Predictors of radiation-induced gastrointestinal morbidity: A prospective, longitudinal study following radiotherapy for carcinoma of the prostate

Abstract

Background Chronic gastrointestinal (GI) morbidity occurs in ≥50% of patients after external beam radiotherapy (EBRT) for carcinoma of prostate (CaP). This prospective, longitudinal study examines which baseline measurements of: 1) homocysteine and micronutrients in plasma; 2) chromosome damage/misrepair biomarkers; and 3) anal and rectal dose volume metrics predict GI morbidity after EBRT. Patients and methods In total, 106 patients with CaP had evaluations of GI symptoms (modified LENT-SOMA questionnaires) before EBRT and at one month, one, two and three years after its completion. Other variables measured before EBRT were: 1) plasma concentrations of homocysteine and micronutrients including caroteinoids and selenium; 2) chromosome damage/DNA misrepair (micronuclei/nucleoplasmic bridge) indices; and 3) mean anal and rectal wall doses and volumes of anal and rectal walls receiving ≥40 Gy and ≥60 Gy. Univariate and multivariate analyzes examined the relationships among: 1) plasma levels of homocysteine and micronutrients; 2) indices of chromosome damage/DNA misrepair; and 3) mean anal and rectal wall doses and volumes of anal and rectal walls receiving ≥40 Gy and ≥60 Gy and total GI symptom scores from one month to three years after EBRT. Results Increased frequency and urgency of defecation, rectal mucous discharge and bleeding after EBRT resulted in sustained rises in total GI symptom scores above baseline at three years. On univariate analysis, total GI symptom scores were significantly associated with: 1) plasma selenium and α tocopherol; 2) micronuclei indices of DNA damage; 3) mean anal and rectal wall doses; and 4) volumes of anal and rectal wall receiving ≥40 Gy and ≥60 Gy (p = 0.08-<0.001). On multivariate analysis, only volume of anal wall receiving ≥40 Gy was significant for increased GI symptoms after EBRT (p < 0.001). Conclusion The volume of anal wall receiving ≥40 Gy predicts chronic GI morbidity after EBRT for CaP.

Pudendal nerve injury impairs anorectal function and health related quality of life measures ≥2 years after 3D conformal radiotherapy for prostate cancer

“…The lesser impairment of pudendal nerve function in this study is reflected in the absence of evidence of atrophy of the anal sphincters on ultrasound although the internal and EASs were thinner in the patients !2 years after 3D-CRT ± HDR brachytherapy compared with age matched patients before radiotherapy. The differences in % of patients treated with 3D-CRT in this study (100%) compared with our previous study (18%) and in the median time since completion of radiotherapy (5 years for present versus 8 years for previous study) suggest that greater sparing by the universal application of 3D-CRT in this study and/or progressive damage to the pudendal nerves in the previous study [20] are likely explanations for the less severe pudendal nerve dysfunction reported here.…”

“…The prevalence of unilateral and/or bilateral pudendal nerve injury in the current study was increased if a number of actual (rather than modeled in our previous study [11]) radiation dose volume parameters were exceeded including pudendal nerve, rectal and anal Dmax >60 Gy. Although these parameters have not been previously reported as dose constraints for radiotherapy treatment planning, Dmean anal and V 40 Gy anal have been associated respectively with an increased risk of FI and increased total GI symptom scores after radiotherapy for prostate carcinoma [20,22]. Differences in the definition of the anal canal (contoured separately from the rectum) and statistical analyses of the data between the studies were proposed to account for the finding of a volume [20] as opposed to a dose [22] constraint in the previous studies [20,22].…”

“…However, the major new observation in the current study of 5Â higher prevalence of pudendal nerve dysfunction !2 years after 3D-CRT ± HDR brachytherapy compared with age matched patients before radiotherapy has important implications for optimizing current radiotherapy treatment planning and delivery techniques to reduce its prevalence and consequent impairment of anorectal function and HRQoL. Currently, universally recognized OAR in planning radiotherapy for carcinoma of the prostate is the anorectum (combining anal canal and rectum), small and large bowel (only if the pelvic nodes are the target of irradiation) and the bladder although we and others have suggested that the anal canal and rectum should be contoured separately [3,20]. Individual pelvic floor muscles have also been proposed as 'organs' at risk [21], The findings of a 5Â higher prevalence of pudendal nerve dysfunction 2 years or more after EBRT ± HDR brachytherapy compared with age matched patients before radiotherapy is consistent with the findings of our previous study [11] although no absent pudendal nerve responses were observed in the present study.…”

“…Differences in the definition of the anal canal (contoured separately from the rectum) and statistical analyses of the data between the studies were proposed to account for the finding of a volume [20] as opposed to a dose [22] constraint in the previous studies [20,22]. It is interesting to note that the current study which used the same contouring definitions of rectum and anal canal as one of our previous studies [20] had similar dose volume parameters of the contoured OAR's and V 40 Gy anal !65% was also found to be associated with an increased prevalence of GI OAR damage after radiotherapy.…”

Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation

“…The technique is based on 3 observations: low dose hyper-radiosensitivity, evidence of a transition dose beyond which DNA damage repair is triggered, and the observation of improved DNA damage repair for normal tissue at low dose rates. [5][6][7][8][9][10] The theory is that tumor cells have a higher dose threshold to initiate DNA repair than normal tissues.…”