Tiziana Rancati

Dose–volume effects for normal tissues in external radiotherapy: Pelvis

A great deal of quantitative information regarding the dose-volume relationships of pelvic organs at risk has been collected and analysed over the last 10 years. The need to improve our knowledge in the modelling of late and acute toxicity has become increasingly important, due to the rapidly increasing use of inverse-planned intensity-modulated radiotherapy (IMRT) and the consequent need of a quantitative assessment of dose-volume or biological-based cost functions. This comprehensive review concerns most organs at risk involved in planning optimisation for prostate and other types of pelvic cancer. The rectum is the most investigated organ: the largest studies on dose-volume modelling of rectal toxicity show quite consistent results, suggesting that sufficiently reliable dose-volume/EUD-based constraints can be safely applied in most clinical situations. Quantitative data on bladder, bowel, sexual organs and pelvic bone marrow are more lacking but are rapidly emerging; however, for these organs, further investigation on large groups of patients is necessary.

Factors predicting radiation pneumonitis in lung cancer patients: a retrospective study.

PURPOSE To evaluate clinical and lung dose-volume histogram based factors as predictors of radiation pneumonitis (RP) in lung cancer patients (PTs) treated with thoracic irradiation. METHODS AND MATERIALS Records of all lung cancer PTs irradiated at our Institution between 1994 and 2000 were retrospectively reviewed. Eighty-four PTs with small or non-small-cell lung cancer, irradiated at >40 Gy, with full 3D dosimetry data and a follow-up time of >6 months from start of treatment, were analysed for RP. Pneumonitis was scored on the basis of SWOG toxicity criteria and was considered a complication when grade> or =II. The following clinical parameters were considered: gender, age, surgery, chemotherapy agents, presence of chronic obstructive pulmonary disease (COPD), performance status. Dosimetric factors including prescribed dose (Diso), presence of final conformal boost, mean lung dose (Dmean), % of lung receiving > or =20, 25, 30, 35, 40, and 45 Gy (respectively V20-->V45), and normal tissue complication probability (NTCP) values were analysed. DVHs data and NTCP values were collected for both lungs considered as a paired organ. Median and quartile values were taken as cut-off for statistical analysis. Factors that influenced RP were assessed by univariate (log-rank) and multivariate analyses (Cox hazard model). RESULTS There were 14 PTs (16.6%) who had > or =grade II pulmonary toxicity. In the entire population, the univariate analysis revealed that many dosimetric parameters (Diso, V20, V30, V40, V45) were significantly associated with RP. No significant correlation was found between the incidence of RP and Dmean or NTCP values. Multivariate analysis revealed that the use of mitomycin (MMC) (P=0.005) and the presence of COPD (P=0.026) were the most important risk factor for RP. In the group without COPD (55 PTs, seven RP) a few dosimetric factors (Dmean, V20, V45) and NTCP values (all models) were associated with RP in the univariate analysis (P< or =0.06). According to the multivariate analysis, the use of MMC was independently associated with RP (P=0.007), while Dmean approached statistical significance (P=0.082). CONCLUSIONS In this study the use of mitomycin or the presence of COPD is associated with a higher risk of RP. In the entire population NTCP values were not significantly correlated with the incidence of RP. Mean lung dose shows a clear trend toward statistical significance in the patient group without COPD.

Clinical and dosimetric predictors of late rectal toxicity after conformal radiation for localized prostate cancer: Results of a large multicenter observational study

