Gianni Fellin

Rectal dose–volume constraints in high-dose radiotherapy of localized prostate cancer

PURPOSE To investigate the relationship between rectal bleeding and dosimetric-clinical parameters in patients receiving three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. METHODS In a retrospective national study (AIROPROS01-01, AIRO: Associazione Italiana Radioterapia Oncologica), planning/clinical data for 245 consecutive patients with stage T1-4N0-x prostate carcinoma who underwent 3D-CRT to 70-78 Gy (ICRU point) were pooled from four Italian institutions. The correlation between late rectal bleeding and rectal dose-volume data (the percentage of rectum receiving more than 50, 55, 60, 65, 70, and 75 Gy [V(50-70)]) and other dosimetric and clinical parameters were investigated in univariate (log-rank) and multivariate (Cox regression model) analyses. Median follow-up was 2 years. RESULTS Twenty-three patients were scored as late bleeders according to a modified RTOG definition (Grade 2: 16; Grade 3: 7); the actuarial 2-year rate was 9.2%. Excepting V75, all median and third quartile V(50-70) values were found to be significantly correlated with late bleeding at univariate analysis. The smallest p value was seen for V(50) below/above the third quartile value (66%). The V70 (cut-off value: 30%) was found to be also predictive for late bleeding. In the high-dose subgroup (74-78 Gy), Grade 3 bleeding was highly correlated with this constraint. The predictive value of both V(50) and V(70) was confirmed by multivariate analyses. CONCLUSIONS The present article provides evidence for correlation between rectal DVH parameters and late rectal bleeding in patients treated with curative intent with 3D-CRT. To keep the rate of moderate/severe rectal bleeding below 5-10%, it seems advisable to limit V(50) to 60-65%, V(60) to 45-50%, and V70 to 25-30%.

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.

Cisplatin, hyperthermia, and radiation (trimodal therapy) in patients with locally advanced head and neck tumors: A phase I–II study

PURPOSE Hyperthermia is now being widely used to treat clinical malignancies especially combined with radiotherapy and more rarely with chemotherapy. The combination of heat, radiation, and chemotherapy (trimodality) can lead to potent interaction. The present Phase I-II study was conducted to evaluate the feasibility and acute toxicity of a combination of cisplatin, hyperthermia, and irradiation in the treatment of superficial cervical nodal metastases from head and neck cancer. METHODS AND MATERIALS Eighteen patients with measurable neck metastases from previously untreated squamous cell head and neck tumors were entered into the trial. Therapy consisted of a conventional irradiation (total dose 70 Gy, 2 Gy five times a week) combined with a weekly administration of 20 mg/m2 iv of cisplatin and a total of two sessions of local external microwave hyperthermia (desired temperature of 42.5 degrees C for 30 min). RESULTS Feasibility of the treatment was demonstrated. Acute local toxicity was mild; no thermal blisters or ulcerations were reported and only two patients experienced local pain during hyperthermia. Cutaneous toxicity appeared greater than in our previous studies with irradiation plus hyperthermia and irradiation plus cisplatin. Systemic toxicity was moderate with major toxic effects observed in three patients (World Health Organization (WHO) grade 3 anaemia). Even though it was not an aim of the study to evaluate the nodal response, we observed a complete response rate of 72.2% (95% confidence interval 51-93.4%), 16.6% of partial response and 11.1% of no change. CONCLUSION The study confirms the feasibility of the combination of cisplatin, heat, and radiation with an acceptable toxicity profile. The trimodal therapy deserves further evaluation as a way to enhance the efficacy of irradiation in the treatment of nodal metastases from head and neck tumors.

Phase I study of gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer

PURPOSE Although the use of radical transurethral resection followed by concurrent radiochemotherapy leads to a similar survival rate to that achieved after cystectomy, the number of long-term survivors is low in both cases. An improvement may be obtained by adding a new drug, such as gemcitabine, which is active in bladder cancer and acts as a radiosensitizer. However, because gemcitabine may be very toxic when associated with radiotherapy, we designed this dose-finding study in an attempt to find the dose that can be safely added to radiotherapy and concurrent cisplatin in patients treated with transurethral resection for infiltrating bladder cancer. PATIENTS AND METHODS After undergoing macroscopically complete transurethral resections for transitional carcinoma of the bladder, patients staged pT2 or higher and without distant metastases concurrently received 54 Gy of fractionated radiotherapy over 6 weeks with cisplatin (100 mg/m(2) q.3 w), starting on Day 1 of radiotherapy. Concomitant gemcitabine was administered on Days 1, 8, and 15 q.3 w for 2 cycles at a dose of 200 mg/m(2), escalated to 500 mg/m(2), with a 100 mg/m(2) increase at each dose level. The maximum tolerated dose was defined as the dose of gemcitabine associated with dose-limiting toxic effects (febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 or 4 enteric toxicity, or Grade 4 nonhematologic toxicity) in 33% of the patients treated at that dose level. Six to 8 weeks after completing the therapy, the patients underwent cystoscopic reevaluation with multiple biopsies of the initial tumor site. RESULTS Of our consecutive series of 16 patients, 5 received a gemcitabine dose of 200 mg/m(2)/week, 3 a dose of 300 mg/m(2)/week, 3 a dose of 400 mg/m(2)/week, and 5 a dose of 500 mg/m(2)/week for 6 weeks. No dose-limiting toxicity was observed at doses of up to 400 mg/m(2)/week. At the dose 500 mg/m(2)/week, 1 patient experienced an intestinal perforation that recovered after surgery, and another suddenly died after developing Grade 3 untreated diarrhea in the last treatment week. All of the 15 evaluable patients were microscopically disease free at the cystoscopic reevaluation; furthermore, the posttreatment computed tomography scans did not reveal any distant metastases. CONCLUSIONS After transurethral resection for the conservative treatment of infiltrating bladder cancer, gemcitabine doses of up to 400 mg/m(2)/week seem to be safe in combination with cisplatin and radiotherapy in organ-sparing management. On the basis of the promising results of this Phase I study, we are currently conducting a Phase II trial to verify the possible improvement in local control resulting from the addition of gemcitabine.

