Anscher 353 Figure 3. Altering dose on the basis of an individual patient’s sensitivity to toxicity can affect the therapeutic ratio. Dosing of chemotherapy or radiation is based on sensitivity to toxicity that is based on population averages (solid line). In reality, any population also contains individuals that will be either more sensitive (dashed line) or more resistant (dot-dash line) to treatment toxicity than the average population. The sensitive patients, which probably comprise 5%–10% of the overall population [1, 2], nonetheless drive the dosing schemes. In this example, by holding the acceptable complication incidence at 10%, a resistant patient (b) could receive an approximately 5% greater dose than an average patient (a) and a 10% greater dose than a sensitive patient. Dose differences of this magnitude have been associated with differences in outcome. tissue also increases in response to radiation or chemother- apy exposure, several researchers have sought to measure circulating TGF- 1 levels in an attempt to predict which patients might be at an increased or a decreased risk for nor- mal tissue injury after exposure to chemotherapy or radia- tion. The first reported study using circulating TGF- 1 levels to predict the risk for normal tissue injury was by An- scher et al. [61]. Those researchers found, in a group of pa- tients treated with induction chemotherapy, high-dose chemotherapy, autologous bone marrow transplant, and in- volved field radiation for high-risk breast cancer, that plasma TGF- 1 measured after induction chemotherapy but before high-dose chemotherapy, radiation, or marrow transplant was strongly correlated with the risk of develop- ing either pulmonary drug toxicity or hepatic veno-occlu- sive disease (Fig. 4). Subsequent studies by Anscher and colleagues, as well as others, have focused on determining whether TGF- 1 could be used in a similar manner to pre- dict the risk of developing pulmonary injury after radiation therapy. The results of these studies have been mixed, with some, but not all, authors finding that TGF- 1 levels could be used to predict the risk for lung injury [64 – 68]. How- ever, most of these studies contained small numbers of pa- tients with relatively few events, thus having little power to detect differences between study groups [9]. Also, toxicity endpoints differed (e.g., some considered only symptom- www.TheOncologist.com Figure 4. Correlation of plasma transforming growth factor (TGF)- 1 concentration and the risk for pulmonary drug tox- icity (PDT) or hepatic veno-occlusive disease (VOD) after high-dose chemotherapy for advanced breast cancer. Blood samples were taken from patients after induction chemother- apy but prior to administration of high-dose chemotherapy (day 6) and bone marrow transplant. There is a strong corre- lation between the plasma TGF- 1 concentration at day 6 and the risk for either PDT or VOD developing after subse- quent high-dose chemotherapy. Reprinted from Anscher MS, Kong FM, Jirtle RL. The relevance of transforming growth factor beta 1 in pulmonary injury after radiation therapy. Lung Cancer 1998;19:109 –120, with permission from Elsevier. atic lung injury, whereas others included asymptomatic ra- diographic changes), as did techniques for measuring TGF- 1 in the blood. A more recent larger pooled analysis supports the contention that plasma TGF- 1 levels can be used to predict the risk for radiation-induced lung injury [69]. Additional work is needed to confirm this finding. In reality, however, because radiation oncologists are skilled at limiting the volume of normal lung receiving a high dose, the incidence of significant symptomatic lung in- jury (grade 2) in most series is low, and plasma TGF- 1 measurements may actually be better suited to determine patients at low risk for lung injury rather than identifying those at very high risk [70]. This observation suggests that plasma TGF- 1 measurements might be useful to identify patients with lung cancer who might be candidates for ra- diation dose escalation. Anscher et al. [71] tested this hy- pothesis in a small clinical trial designed to assess the maximum-tolerated dose of radiation that could be deliv- ered to the lung using TGF- 1 to estimate the risk for dose- limiting lung toxicity. Patients with locally advanced or medically inoperable non-small cell lung cancer were treated with the institutional standard high-dose radiation approach at the time (1.6 Gy twice daily using a concurrent boost technique) to a dose of 73.6 Gy. Concurrent chemo- therapy was not allowed, and the technique included elec- tive nodal irradiation. TGF- 1 was measured at baseline and after 73.6 Gy. If the TGF- 1 level normalized by 73.6 Gy, then the dose was escalated in increments of 6.4 Gy to successive patients until a dose-limiting toxicity was