Using a Bigger Hammer: The Role of Stereotactic Body Radiotherapy in the Management of Oligometastases

One of the foundations of radiation therapy is fractionation: dividing the total dose into many daily treatments. In a classic experiment performed almost 100 years ago, Regaud and Ferraux demonstrated that by fractionating radiation, the scrotum could be spared severe radiation dermatitis while producing sterilization. Although the concept that this was a model for tumor radiation had flaws, Coutard shortly thereafter successfully used fractionation to control head and neck cancer with decreased normal tissue injury. Additional experimental work elucidated the four Rs of radiation therapy—repopulation, reoxygenation, redistribution, and repair—that contribute to establishing a therapeutic index between tumor killing and normal tissue injury, which permitted the cure of tumors (especially when combined with chemotherapy) with acceptable normal tissue injury. Stereotactic body radiotherapy (SBRT) turns the concept of fractionation on its head. SBRT uses high-dose, hypofractionated, highly conformal external beam radiotherapy delivered under direct physician supervision using image guidance. Most commonly, it consists of one, three, or five fractions of approximately 10 to 20 Gy. The use of many (typically eight to 14) cross-firing beams directed at a small tumor produces a high dose in the middle of the tumor and a sharp decrease at the edge. In contrast to fractionated treatment, in which treatment has a small therapeutic index and cure is obtained by many applications, the concept of SBRT is to ablate the irradiated region without regard to the difference between tumor and normal tissues. This ablative approach (usually described as radiosurgery) has been used successfully since 1951 for the treatment of brain metastases and some nonmalignant conditions such as arterial venous malformation. SBRT is an implementation of this technique for sites outside the cranium. Because SBRT delivers potentially ablative doses, it is of utmost importance to exclude normal adjacent tissue from the volume irradiated. Given that the thin rim of normal tissue that surrounds a tumor becomes larger with the cube of the radius, one must choose small tumors. Furthermore, the sharp decrease of dose becomes harder to achieve as tumor size exceeds 4 to 5 cm. Another important and related issue is the need to control target motion, given that the strategy of increasing the target volume is unacceptable. Modern SBRT accomplishes this by restriction of motion (such as with an abdominal compression device), target tracking or gating. The use of SBRT is particularly appealing in the management of oligometastases, that is, a limited number of metastases that may represent the only distant sites of disease. Effective local therapy for these oligometastases could result in cures; indeed, complete resection of pulmonary and hepatic metastases from colorectal cancer have been shown to result in long-term (10-year) survival in 20% to 35% of patients, in settings in which systemic agents or conventionally fractionated radiotherapy are only palliative. The systematic, prospective evaluation of SBRT as a treatment for liver and lung metastases is the subject of three articles published in this issue of Journal of Clinical Oncology that represent important contributions to this relatively new approach. Rusthoven et al update the results of a multi-institutional phase I/II trial of SBRT for patients with one to three lung metastases, mostly smaller than 3 cm in diameter. After escalating the dose from 36 Gy to 60 Gy in three fractions, 29 patients were treated at the established phase II dose. In total, 63 lesions were treated. With a median follow-up time of 15.4 months, they report no grade 4 toxicity, low grade 3 toxicity (8%), and excellent 2-year local control (96%). Overall survival was poor (median of 19 months), most likely a reflection of the selection of patients with multiple features of unfavorable prognosis. A second article by Rusthoven et al updates the results of a multi-institutional phase I/II trial of SBRT for patients with one to three liver metastases, mostly smaller than 3 cm in diameter. In this trial, too, the dose was escalated from 36 Gy to 60 Gy and 36 patients were treated at the established phase II dose. A total of 63 lesions were treated. With a median follow-up time of 16 months, they report low grade 3 to 4 toxicity (2%) and excellent 2-year local control (92%). For lesions smaller or equal to 3 cm, the 2-year local control was 100%. Median overall survival was only 20 months. In a third article, Lee et al report on a different approach to the use of SBRT for liver metastases. In this phase I trial, the investigators escalated the radiation dose in an individualized fashion, on the basis of each patient’s expected risk of radiation-induced liver disease (5%, 10%, or 20%). The expected risk was calculated from a model developed at the University of Michigan, on the basis of an analysis of the relationship between the dose volume histograms of the normal liver (expressed in terms of the effective volume [Veff]) and subsequent complications in more than 200 patients. The lesions treated in this trial were significantly larger that in the other trials, with 35 and 20 patients in the mid and high Veff strata, respectively. Thus, the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 10 APRIL 1 2009