PURPOSE Assessing the predictors of late rectal toxicity after high-dose conformal radiotherapy for prostate cancer. METHODS One thousand one hundred thirty-two patients entered a prospective observational multicentric study; late rectal toxicity was evaluated by a self-reported questionnaire. Results concerning bleeding and faecal incontinence of 718/1132 patients with a complete follow-up at 36 months were analysed. The correlation between a number of clinical-dosimetric parameters and moderate/severe toxicity was investigated by univariate and multivariate logistic analyses. RESULTS Fifty-two (7.2%) and 57/718 (7.9%) patients were scored as moderate/severe bleeders and faecal incontinents, respectively; 19/57 incontinent patients showed persistent incontinence at 36 months. Bleeding was mainly correlated with V75 Gy while severe bleeding was mainly correlated with the previous abdominal/pelvic surgery; a different rectal dose-volume relationship in the two groups of patients (with/without surgery) was found. Moderate/severe acute toxicity was weakly correlated to late bleeding. The best predictor of faecal incontinence was acute toxicity (OR=4 and 7 for chronic and actuarial incontinence, respectively). CONCLUSION The application of rectal dose-volume constraints limited the incidence of rectal bleeding. The risk of bleeding may be further reduced by limiting V75 Gy<5% and, in the case of patients previously submitted to abdominal/pelvic surgery, V70 Gy<15-20%. Faecal incontinence seems to be mainly a consequential effect after acute toxicity.

Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT.

PURPOSE To predict acute Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) and Subjective Objective Signs Management and Analysis/Late Effect of Normal Tissue (SOMA/LENT) toxicities of the lower gastrointestinal (LGI) syndrome in patients with prostate cancer undergoing three-dimensional conformal radiotherapy using a tool (nomogram) that takes into account clinical and dosimetric variables that proved to be significant in the Italian Association for Radiation Oncology (AIRO) Group on Prostate Cancer (AIROPROS) 0102 trial. METHODS AND MATERIALS Acute rectal toxicity was scored in 1,132 patients by using both the RTOG/EORTC scoring system and a 10-item self-assessed questionnaire. Correlation between clinical variables/dose-volume histogram constraints and rectal toxicity was investigated by means of multivariate logistic analyses. Multivariate logistic analyses results were used to create nomograms predicting the symptoms of acute LGI syndrome. RESULTS Mean rectal dose was a strong predictor of Grade 2-3 RTOG/EORTC acute LGI toxicity (p = 0.0004; odds ratio (OR) = 1.035), together with hemorrhoids (p = 0.02; OR = 1.51), use of anticoagulants/antiaggregants (p = 0.02; OR = 0.63), and androgen deprivation (AD) (p = 0.04; OR = 0.65). Diabetes (p = 0.34; OR = 1.28) and pelvic node irradiation (p = 0.11; OR = 1.56) were significant variables to adjust toxicity prediction. Bleeding was related to hemorrhoids (p = 0.02; OR = 173), AD (p = 0.17; OR = 0.67), and mean rectal dose (p = 0.009; OR = 1.024). Stool frequency was related to seminal vesicle irradiation (p = 0.07; OR = 6.46), AD administered for more than 3 months (p = 0.002; OR = 0.32), and the percent volume of rectum receiving more than 60 Gy (V60Gy) V60 (p = 0.02; OR = 1.02). Severe fecal incontinence depended on seminal vesicle irradiation (p = 0.14; OR = 4.5) and V70 (p = 0.033; OR = 1.029). CONCLUSIONS To the best of our knowledge, this work presents the first set of nomograms available in the literature specific to symptoms of LGI syndrome and provides clinicians with a tailored probability of the specific outcome. Validation of the tool is in progress.

Inclusion of clinical risk factors into NTCP modelling of late rectal toxicity after high dose radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE To fit an NTCP model including clinical risk factors to late rectal toxicities after radiotherapy for prostate cancer. METHODS AND MATERIALS Data of 669 patients were considered. The probability of late toxicity within 36months (bleeding and incontinence) was fitted with the original and a modified Logit-EUD model, including clinical factors by fitting a subset specific TD(50)s: the ratio of TD(50)s with and without including the clinical variable was the dose-modifying factor (D(mod)). RESULTS Abdominal surgery (surg) was a risk factor for G2-G3 bleeding, reflecting in a TD(50)=82.7Gy and 88.4Gy for patients with and without surg (D(mod)=0.94; 0.90 for G3 bleeding); acute toxicity was also an important risk factor for G2-G3 bleeding (D(mod)=0.93). Concerning incontinence, surg and previous diseases of the colon were the clinical co-factors. D(mod)(surg) and D(mod)(colon) were 0.50 and 0.42, respectively for chronic incontinence and 0.73 and 0.64, respectively for mean incontinence score ⩾1. Best-fit n values were 0.03-0.05 and 1 for bleeding and incontinence, respectively. The inclusion of clinical factors always improved the predictive value of the models. CONCLUSIONS The inclusion of predisposing clinical factors improves NTCP estimation; the assessment of other clinical and genetic factors will be useful to reduce parameter uncertainties.

