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Figure 1. Balance between radiation-induced stimulation and suppression of the immune system. RT: Radiation therapy.
(Figure omitted. See article PDF.)
Dose-response effect in radiation therapy
Today's radiation oncologists were bought up on the concept of 'the more the better', encouraged on by Puck's seductive in vitro clonogenic cell survival curves that suggest an exponential relationship between radiation dose and cell kill [1]. Clinicians extrapolated these findings into the clinic, pursuing ever-higher radiation doses in the pursuit of local control, and the sometimes-elusive cancer cure. Clinicians sought to enlarge radiation field size, with the aim of sterilizing at-risk regional lymph-nodes. There is good evidence for the importance of irradiating 'high-risk' lymphoid tissue in Hodgkin's disease and cervical cancer, but the concept has influenced tumor planning in all cancer sites.
A number of key clinical trials from recent decades have contradicted these concepts. Although clearly a minimal dose of radiation is necessary (e.g., 60 Gy in glioblastoma and non-small-cell lung cancer), attempts to escalate doses further have failed to deliver benefit in a range of cancers: esophageal, low-grade glioma, glioblastoma and, most recently, non-small-cell lung cancer [2]. Furthermore, large radiation fields are often poorly tolerated, especially in the context of concomitant chemotherapy. Theodore Puck succeeded in creating cell-survival curves, where more radiation killed more cells, by developing techniques to grow cell monolayers in vitro . In doing so he negated systemic effects and the role of the microenvironment [1].
Prostate cancer: field size & radiation dose
In prostate cancer, multiple randomized trails have indeed validated the concept of higher radiation dose achieving better tumor control [3]. However, the utility of larger radiation fields - that is, prophylactic irradiation of the whole pelvis, remains in doubt. A large cooperative group trial (RTOG 9413) enrolled 1323 patients in a two-by-two randomized trial seeking to assess the role of whole-pelvic radiation compared with prostate radiation only; and neoadjuvant hormonal therapy compared with adjuvant therapy. Unfortunately, this trial did not succeed in providing clear answers, possibly owing to an unexpected interaction between the size of the radiation field and hormonal therapy [4]. The currently accruing trial RTOG 0924 is trying to answer the question regarding field size.
The manuscript published in this issue by Pinkawa et al. provides important insight...