Excellent Outcomes With Proton Therapy in Prostate Cancer

Roxanne Nelson

March 04, 2014

Proton-beam therapy is a controversial alternative to conventional radiotherapy for prostate cancer patients; opponents say that evidence supporting its use just isn't there.

However, a new study shows "extremely high efficacy" in 5-year outcomes for patients in all risk categories treated with proton-beam therapy. The 5-year rates of freedom from biochemical and/or clinical progression were 99% in low-risk patients, 99% in intermediate-risk patients, and 76% in high-risk patients.

The 5-year overall survival rates were 93%, 88%, and 90%, respectively, for the 3 risk categories.

The study was published in the March 1 issue of the International Journal of Radiation * Oncology * Biology * Physics.

Because only 211 participants were evaluated in this trial, the results will need to be confirmed in a larger cohort, and with a longer follow-up, explained lead author Nancy P. Mendenhall, MD, medical director of the University of Florida Proton Therapy Institute in Jacksonville.

She noted that so far, her team's results compare very favorably with those of intensity-modulated radiation therapy (IMRT). The disease control results were particularly good for intermediate-risk disease, where rates of 70% to 85% are typical.

Comparative Data Promising

Very few trials have compared different radiologic therapies. A trial comparing photon-beam therapy with IMRT is ongoing, but it will be several years before the results are available.

An IMRT study conducted by researchers at the Memorial Sloan-Kettering Cancer Center (MSKCC) had a median follow-up of 5.5 years (Int J Radiat Oncol Biol Phys. 2013;85:686-692), which is similar to the 5.2-year follow-up in the current study, Dr. Mendenhall reported. Five-year freedom from biochemical and/or clinical progression in the MSKCC study was 97% for low-risk patients, 85% for intermediate-risk patients, and 67% for high-risk patients.

"There is a great deal of heterogeneity within high-risk groups," Dr. Mendenhall told Medscape Medical News. "We found that overall, 76% of our patients were disease-free at 5 years, compared with their 67%. On the surface, our numbers look better, but we don't know the mix of their high-risk patients. We can't really compare them without knowing the particulars of that group."

Most interesting was the intermediate-risk group, she explained. "While very low-risk and high-risk patients tend to be heterogeneous, intermediate-risk patients are more homogenous. Again, we don't know the mix at MSKCC," she said, but their 5-year disease-control rates with IMRT are very different from ours with proton therapy (85% vs 99%).

The MSKCC results are typical of results reported in other series. Dr. Mendenhall emphasized that her team evaluated only 82 intermediate-risk patients. "That is not a huge number and we'd like to confirm that we can achieve that result that with a larger group," she said.

Dr. Mendenhall and her team will be doing a larger follow-up with 1300 patients who were treated up to 2010. "We don't have 5-year follow-up data yet from this group, but we are beginning to look at them to see if we can confirm these results," she explained.

These data compare favorably with the best published results from radical prostatectomy, brachytherapy, and IMRT, said Carl Rossi, MD, medical director of the Scripps Proton Therapy Center in San Diego.

He told Medscape Medical News that he would not characterize this as a "small study." Rather, it represents a significant effort. "What you have here are more than 200 prospectively followed patients, all of whom were treated at the same institution using identical techniques, and on whom not only physician-reported but patient-reported quality-of-life data were gathered and analyzed," he said.

"These data correlate quite nicely with the results of the PROG-9509 proton-beam-based randomized dose-escalation trial, which reported similar 5-year disease-free survival and quality of life" in 393 patients.

Continued Controversy

Proton-beam therapy is not new, but its use for medicinal purposes has greatly increased during the past decade. Much of the controversy related to this treatment arose because of cost.

The cost to construct and equip a facility to provide proton-beam therapy ranges from $25 million to $150 million. In comparison, acquisition costs for IMRT systems range from $1.8 million to $5.4 million, according to a 2009 report by the Institute for Clinical and Economic Review (ICER) on management options for low-risk prostate cancer.

The cost of therapy is also an issue. For a 65-year-old man with localized low-risk prostate cancer, the average lifetime cost of treatment with IMRT is $43,122 and with proton-beam therapy is $59,979, according to the ICER report.

Ezekiel Emanuel, MD, an oncologist and former adviser to President Barack Obama, has criticized the Mayo Clinic for building 2 proton-beam facilities at a cost of more than $180 million each. He referred to it as being part of a "medical arms race," and noted that proton-beam radiotherapy has not been proven to be better than less-expensive options for many patients.

It is "crazy medicine and unsustainable public policy," he wrote in an opinion piece published in the New York Times.

The higher price would be worth it if proton-beam radiotherapy cured more people or significantly reduced adverse effects. But to date, the evidence is not there, save for a "handful of rare pediatric cancers," such as brain and spinal cord cancer, he explained.

Several major insurers have announced that they will not pick up the tab for the treatment of early prostate cancer with proton-beam therapy.

