Defining Ideas

A Different Kind Of Cancer Treatment

Tuesday, March 6, 2018
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Cancer strikes almost every family in the United States, so virtually everybody has had some contact with the disease. Most people know that surgery and chemotherapy are commonly used to treat cancer. And, in recent years, thanks to breakthroughs in immunotherapy, doctors are learning how to manipulate a patient’s own immune system to defeat the disease. But cancer treatment increasingly relies on a combination of approaches, one of the most essential of which is radiation therapy. It is exquisitely targeted and works synergistically with other forms of treatment to shrink or eliminate tumors—but it gets very little press and too little funding.

Wilhelm Conrad Roentgen, a German physicist, discovered X-rays in 1886, and the use of radium and low-voltage X-ray machines to treat cancer began shortly thereafter. Outside the medical profession, radiation therapy is perhaps the least understood intervention, although it has been around for more than a century and is widely used. About half of all cancer patients will receive radiation therapy at some point in their treatment, often as part of potentially curative therapy, and the rest to slow disease progression or for palliation of symptoms.

After the development of the first chemotherapy drugs for acute leukemia in children in the 1950s, some in the medical community assumed that radiation therapy would become obsolete, but this has not been the case; in recent decades, the improvements in the techniques and technology of radiation therapy have been stunning.

Radiation therapy works by killing cancer cells through biological mechanisms—by damaging the DNA in the tumor cells so that they die when they try to divide. Radiation treatments most commonly use a beam of X-rays that penetrates the body in a similar way as diagnostic X-rays do, but radiation therapy uses high energy X-ray beams that are aimed from many different angles to focus on the area that needs to be treated. Over the years, radiation oncology has gone through dramatic changes that have improved our ability to treat a tumor while minimizing unwanted effects on normal tissues. 

A high enough dose of radiation can kill virtually any cell, so high doses can damage normal cells and organs. Therefore, the radiation oncologist must determine what needs to be treated, what shouldn’t be treated and what dose is optimal—and then figure out (with a team of physicists and dosimetrists) how best to accomplish that.

The therapy is not without its side effects and risks. The most common early side effects, which occur shortly after treatment, are fatigue and skin changes; others are related to specific areas of the body that have been treated, such as hair loss, headache, and nausea after radiation to the brain. Late side effects, which can take months or even years to develop, can occur in any normal tissue in the body that has received radiation. The risk depends on the area treated as well as the radiation dose that was administered.

For many kinds of cancer, radiation therapy combined with chemotherapy and/or surgery is now routine, but in some situations, it suffices alone. For example, a large study of almost 450 men from UCLA with prostate cancer limited to the prostate gland, showed that there was no evidence of tumor progression at 10 years in almost 98 percent of patients after treatment with radiation therapy alone.

Another important application of radiation therapy is to eradicate a single metastasis (or even a small number of metastases) to an organ such as the lung or liver. It used to be thought that even a single metastasis indicated that the patient had a widespread tumor and that any local therapy would be fruitless. But we now know better. Patients with limited metastatic disease in the liver from colon cancer, for example, can be cured with local therapy (surgery, ablation, and/or radiation therapy) about 40 percent of the time, but focal radiation therapy alone at very high doses is often used in these situations and can cure tumors previously thought to be incurable.

A number of innovations in recent years have allowed radiation treatments to be much more effective. The first was the development of X-ray machines with higher energy than earlier versions. We now routinely use machines with energies in the range of millions of electron volts compared to thousands of electron volts for diagnostic X-ray machines. (Energies much higher than millions of electron volts don’t bring enough of a marginal benefit to be worthwhile.) That eliminated many of the skin burns that were seen in the early days of radiation therapy.

But higher energy alone was not sufficient. In the past, before imaging technologies gave physicians precise information about where a tumor was located, radiation therapists were only able to make rough approximations of where to focus their beams. Today, sophisticated diagnostic tests including CT, MRI, and PET scans help determine precisely where a tumor is (or might be). 

