smear’ (thin) the range compensator such that target coverage is ensured even if the position is slightly off. However, this will push the dose into the normal tissues distal to the target volume. Smearing may be used to address patient setup and organ motion issues. Because of the uncertainties of the beam when it encounters bone and different densities of tissue, users have had to be less precise and ‘smear’ the dose around to make sure the tumor or target is getting the appropriate dose.”

However, the realm of medical physics in protons is expanding and now some users of proton therapy have adopted what is called intensity modulated proton therapy (IMPT), delivered with a technology called a scanning pencil beam. “Now the dose deposition is far more precise and far more accurate. Whereas earlier this unique beam had to be degraded because of uncertainty about what would happen when it hit bone or various other tissues, now we have a much more precise beam application. Instead of smearing the beam, IMPT delivers dose, layer by layer, with this very narrow beam,” said Dicker.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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