Letter in response to article: a pilot study examining circulating interleukin-6 and transforming growth factor-β levels during pelvic radiation therapy.

In Reply: We read with interest the article regarding cytokines and growth factors during pelvic radiotherapy. Although this pilot study did not demonstrate an association between circulating levels of interleukin (IL)-6 and tissue growth factor (TGF)-b and clinically evident “radiation enteritis” (assessed using Common Terminology Criteria for Adverse Events v.3) or volume of bowel irradiated, we hope readers will not assume that this is a fruitless line of research. Identifying better, more objective measures of toxicity during radiotherapy has been identified as a clinical priority not least to reduce the risk of acute treatment-induced toxicity but also to minimize the risk of late emerging, potentially severe effects. We would like to add 3 arguments in support of our assertions and of the authors’ valuable contribution to this area. First, it is widely held that the late gastrointestinal side effects of therapeutic pelvic irradiation result from fibrotic processes initiated during the acute phase of treatment. Although no single marker has been implicated, a number of clinical studies have identified factors that may be responsible. They include connective TGF, increased expression of which is exhibited in patients in receipt of pelvic radiotherapy; TGF-b, levels of which correlate with degree of histologic damage in patients with irradiated bowel and which induces connective TGF expression in smooth muscle cell biopsies from patients with radiation-induced enteropathy; matrix metalloproteinases (MMP) “2” and “9” (gelatinase A and B), the activity of which has been shown to be increased in rectal mucosa of patients receiving pelvic radiotherapy; tissue inhibitors of matrix metalloproteinase (TIMPs) levels of which, in conjunction with MMPs, are elevated in late radiation enteropathy; IL-6, which may be elevated in patients receiving therapeutic radiotherapy for prostate cancer; and IL-2, elevated levels of which have been shown to be associated with increased probability of gastrointestinal toxicity during pelvic radiotherapy. Second, in line with the authors’ findings, we (and others) have noted an association between acute treatmentinduced gastrointestinal toxicity during pelvic radiotherapy and the prevalence of late gastrointestinal effects independent of dose the so-called consequential effect (see Wedlake et al for a full list of references on this topic). Also, the association of objective markers of toxicity with symptoms remains a challenge. As we have previously found, tools validated in this setting do not always accurately represent all symptoms experienced by patients nor is there a predictable pathway of damage with histologic evidence neatly supporting emergence of overt symptoms. Third, data from a recent pilot study that we have obtained (data unpublished) provides convincing evidence of the potential predictive value of selected markers. Patients undergoing radical pelvic radiotherapy with normal bowel function before treatment were followed prospectively. Toxicity was assessed using the Inflammatory Bowel Disease Questionnaire bowel subset. Change in serum concentration of IL-2, IL-6, MMP-9, TIMP-1, and platelet derived growth factor was measured before and during treatment in patients who developed minimal toxicity versus those with most severe toxicity. Correlation coefficients between change in marker levels and Inflammatory Bowel Disease Questionnaire bowel subset scores were calculated together with ROC curves for marker predictive value. The 3 patients with minimal toxicity and 9 with severe toxicity had similar (mild to none) toxicity scores at baseline. Scores hardly changed in the minimal toxicity group, but fell by 24.5 points in the maximal toxicity group. Correlation and receiver operating characteristic curve values were as shown in Table 1 and suggest that all markers measured had some prognostic value for presence of toxicity. Defining objective markers of radiation-induced toxicity will revolutionize the delivery of therapy and the management of late effects. Despite what some may regard as a “negative” study, we intend to continue with this valuable line of research and encourage the authors of this important paper to do the same.