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.

Increasing the risk of late rectal bleeding after high-dose radiotherapy for prostate cancer: The case of previous abdominal surgery. Results from a prospective trial

PURPOSE To evaluate and discuss the role of specific types of abdominal surgery (SURG) before radical radiation therapy as a risk factor for late rectal toxicity in prostate cancer patients. METHODS Results concerning questionnaire-based scored late bleeding and faecal incontinence in 718 patients with a complete follow-up of 36 months were analysed, focusing on the impact of specific pre-radiotherapy abdominal/pelvic surgery procedures. Patients were accrued in the prospective study AIROPROS 0102. Different types of surgery (rectum-sigma resection, kidney resection, cholecystectomy or appendectomy) were considered as covariates together with a number of different parameters previously found to be predictive of late toxicity and including clinical as well as dosimetric parameters. Univariate (UVA) and multivariate (MVA) logistic analyses were carried out. RESULTS In total 69/718 patients were previously submitted to one or more surgical procedures, mostly cholecystectomy (n=21) and appendectomy (n=27). Actuarial incidences of G2-G3 and G3 bleeding were 52 (7.2%) and 24 (3.3%) respectively; 19 (2.6%) chronic incontinence events were registered. Cholecystectomy was found to be highly correlated with late rectal bleeding at UVA: OR=4.3 and p=0.006 for G2-G3 and OR=5.4 and p=0.01 for G3. Considering MVA (including dosimetric and clinical factors), G2-G3 bleeding was significantly correlated to cholecystectomy (OR=6.5, p=0.002), V75 Gy (OR=1.074, p=0.003) and secondarily with appendectomy (OR=2.7, p=0.10), presence of acute radioinduced rectal bleeding (OR=1.70, p=0.21) and androgen deprivation (OR=0.67, p=0.25). Appendectomy (OR=5.9, p=0.004) and cholecystectomy (OR=5.5, p=0.016) were very strong predictors of G3 bleeding with V75 Gy playing a less significant role (OR=1.037, p=0.26). Conversely, no specific surgery was correlated with actuarial or chronic incontinence. CONCLUSIONS This analysis highlights previous SURG as the best predictor of late rectal bleeding. Among the different types of abdominal surgery, cholecystectomy and appendectomy play the major role, especially for severe late bleeding.

Late Fecal Incontinence After High-Dose Radiotherapy for Prostate Cancer: Better Prediction Using Longitudinal Definitions

PURPOSE To model late fecal incontinence after high-dose prostate cancer radiotherapy (RT) in patients accrued in the AIROPROS (prostate working group of the Italian Association of Radiation Oncology) 0102 trial using different endpoint definitions. METHODS AND MATERIALS The self-reported questionnaires (before RT, 1 month after RT, and every 6 months for ≤3 years after RT) of 586 patients were available. The peak incontinence (P_INC) and two longitudinal definitions (chronic incontinence [C_INC], defined as the persistence of Grade 1 or greater incontinence after any Grade 2-3 event; and mean incontinence score [M_INC], defined as the average score during the 3-year period after RT) were considered. The correlation between the clinical/dosimetric parameters (including rectal dose-volume histograms) and P_INC (Grade 2 or greater), C_INC, and M_INC of ≥1 were investigated using multivariate logistic analyses. Receiver operating characteristic curves and the area under the curve were used to assess the predictive value of the different multivariate models. RESULTS Of the 586 patients, 36 with a Grade 1 or greater incontinence score before RT were not included in the present analysis. Of the 550 included patients, 197 (35.8%) had at least one control with a Grade 1 or greater incontinence score (M_INC >0). Of these 197 patients, 37 (6.7%), 22 (4.0%), and 17 (3.1%) were scored as having P_INC, M_INC ≥1, and C_INC, respectively. On multivariate analysis, Grade 2 or greater acute incontinence was the only predictor of P_INC (odds ratio [OR], 5.9; p = .0009). Grade 3 acute incontinence was predictive of C_INC (OR, 9.4; p = .02), and percentage of the rectal volume receiving >40 Gy of ≥80% was predictive of a M_INC of ≥1 (OR, 3.8; p = .008) and of C_INC (OR, 3.6; p = .03). Previous bowel disease, previous abdominal/pelvic surgery, and the use of antihypertensive (protective factor) correlated highly with both C_INC and M_INC ≥1. The predictive values of the models for C_INC (area under the curve, 0.83) and M_INC ≥1 (area under the curve, 0.73) were greater than the ones for P_INC (area under the curve, 0.62) and more reliable (p = .0001-.0003 against p = .02). Nomograms for the two longitudinal definitions were derived. CONCLUSIONS The longitudinal definitions of fecal incontinence (C_INC and M_INC ≥1) were helpful in accounting for both the persistence and the severity of the incontinence. A significant fraction of peak events was consequential to acute incontinence, and a longer duration of symptoms mainly depended on the rectal dose bath (percentage of rectal volume receiving >40 Gy), and pretreatment clinical factors.

Gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer: Long-term cumulative results of 2 prospective single-institution studies.

Cystectomy is the standard treatment for patients with infiltrating bladder cancer, but conservative treatment with cystoscopic resection followed by radiochemotherapy may be an alternative for highly selected patients. The addition of gemcitabine to cisplatin and radiotherapy may enhance disease control.