Proton Radiation Therapy for Lung Cancer: Is There Enough Evidence?

Proton radiation for cancer offers the ability to conform the high-dose region of radiation therapy to the tumor while reducing the dose of radiation to adjacent normal tissues. In lung cancer, this equates to greater sparing of uninvolved lung, heart, esophagus, and spinal cord. Sparing these normal tissues permits the delivery of higher-radiation doses to the tumor. Studies that compare the distribution of radiation doses for lung cancer show that proton radiation is superior, even when factors such as respiratory motion are considered. Clinical experience confirms the feasibility of proton radiation for early-stage non-small-cell lung cancers, and clinical trials are being conducted in locally advanced tumors: To date, evidence indicates that proton radiation should be further explored.

Lung cancer remains a leading cause of cancer death in North America.[1] Non-small-cell lung cancers (NSCLCs) predominate over the small-cell variant of lung cancer, and are usually associated with a poor prognosis, owing to locally advanced or metastatic presentations. The only NSCLC subgroup that has a better than 50% five-year survival is that comprised of patients with peripherally located T1 or T2 tumors without evidence of nodal or distant metastases.[2] However, unfortunately more than 80% of patients present with stage III or IV disease.

The goal of definitive radiotherapy is to eradicate intra-thoracic disease while respecting the radiation tolerance of nearby normal structures by minimizing the dose to such structures. Various photon radiation techniques have been tried in order to effect a therapeutic advantage, among them hyperfractionation (multiple treatments per day), accelerated fractionation (shorter treatment periods), and dose escalation.[3-6] Most innovative techniques have focused on conformal treatment delivery with computer assisted three-dimensional therapy planning and, in some cases, intensity-modulated radiotherapy in which more complex treatment planning and delivery can allow the radiation oncologist to have better control of doses to healthy tissues.[7-8] Here, the goal has been to deliver higher doses to target volumes in an effort to improve local tumor control within the constraints of surrounding regions of normal tissues such as the heart, lung, esophagus, and spinal cord. Tumor control rates with photon radiation therapy, however, continue to be disappointing, in part because of the dose-limiting constraints associated with these normal structures.

FIGURE 1

Percent dose deposited per depth in tissue for photon beams of various energies, and a broton beam (shown in red).

Physical Characteristics of Proton Beams
Because of their their mass (about 1800 times that of an electron) and charge, proton beams can be controlled in three dimensions so that radiation doses can be more accurately deposited within target volumes while the dose to surrounding non-targeted tissues is often minimized-or even eliminated. This ability to spare normal tissues is an important consideration: The greater the extent to which the physician can reduce or eliminate the radiation dose to normal tissues, the lesser the likelihood that treatment will need to be compromised because of unacceptable side effects. In other words, the reduced lateral scatter and sharp dose fall-off of the proton beam not only allows delivery of the total needed dose but also affords opportunities to deliver higher doses without increasing side effects.

The importance of reducing the volume integral dose to normal tissues has been noted for years. In studies spanning more than four decades, Rubin and several collaborators identified the clinicopathologic courses of radiation injury in organs and tissues throughout the body and identified tolerance doses for those organs. Tolerances were identified in ranges of total doses in which severe or life-threatening complications were likely to occur within five years of therapeutic radiation; i.e., severe sequelae would likely occur in 5% of patients treated at the lower end of the range (TD5/5) and in 50% of patients treated to the dose at the top of the range (TD50/5).[9] Although organs and tissues were separated into categories according to their importance for survival,[10] no “safe” dose (TD0/5) was identified for any organ; rather, in a classic series of graphs, Rubin and Casarett demonstrated that sublethal doses of radiation initiate a course that can eventuate in clinical manifestations of radiation injury, some of which progress further to lethality.[11]

In later studies of relevance to lung cancer treatment, Rubin and colleagues demonstrated early and persistent elevation of cytokine production following pulmonary irradiation. The temporal relationship between elevation of specific cytokines and histological and biochemical evidence of fibrosis illustrated the continuum of response which, the authors speculated, underlies pulmonary radiation reactions and supports the concept that a perpetual cascade of cytokines is produced immediately after radiation treatment and persists until pathologic and clinical late effects are expressed.[12]