To bleed or not to bleed. A prediction based on individual gene profiling combined with dose-volume histogram shapes in prostate cancer patients undergoing three-dimensional conformal radiation therapy.

PURPOSE The main purpose of this work was to try to elucidate why, despite excellent rectal dose-volume histograms (DVHs), some patients treated for prostate cancer exhibit late rectal bleeding (LRB) and others with poor DVHs do not. Thirty-five genes involved in DNA repair/radiation response were analyzed in patients accrued in the AIROPROS 0101 trial, which investigated the correlation between LRB and dosimetric parameters. METHODS AND MATERIALS Thirty patients undergoing conformal radiotherapy with prescription doses higher than 70 Gy (minimum follow-up, 48 months) were selected: 10 patients in the low-risk group (rectal DVH with the percent volume of rectum receiving more than 70 Gy [V70Gy] < 20% and the percent volume of rectum receiving more than 50 Gy [V50Gy] < 55%) with Grade 2 or Grade 3 (G2-G3) LRB, 10 patients in the high-risk group (V70Gy > 25% and V50Gy > 60%) with G2-G3 LRB, and 10 patients in the high-risk group with no toxicity. Quantitative reverse-transcriptase polymerase chain reaction was performed on RNA from lymphoblastoid cell lines obtained from Epstein-Barr virus-immortalized peripheral-blood mononucleated cells and on peripheral blood mononucleated cells. Interexpression levels were compared by using the Kruskal-Wallis test. RESULTS Intergroup comparison showed many constitutive differences: nine genes were significantly down-regulated in the low-risk bleeder group vs. the high-risk bleeder and high-risk nonbleeder groups: AKR1B1 (p = 0.019), BAZ1B (p = 0.042), LSM7 (p = 0.0016), MRPL23 (p = 0.015), NUDT1 (p = 0.0031), PSMB4 (p = 0.079), PSMD1 (p = 0.062), SEC22L1 (p = 0.040), and UBB (p = 0.018). Four genes were significantly upregulated in the high-risk nonbleeder group than in the other groups: DDX17 (p = 0.048), DRAP1 (p = 0.0025), RAD23 (p = 0.015), and SRF (p = 0.024). For most of these genes, it was possible to establish a cut-off value that correctly classified most patients. CONCLUSIONS The predictive value of sensitivity and resistance to LRB of the genes identified by the study is promising and should be tested in a larger data set.

Is It Time to Tailor the Prediction of Radio-Induced Toxicity in Prostate Cancer Patients? Building the First Set of Nomograms for Late Rectal Syndrome

