|Dr. Najat C. Daw|
Radiotherapy (RT) has come far since the discovery of x-rays and radium in the late 19th century. One of the most promising advances is proton therapy; although first used in 1954 at Lawrence Berkeley Laboratory, there are still only 11 proton therapy centers operating in the United States, with at least five more in development. There are clear advantages to proton therapy when compared with more standard photon-based RT, but do those advantages translate to an equally clear decision-making process in the treatment of certain patients? Experts debated protons and photons and their use in pediatric non–central nervous system (CNS) cancers during an Education Session on Saturday.
“[RT] induces damage to DNA in tumor cells causing unrepaired or misrepaired strand breaks, which lead to cell death,” said Session Chair Najat C. Daw, MD, of The University of Texas MD Anderson Cancer Center. The attendant potential adverse effects include development of secondary malignancies, organ dysfunction, and growth abnormalities—especially in children.
Among the best strategies for reducing RT-related toxicities, according to Anita Mahajan, MD, of The University of Texas MD Anderson Cancer Center, is to reduce the volume of irradiated tissue. Dr. Mahajan argued that proton-based therapy is particularly effective in that regard, limiting the radiation to only the tumor itself and limited amounts of nearby tissue. For example, in retinoblastoma, she said that with proton therapy “the radiation is really restricted to the orbit itself.”
Such limitation is crucial given the number of organs and functions at risk in surrounding body areas. For example, cataracts can form following just 1 Gy -2 Gy exposure; bone growth can be affected by exposures of 10 Gy-25 Gy, Dr. Mahajan said. She cited a study of 17 pediatric patients treated with proton RT for parameningeal rhabdomyosarcomaat Massachusetts General Hospital;1 the late effects of 10 patients that were recurrence-free compared favorably to previously published reports using photon therapy, and included failures to maintain height velocity, endocrinopathies, and mild facial hypoplasia.
Protecting Sensitive Tissue
Outside the head and neck region there are other tissues that should be protected as much as possible from excess radiation. The gonads and kidneys in particular have been found to suffer adverse effects at relatively low doses of radiation (2 Gy-10 Gy and 15 Gy-20 Gy, respectively). Even exceptionally small exposures to the testes can lead to 100% azoospermia, Dr. Mahajan said. “A very low dose can have significant consequences down the road.”
In a study published in 2011, investigators compared treatment plans for proton therapy and intensity-modulated RT (IMRT) for seven children with bladder/prostate rhabdomyosarcoma, and found significantly less radiation exposure to nearby tissues with proton RT.2 The median dose was 25.1 Gy to the bladder with proton therapy and 33.2 Gy with IMRT (p = 0.03); for the femoral heads, the doses were 1.6 Gy and 10.6 Gy, respectively (p = 0.016). Proton therapy led to no radiation exposure at all to the testes, compared with 0.6 Gy with IMRT (p = 0.016).
For tumors in the thorax region, the issue of a moving target becomes important. “Patients do breathe,” Dr. Mahajan said. “We are now able to incorporate a lot of the technologies that have been developed for x-ray delivery systems…that allow for a moving target.”
She said that patients who need a relatively high dose of RT are among the best candidates for proton therapy, as are patients whose tumors are surrounded by tissues such as the liver, the lungs, or the brain. Pediatric patients are generally good candidates, given their higher vulnerability for long-term damage to developing tissues and the risk of a second malignancy later in life.
Worth the Cost?
If proton therapy is universally accepted to deliver lower doses of radiation to vulnerable tissue, what is the argument against its use? According to Frank H. Saran, MD, of The Royal Marsden NHS Foundation Trust, United Kingdom, the arguments are largely practical. Proton therapy is extremely expensive, unavailable in many places, and the pediatric tumors under discussion on Saturday—that could arguably be very good candidates for proton therapy—make up an extremely small portion of all cancers. In fact, Dr. Saran said, a simple calculation suggests that in the United States, it might be only approximately 1,400 patients per year with certain pediatric non-CNS malignancies who are eligible for proton therapy. That equates to the volume of only one proton facility.
Furthermore, and perhaps more importantly, he said that “there are no clinical data to suggest that protons are superior to photons for pediatric indications.” Although evidence has been slowly accumulating on the efficacy of proton RT, there is a vastly larger pool of standard RT literature from the last 10 years.
Dr. Saran acknowledged that there is clearly a lower radiation dose delivered by proton therapy compared with photon therapy, but the benefit of that is unclear. There can be problems specific to proton therapy. For example, a change in the patient’s body weight and shape over the course of treatment could require a full change of treatment plan with proton therapy, but likely would not with standard RT. There are simple methods for avoiding irradiation of nearby tissues, such as using a spacer to move the bowel away from a tumor and prevent the splash of radiation from hitting it.
There is also a convincing economic argument against proton therapy. Dr. Saran used the example of medulloblastoma and secondary malignancies. Even if one allows that proton therapy can reduce the rate of such secondary malignancies by 50%, that is still dropping from a baseline rate of 10% at 30 years post-treatment. To prevent one secondary malignancy, 20 patients would have to undergo proton therapy, with each one costing at least $150,000 more than standard RT. This translates to many millions of dollars spent per one secondary malignancy prevented.
“Proton radiotherapy still has significant technical limitations. I think photon radiotherapy is technically sound, and proven to be safe and deliverable,” Dr. Saran said. “Proton radiotherapy sells hope at the moment, and no clear measurable benefit that we can actually translate and explain to a patient… I think you’ve been spending money on something that, at the moment, doesn’t deliver. It may deliver in the future, but that’s probably after my retirement.”