Proponents of the therapy point out that protons allow for the more precise delivery of radiation to a target than conventional radiotherapy, reducing the amount of normal tissue that is affected. Opponents acknowledge that it might be superior for certain cancers, such as pediatric cancers of the brain or spinal cord, because it can do a better job of limiting damage to normal brain cells, reducing the risk for adverse effects such as cognitive impairment and hearing loss. However, clinical superiority has not been observed for other cancers, they argue.


If the current results are confirmed in a larger population, they might also show that proton-beam therapy can be cost-effective, Dr. Mendenhall explained. When the cost of care is considered, it doesn't usually include what happens after treatment.

"The cost of prostate cancer recurrence is huge," she said. The cost being accounted for is the initial treatment, "and proton-beam therapy is reimbursed for 1.2 to 1.7 times that of IMRT. But if you have 15% recurrence rate..., that is a huge economic burden that needs to be accounted for."

Dr. Rossi pointed out that proton-beam therapy is an emerging technology and, like all such technologies, the cost of delivering treatment will and is decreasing over time. "This trend has been seen in other radiotherapy modalities, including IMRT, and will no doubt continue," he said.

He also believes that proton-beam therapy will become the treatment of choice in curative situations once the costs even out. "It markedly reduces the patient's total exposure to a known, harmful substance — radiation," Dr. Rossi explained. "It is always in the patient's best interest to receive as little of a known toxin as possible, be it a child or an adult. This is backed up by more than 100 years' worth of knowledge about the effects of radiation on the human body."

Dr. Rossi pointed out that in 2013, the reimbursement rate per fraction was 270% higher for IMRT than for 3-dimensional external-radiation therapy (3D-XRT), a greater difference than exists between IMRT and proton-beam therapy. However, "I do not see anybody complaining about this difference, nor insisting that IMRT not be used to treat prostate cancer until prospective randomized trials have been completed showing a benefit of IMRT over 3D-XRT."

"If cost is the concern, why not insist that costly IMRT, which has never been proven in a prospective randomized trial to be better than 3D-XRT, be curtailed until evidence of its efficacy can be developed?" he asked.

Study Details

The 89 low-risk patients in this study were treated with 78 CGE in 39 fractions; the 82 intermediate-risk patients were treated with 78 to 82 CGE; and the 40 high-risk patients were treated with 78 CGE and concomitant docetaxel therapy followed by androgen-deprivation therapy.

Radiation doses in this study were higher and delivered over a shorter period of time than those in the MSKCC study. The proton-beam therapy consisted of 78 to 82 CGE in 39 to 41 daily fractions of 2.0 CGE over 8 weeks, whereas the IMRT in the MSKCC study consisted of 86.4 Gy in 48 daily fractions of 1.8 Gy over 9.5 weeks.

At 5 years, 20 patients had died from intercurrent disease and 3 had died from prostate cancer. Ten patients experienced disease progression: 1 low-risk patient, 1 "unfavorable intermediate-risk" patient, and 8 high-risk patients. Median time to clinical and/or prostate-specific antigen progression was 31 months.

Toxicity was low; grade 3 gastrointestinal toxicity was 1.0% and urologic toxicity was 5.4%. Initially, the researchers thought that this toxicity was higher than that in the MSKCC study.

However, they used version 3 of the Common Terminology Criteria for Adverse Events to grade toxic effects, whereas the MSKCC team used version 4. "We looked at the differences in the reporting system and they are very different. You can't take the numbers at face value," Dr. Mendenhall explained.

When the researchers retrospectively analyzed their data using version 4, adjusted gastrointestinal toxicity was 0.5% and urologic toxicity was 1.0%, which is similar to what was reported in the MSKCC study.

Proton-beam therapy has continued to evolve, and normal tissue sparing is now even greater than it was when this study was conducted, Dr. Rossi noted.

"The development and deployment of intensity-modulated proton therapy further reduces the radiation dose to normal tissues by allowing even greater specificity for radiation placement, and by reducing the neutron dose to levels below those achievable with either IMRT or contemporary passively scattered proton-beam treatment systems," he explained.

For example, Gerald Chodak, MD, director of the Midwest Prostate and Urology Health Center in Michiana Shores, Indiana, explained in the Medscape Chodak on Urology videoblog that though proton therapy is supposed to focus the beams more tightly and thereby reduce complication rates, but there is no real evidence for this.

Proton therapy "is a technology that is at least 30% more costly than IMRT, with no clear evidence that it does reduce long-term side effects and absolutely no data to show that it provides better outcomes," he said.

Although some centers have been using this technology for a substantial period of time, "we have yet to see a single report talking about long-term mortality," Dr. Chodak added.

Coauthor Bradford Hoppe, MD, from the University of Florida Proton Therapy Institute, reports receiving an honorarium from ProCure for a lecture on proton therapy techniques for lung cancer. The other authors have disclosed no relevant financial relationships.

Int J Radiat Oncol Biol Phys. 2014;88:596-602. Abstract


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