PURPOSE Development of user-friendly tools for the prediction of single-patient probability of late rectal toxicity after conformal radiotherapy for prostate cancer. METHODS AND MATERIALS This multicenter protocol was characterized by the prospective evaluation of rectal toxicity through self-assessed questionnaires (minimum follow-up, 36 months) by 718 adult men in the AIROPROS 0102 trial. Doses were between 70 and 80 Gy. Nomograms were created based on multivariable logistic regression analysis. Three endpoints were considered: G2 to G3 late rectal bleeding (52/718 events), G3 late rectal bleeding (24/718 events), and G2 to G3 late fecal incontinence (LINC, 19/718 events). RESULTS Inputs for the nomogram for G2 to G3 late rectal bleeding estimation were as follows: presence of abdominal surgery before RT, percentage volume of rectum receiving >75 Gy (V75Gy), and nomogram-based estimation of the probability of G2 to G3 acute gastrointestinal toxicity (continuous variable, which was estimated using a previously published nomogram). G3 late rectal bleeding estimation was based on abdominal surgery before RT, V75Gy, and NOMACU. Prediction of G2 to G3 late fecal incontinence was based on abdominal surgery before RT, presence of hemorrhoids, use of antihypertensive medications (protective factor), and percentage volume of rectum receiving >40 Gy. CONCLUSIONS We developed and internally validated the first set of nomograms available in the literature for the prediction of radio-induced toxicity in prostate cancer patients. Calculations included dosimetric as well as clinical variables to help radiation oncologists predict late rectal morbidity, thus introducing the possibility of RT plan corrections to better tailor treatment to the patients characteristics, to avoid unnecessary worsening of quality of life, and to provide support to the patient in selecting the best therapeutic approach.

The 6-year attendance of a multidisciplinary prostate cancer clinic in Italy: incidence of management changes

Study Type – Therapy (decision analysis)

Predictive models of toxicity with external radiotherapy for prostate cancer: clinical issues.

The objective of the current study was to analyze the state of the art and present limitations of available predictive clinical models (when available) estimating the risk of genitourinary tract and small bowel complications, erectile dysfunction, and acute and late symptoms of the rectal syndrome caused by prostate cancer external irradiation. An analysis of the literature indicated that very limited attention has been devoted to the development of “integrated,” patient‐tailored, user‐friendly, and clinically usable tools for the prediction of external beam radiotoxicity. In this article, the authors reported on the multivariate correlation between late genitourinary and gastrointestinal toxicities and clinical/dosimetric risk factors, as well as on the first set of nomograms developed to predict acute and late rectal side effects. At the present state of knowledge, the use of nomograms as predictive instruments of radiotoxicity appears to be particularly attractive for several main reasons. They are “user friendly” and easily developed using the results of multivariate analyses, as they weigh the combined effects of multiple independent factors found to be correlated with the selected clinical endpoint. The integrated evaluation of clinical and dosimetric parameters in the single patient can help to provide a tailored probability of the specific outcome considered. Predicting a high probability of toxicity could avoid unnecessary daily costs for the individual patient in terms of quality of life modification during and after treatment, helping patients in the decision‐making process of choosing the best individual, quality of life–related treatment, and clinicians in better tailoring the treatment to patients characteristics. Cancer 2009;115(13 suppl):3141–9.

Predictive models of toxicity in external radiotherapy: dosimetric issues.

Dose‐volume modeling of late and acute toxicity in radiotherapy for prostate cancer is a rapidly evolving field of investigation. The availability of individual, 3‐dimensional dose distribution and dose‐volume histograms (DVHs) permits the quantitative assessment of dose‐volume relations for specific endpoints by investigating the correlation between individual dose‐volume data and clinical outcomes. These studies often entail a huge effort in collecting data from large populations that have been followed properly for long time. The rectum is the most investigated organ, especially concerning late bleeding, and a good consensus regarding serial‐like behavior for this endpoint comes from various investigations. Concerning the bladder, the existence of a clear dose effect when the organ is wholly or partially irradiated is well known. Concerning erectile dysfunctions, the wide use of hormone therapy and drugs against impotence suggests that large, prospectively scored populations will be necessary to definitively assess dose‐volume relations. Bowel irradiation during prostate cancer radiotherapy occurs during pelvic lymph node irradiation, and severe acute toxicity has yet to be modeled clearly. Evidence of a correlation between the DVH of the intestinal cavity and bowel toxicity recently was reported, providing important information about optimal dose‐volume constraints to be used during whole‐pelvis irradiation with intensity‐modulated radiotherapy. Cancer 2009;115(13 suppl):3135–40.