The therapy machines have become more sophisticated as well. Advances in computer software and hardware have allowed for the design and precise delivery of the radiation therapy beams. Coming from many directions, they shape the radiation dose around the tumor while sparing normal tissues. This greater precision was facilitated by advanced computational techniques, with most treatments planned with sophisticated 3-D models of both the tumor and the normal tissues. Then, over the last decade came the advent of extraordinary 4-D models that accounted for the movement of tissues during treatment due to breathing and other movements. The availability of 4-D models often boosts the effectiveness of therapy by allowing higher doses to be delivered safely while reducing side effects.

There is now another type of radiation treatment machine being installed in many centers that uses a radiation beam consisting of charged atomic particles, most commonly protons—in contrast to X-rays that have neither charge nor mass. This enables radiation to penetrate a patient and stop once the beam gets past the tumor, much like programming a bullet to stop moving once it hits its target, in order to avoid collateral damage. Although the approach is controversial largely because of its expense, it has substantial advantages for the treatment of certain tumors, especially pediatric malignancies where decreasing the radiation dose to normal tissues is extremely important for the long-term well-being of the child.

Because of the synergy among different approaches to cancer treatment, the field of radiation therapy has benefited from the increased knowledge of cancer biology and immunology. Physicians have discovered that when administered properly, radiation can stimulate the immune system and thus augment the killing of tumor cells in areas of the body that have not been irradiated. Scientists have also benefited from the genomics revolution, which enables them to define more precisely, from biological characteristics, the patients who are likely to benefit from radiation treatments and those who are not. For example, we now know that many tumors arising in the region of the mouth have an abnormality of a gene called p16. When that gene variant is present, the tumors are very sensitive to radiation treatment and excellent tumor control can be obtained with a relatively low dose of radiation, thus substantially decreasing side effects of treatment.

Still, there is much we don’t know. In general, our knowledge of cancers is based on our knowledge of how broad categories of cancer respond to therapy. A better understanding of the biology will allow us to predict the response to therapy (as for the oral cancers mentioned above), especially which cancers will benefit from combined radiation therapy and chemotherapy.

Our knowledge of the interaction between radiation and the immune system is still in its infancy and will be a critical part of the future of cancer management. There is also a burgeoning area of investigation into precisely how radiation affects DNA, and into devising ways to manipulate that response. And if history is a guide, there will be still further technological advances allowing for more accurate radiation delivery.

Thanks to advances in engineering, radiation physics, genetics, and tumor biology, we have made enormous strides in the past few decades in all aspects of cancer management. Radiation therapy remains an integral part of the management of a large number of cancers, including prostate, brain, breast, lung, uterine cervix, rectum, head and neck, as well as many others that can now be treated with therapies that are both more effective and produce fewer side effects.

In spite of its importance, radiation therapy gets short shrift in federal funding. Inexplicably, grants from the Radiation Research Program (RRP) of the National Cancer Institute (the major provider of cancer research funding) shrank 33 percent from FY 2009 to FY 2014 (the last year for which data are published). The support for the RRP (although an underestimate of total radiation program support) represents only about 1 percent of the total NCI budget. Perhaps other therapies are sexier and get more press coverage, but radiation therapy continues to have a major role in therapy because of the accumulation of a large number of small advances in both biology and technology.

The key to effective cancer treatment is synergy among different modalities, and radiation therapy is a key player. The research community is on the cusp of devising better treatment options, such as using radiation therapy to boost a patient’s immune system and enhance the effectiveness of immunotherapy. Understanding how and why these combination therapies eliminate cancer cells is critical to further refining and personalizing treatments. That will require sustained, predictable growth in funding that supports collaboration among different scientific and medical specialties.

Henry Miller, a physician and molecular biologist, is the Robert Wesson Fellow in Scientific Philosophy and Public Policy at Stanford University’s Hoover Institution. He was the founding director of the Office of Biotechnology at the FDA.

Joel E. Tepper, a physician and radiation oncologist, is the Hector MacLean Distinguished Professor in Cancer Research at the University of North Carolina, Chapel Hill. He is currently the recipient of grants from the National Cancer Institute and is a consultant for EMD Serono, a biopharmaceutical company.