Current and Future Applications of Proton Therapy: It's All About the Therapeutic Ratio
The following is a summary of a presentation by Nancy P. Mendenhall, MD from a panel session at the ASTRO 2007 Annual Meeting.
The clinical concepts underlying proton beam radiotherapy are the same principles that have governed our use of x-ray therapy since its inception. For the most part, we are lacking large, randomized, prospective trials with long-term follow up investigating the use of proton therapy, and we are thus forced to rely on the concepts and principles that have guided treatment with other forms of radiation in order to design the trials that are needed. Understanding the therapeutic ratio, as well as the concepts of integral and threshold dose, will guide us as we advance into a new era of widespread proton availability.
The therapeutic ratio in medicine is defined as [the probability of tumor control]/ [the probability of toxicity for a given dose]. In an ideal setting, the probability of tumor control would meet or exceed 95%, and that chance of causing severe toxicity would be less than 1%. Our ideal therapeutic ratio is thus at least 95; unfortunately, this is rarely achieved. The balance of benefit and risk that determines the therapeutic ratio determines every radiation dose prescription that is written, as well as the informed consent that is given by every patient treated with radiation. The impact of integral dose, defined as the dose delivered to normal tissues, may not be fully appreciated until many years after radiation treatment, as radiation late effects may take over 20 years to fully emerge. For this reason, the therapeutic ratio decreases with time after completion of radiotherapy. Furthermore, our concept of "threshold dose," the dose below which no normal tissue injury will occur, continues to shift with observation of long-term cancer survivors who have undergone radiation -- in truth, a threshold dose may not actually exist. The accepted therapeutic ratio for a given treatment plan is usually dictated by our best understanding of the risk of serious normal tissue damage with a given integral dose. This is reasonable, as physicians continue to attempt to practice by Hippocrates’ principle "do no harm."
Factors that affect the therapeutic ratio include dose distribution, treatment time, dose fractionation, other treatments (including chemotherapy, hormonal treaments, and biologic treatments), and normal tissue tolerance. The lattermost of these may vary with tissue type, age, genotype, and underlying tissue condition. Although, as described above, we rarely achieve an ideal therapeutic ratio, the past 25 years have shown steady improvement in our ability to deposit dose in the tumor region and decrease dose to normal tissue. As an example, in the 1970s, a tumor located within the central region of the brain would have been treated with two opposing lateral photon beams of relatively low energy (6 MV). This method resulted in a poor dose distribution, with more dose being deposited in normal brain tissue than at the tumor site. The development of higher energy photon beams for therapeutic use allowed improved dose distribution, and use of 3-dimensional imaging and non-coplanar beams allowed further advancement. Finally, use of intensitity modulated radiation treatment (IMRT) has become a "gold standard" for improved x-ray dose distribution. Because of the nature of heavy charged particle beams, such as proton beams, dose distribution can be even further improved with their therapeutic use. Protons do not carry an exit dose, and treatment planning can be performed such that the protons deposit a large amount of energy at the tumor site. These two properties allow increased target dose, with less dose to normal tissue, and hopefully increased cure by increasing the therapeutic ratio.
Current applications for proton therapy include any case with a suboptimal therapeutic ratio, and improved dose distribution with protons. Several groups have begun to publish clinical results in patients treated with protons, and the body of literature of this type continues to grow. Researchers at Massachusetts General Hospital have investigated the use of proton therapy to treat chordoma, a tumor that usually lies in extremely close proximity to the brainstem and optic nerves. Mature data with 10-year outcomes has demonstrated that protons may be used to deliver high dose to the tumor, while reducing the volume of the optic chiasm, optic nerves, retinas, and lenses exposed to radiation. This improved dose distribution allows higher dose to be delivered with less risk of normal tissue injury and potential preservation of vision, increasing the therapeutic ratio and providing patients with much improved overall care. Similar improvements in dose distribution have been demonstrated in other pediatric tumors, including Ewing’s sarcoma, medulloblastoma, and orbital rhabdomyosarcoma. These improvements have been demonstrated to decrease risk of functional deficit, as well as infertility, cardiac risk, cognitive damage, and second malignant neoplasm. Other groups have studied the use of proton beam therapy to treat adult malignancies such as early-stage lung cancer and prostate cancer. In these settings, use of protons, either alone or in a "boost" form following x-ray treatment, can allow dose escalation to the tumor site. Again, this is possible because of the characteristics of protons that allow increased dose deposition at the tumor with decreased integral dose.
Based on the available data, proton beam therapy may be helpful to patients with tumors of the eye, brain/ spinal cord, lung, and prostate, as well as soft tissue sarcomas. Our current understanding suggests further use in the treatment of head and neck malignancies, advanced pelvic malignancies, lymphomas, and difficult or advanced breast cancers. As protons become more widely available, we must be mindful not only of their many indications for use, but of the fact that they do and will represent a limited resource. For this reason, protons should likely not be used to treat tumors for which the therapeutic ration with x-ray treatment exceeds 95, or in situations in which the proton distribution is not improved significantly over the x-ray distribution. Additionally, we must continue to attempt to improve treatment planning and efficiency of treatment delivery. It will be our collective responsibility to work to study and document outcomes in order to continue to develop our understanding of the benefits of proton beam therapy as we attempt to increase the therapeutic ratio for our patients once again.
Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.