Proton-Beam vs Intensity-Modulated Radiation Therapy: Too Soon for a Randomized Trial

The authors address the “theoretical” advantages of protons vs photons as well as what they consider to be key issues and uncertainties in proton therapy. Essentially, the paper concedes certain advantages of proton therapy, such as its high degree of conformability with the use of fewer beams and its reduced-volume integral dose with respect to intensity-modulated x-ray therapy (IMXT), and notes some future directions in proton therapy in terms of partial prostate boosting, intensity-modulated proton therapy (IMPT), and in vivo dosimetry verification with positron-emission tomography (PET). The authors conclude, however, that the present advantages may not be salient in the case of prostate cancer and, given the professed uncertainties, the current higher cost of proton therapy as compared to IMXT, and what they term “no clear evidence to show that proton therapy would be superior to highly conformal photon treatments,” a randomized trial of protons vs IMXT is “urgent.”

Still-Evolving Modality

In our view, such a trial at this time would be premature. Randomized clinical trials should compare apparently equivalent, mature disciplines, but proton therapy is a still-evolving modality, as the authors note, and the same may be true for IMXT. At our institution, treatment strategies have evolved over nearly 2 decades and continue to do so. Our present paradigms are the result of protocols that began with combined photon-proton approaches, evolved to proton-only approaches, and evolved further in a series of dose-escalation protocols, all without increasing treatment-related toxicity.

We are now devising hypofractionation protocols, building on our experience with breast, lung, and liver cancer.[1-3] This will, we believe, enable us to reduce the number of fractions from 45 to about 20, again without increasing treatment-related toxicity thanks to the properties of protons. Further, an IMPT system is on the verge of being implemented; this system, together with inverse treatment-planning algorithms, will lead to optimized dose distributions that are likely to be better than IMXT plans.

We also are exploring other avenues, such as partial prostate boosting[4] and in vivo dosimetry verification with PET. We are addressing issues of range uncertainties and interfracton variability by developing proton computed tomography (CT), which will reduce range errors to less than 1% of maximum beam range and is a dose-efficient imaging modality suitable for image guidance.[5] A proton CT system can also potentially be utilized for real-time dosimetry with PET.[6]

Proton Therapy in Prostate Cancer

The authors review the current status of evidence supporting the use of proton therapy in prostate cancer and attempt to discuss what they see as controversy surrounding the use of protons in prostate cancer. The concept of using proton therapy in prostate cancer is not new, having started at the Harvard Cyclotron Laboratory in the late 1970s and more recently at Loma Linda University in 1991. Subsequently, numerous dose-escalation trials have shown that higher doses to the prostate are possible without increasing treatment-related toxicity. All of these trials have primarily used the same imaging and dose-per-fraction parameters that have been historically used. As the article points out, one of the most recent randomized trials in proton therapy dose escalation showed a significant increase in biochemical disease-free survival without significant increases in severe treatment-related toxicity.

The authors state a concern that conventionally delivered doses will not allow for dose escalation beyond what is possible with IMXT, and question the potential risks to normal structures such as the hip. While not all the answers are in on what will be the best treatment approach, this is what should be expected from the introduction of new technology. Further, at Loma Linda, in over 8,000 prostate patients treated with lateral beams that do go through the hip, the long-term sequelae from this have been minimal, if any, with over 15 years of follow-up.[7] It is unclear why the authors believe there is an “urgent” need for a randomized trial to answer this question when review of existing data does not indicate a clinical issue.

Cost Issues

The authors also discuss costs of proton therapy. As with most developing modalities, costs can be high. Proton therapy is in its infancy and most developing centers are, in effect, individual prototypes. Over time, manufacturers will go from developing individual prototypes to full production models, with ultimate decreases in costs. This has happened in all fields of medicine and technology, and there is no reason to suppose that it will not happen with proton therapy.

It is important to note, however, that the most significant factor relating to the cost for an individual patient is not the cost of the facility; rather, it is the number of treatments delivered. If that number can be decreased, it can affect costs significantly for a given patient. Trials in prostate cancer are being done to address this issue, but as an example, if one could decrease the number of fractions from 45 to 20, overall costs could drop by up to 50%. That said, we must be cautious about trying to evaluate the efficacy of a developing modality based on cost; instead we should concentrate on ways of optimizing therapy. Ultimately, costs will decrease.

Conclusions

As proton therapy develops, we appear to be at a fork in the road in the minds of some, who apparently think that we have reached the optimum in treating prostate cancer with protons, and so it is time to randomize to see which modality, if either, is better. If this approach had been taken 50 years ago, would we have discontinued advancement of linear accelerator–based photon therapy because the first low-energy accelerators could not show significant improvement over cobalt therapy? Would we have compared cobalt radiation vs orthovoltage in a trial?[8] Obviously, scientific and technologic progress does not work that way. Instead, we typically maximize the potential of new modalities and then, based on prospectively collected clinical data, decide whether a randomized trial is needed. To consider a randomized trial now, with the ongoing changes and developments in proton therapy, would be premature. Ultimately, we need to maximize the efficacy and treatment delivery of both these technologies. Once that is achieved, a randomized clinical trial may be appropriate.

-Jerry D. Slater, MD
-Reinhard W. Schulte, MD

References:

References

1. Bush DA, Slater JD, Garberoglio C, et al: A technique of partial breast irradiation utilizing proton beam radiotherapy: Comparison with conformal x-ray therapy. Cancer J 13:114-118, 2007.

2. Bush DA, Hillebrand DJ, Slater JM, et al: High-dose proton beam radiotherapy of hepatocellular carcinoma: Preliminary results of a phase II trial. Gastroenterology 127(5 suppl 1):S189-S193, 2004.

3. Bush DA, Slater JD, Shin BB, et al: Hypofractionated proton beam radiotherapy for stage I lung cancer. Chest 126:1198-1203, 2004.

4. Schulte RW, Li T: Innovative strategies for image-guided proton treatment of prostate cancer. Technol Cancer Res Treat 5:91-100, 2006.

5. Schulte R, Bashkirov V, Li T, et al: Design of a proton computed tomography system for applications in proton radiation therapy. IEEE Trans Nucl Sci 51:866-872, 2004.

6. Bashkirov VA, Schulte RW, Penfold SN, et al: Proton computed tomography: Update on current status. Nuclear Science Symposium Conference Record, 2007. NSS ‘07. IEEE. 6:4685-4688, 2007.

7. Slater JD: Clinical applications of proton radiation treatment at Loma Linda University: Review of a fifteen-year experience. Technol Cancer Res Treat 5:81-89, 2006.

8. Suit HD, Kooy H, Trofimov A, et al: Should positive phase III clinical trial data be required before proton beam therapy is more widely applied? No. Radiother Oncol 86:148-153, 2008.