Proton radiotherapy is here to stay. Despite the high initial cost, the number of proton therapy machines in the United States and elsewhere is increasing rapidly. The major questions now relate to defining and optimizing their appropriate use.
In this issue of ONCOLOGY, Hoppe et al argue that early-stage Hodgkin lymphoma (HL) is a disease that can benefit significantly from proton therapy, relative to current state-of-the-art photon-based treatments. As with all disease sites potentially amenable to proton therapy, the argument for using this therapy in HL is twofold: 1) radiation doses to radiosensitive organs proximal to the treatment volume are reduced, and 2) total body doses are reduced. The first of these points, of course, relates to classical early and late sequelae, and the second relates to the risks of radiation-induced second cancers.
With regard to the dose to organs proximal to the treatment volume, there is no doubt that proton therapy for HL can produce comparatively low radiation doses to the heart, the lungs, and the breasts. However, it is not clear whether protons do significantly better in this context than optimized photon-based involved-node intensity-modulated radiotherapy (IN-IMRT). Hoppe et al quote mean heart/lung/breast doses for early-stage mediastinal HL treated with protons of 8.9 Gy/7.1 Gy/4.6 Gy, which are not so different from the corresponding mean doses recently reported by Koeck et al for photon-based IN-IMRT: 7.4 Gy/9.6 Gy/4.0 Gy.
By and large, therefore, the main potential advantage of proton therapy for early HL is that it reduces total body doses. As Hoppe et al rightly point out, while photon IMRT generally redistributes out-of-tumor dose throughout the body (compared with 3D conformal radiotherapy), proton therapy actually reduces it. It follows that proton therapy should reduce overall second cancer risks relative to any comparable photon modality. The issue of second cancer is particularly important for HL survivors because radiotherapy-induced second cancers largely occur more than 10 years post treatment, and 10-year survival rates after HL are high—over 80%.
Where we would disagree with Hoppe and colleagues is in regard to their dismissal of the issue of the secondary neutrons produced in contemporary proton therapy. Almost all current proton beams are spatially spread out to cover the tumor, using passive scattering and collimation; this results in a whole-body low dose of high-energy neutrons, primarily from neutrons produced by proton interactions with the final collimator. Neutrons are well known to be highly carcinogenic,[4-7] and the relative biological effectiveness (RBE) for low-dose neutron carcinogenesis is high compared with photons. However, because quantitative neutron RBE values are not well established, there is some uncertainty as to the significance of secondary neutrons in the context of proton therapy. If a low-end value for the RBE is assumed, as in several published calculations,[8-10] then the predicted neutron-related second cancer risk is comparatively small. However, if we consider the range of RBEs for neutron carcinogenesis that are consistent with the limited experimental and clinical evidence,[4-7] then it is very possible that neutron-induced second cancer risks will be significant for contemporary proton radiotherapy.[4,11]
Hoppe and colleagues, basing their conclusion on data from a 2008 conference abstract, suggest that the impact of neutrons will be “immeasurably small”; however, the quoted abstract describes a small, nonrandomized study of second cancers after proton therapy with a median follow-up of 6 to 7 years—only long enough to detect a very small proportion of any potential radiation-induced second cancers. Given that new designs for proton machine treatment heads can markedly reduce scattered neutron doses,[13,14] it is surprising that these are not being installed or retrofitted to current proton machines. Using a high-tech pinpoint-accurate proton system for radiotherapy, and then irradiating the patient with a larger-than-necessary low dose of whole-body neutrons, is surely not optimal.
In summary, Hoppe and colleagues provide an excellent review of the clinical issues. They naturally emphasize the potential positives associated with proton therapy for HL, but they do somewhat skirt round some of the potential negatives and uncertainties:
The issue of neutron risks, with all its inherent uncertainties, needs to be faced rather than avoided. We are reminded of the long-term outcome of the neutron therapy trials that took place in the 1970s and 80s, amid much optimism. By 1994, it had been concluded that “there is no convincing evidence that fast neutrons are as safe …. as photon therapy.” We really don’t want to be doing the same sorts of retrospective analyses one or two decades hence about secondary neutrons from proton radiotherapy.
No mention is made of how to go about quantifying any potential benefit for protons compared with photons in treating HL. Are theoretical expectations good enough, or should there be a plan for some type of prospective trial?
As with the issue of quantifying potential benefit, it is surprising in today’s economic climate that a review of proton radiotherapy does not include some quantitative cost-benefit analysis. Hoppe’s suggestion that “the use of PT [for HL] should pay for itself over time” may indeed be true, but surely needs to be backed up by some detailed quantitative analysis, as has been done for proton therapy for other tumor sites.[16-18]