Pelvic bone marrow dose-volume predictors of late lymphopenia following pelvic lymph node radiation therapy for prostate cancer.

BACKGROUND AND PURPOSE: Given the substantial lack of knowledge, we aimed to assess clinical/dosimetry predictors of late hematological toxicity on patients undergoing pelvic-nodes irradiation (PNI) for prostate cancer (PCa) within a prospective multi-institute study. MATERIALS AND METHODS: Clinical/dosimetry/blood test data were prospectively collected including lymphocytes count (ALC) at baseline, mid/end-PNI, 3/6 months and every 6 months up to 5-year after PNI. DVHs of the Body, ileum (BMILEUM), lumbosacral spine (BMLS), lower pelvis (BMPELVIS), and whole pelvis (BMTOT) were extracted. Current analysis focused on 2-year CTCAEv4.03 Grade ≥ 2 (G2+) lymphopenia (ALC < 800/µL). DVH parameters that better discriminate patients with/without toxicity were first identified. After data pre-processing to limit overfitting, a multi-variable logistic regression model combining DVH and clinical information was identified and internally validated by bootstrap. RESULTS: Complete data of 499 patients were available: 46 patients (9.2 %) experienced late G2+ lymphopenia. DVH parameters of BMLS/BMPELVIS/BMTOT and Body were associated to increased G2+ lymphopenia. The variables retained in the resulting model were ALC at baseline [HR = 0.997, 95 %CI 0.996-0.998, p < 0.0001], smoke (yes/no) [HR = 2.9, 95 %CI 1.25-6.76, p = 0.013] and BMLS-V ≥ 24 Gy (cc) [HR = 1.006, 95 %CI 1.002-1.011, p = 0.003]. When acute G3+ lymphopenia (yes/no) was considered, it was retained in the model [HR = 4.517, 95 %CI 1.954-10.441, p = 0.0004]. Performances of the models were relatively high (AUC = 0.87/0.88) and confirmed by validation. CONCLUSIONS: Two-year lymphopenia after PNI for PCa is largely modulated by baseline ALC, with an independent role of acute G3+ lymphopenia. BMLS-V24 was the best dosimetry predictor: constraints for BMTOT (V10Gy < 1520 cc, V20Gy < 1250 cc, V30Gy < 850 cc), and BMLS (V24y < 307 cc) were suggested to potentially reduce the risk.

Quality of Life Longitudinal Evaluation in Prostate Cancer Patients from Radiotherapy Start to 5 Years after IMRT-IGRT.

PURPOSE: The purpose of this study is to study the evolution of quality of life (QoL) in the first 5 years following Intensity-modulated radiation therapy (IMRT) for prostate cancer (PCa) and to determine possible associations with clinical/treatment data. MATERIAL AND METHODS: Patients were enrolled in a prospective multicentre observational trial in 2010-2014 and treated with conventional (74-80 Gy, 1.8-2 Gy/fr) or moderately hypofractionated IMRT (65-75.2 Gy, 2.2-2.7 Gy/fr). QoL was evaluated by means of EORTC QLQ-C30 at baseline, at radiation therapy (RT) end, and every 6 months up to 5 years after IMRT end. Fourteen QoL dimensions were investigated separately. The longitudinal evaluation of QoL was analysed by means of Analysis of variances (ANOVA) for multiple measures. RESULTS: A total of 391 patients with complete sets of questionnaires across 5 years were available. The longitudinal analysis showed a trend toward the significant worsening of QoL at RT end for global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. QoL worsening was recovered within 6 months from RT end, with the only exception being physical functioning. Based on ANOVA, the most impaired time point was RT end. QoL dimension analysis at this time indicated that acute Grade ≥ 2 gastrointestinal (GI) toxicity significantly impacted global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. Acute Grade ≥ 2 genitourinary (GU) toxicity resulted in lower role functioning and higher pain. Prophylactic lymph-nodal irradiation (WPRT) resulted in significantly lower QoL for global health, fatigue, appetite loss, and diarrhoea; lower pain with the use of neoadjuvant/concomitant hormonal therapy; and lower fatigue with the use of an anti-androgen. CONCLUSIONS: In this prospective, longitudinal, observational study, high radiation IMRT doses delivered for PCa led to a temporary worsening of QoL, which tended to be completely resolved at six months. Such transient worsening was mostly associated with acute GI/GU toxicity, WPRT, and higher prescription doses.

Acute patient-reported intestinal toxicity in whole pelvis IMRT for prostate cancer: Bowel dose-volume effect quantification in a multicentric cohort study.

BACKGROUND AND PURPOSE: To assess bowel dose-volume relationships for acute patient-reported intestinal symptoms of patients treated with whole-pelvis intensity-modulated radiotherapy (WPRT) for prostate cancer. MATERIALS AND METHODS: Complete data of 415 patients enrolled in a multi institute, prospective trial (#NCT02803086) treated with radical (31%), adjuvant (33%) and salvage (36%) intent at a median dose to pelvic nodes/lymph-nodal area of 53 Gy were available. The most severe changes between baseline and radiotherapy mid-point/end toxicity assessed by Inflammatory Bowel Disease Questionnaire (only Bowel Domain) were considered (ΔIBDQ). The 25th percentile values of these score variations were set as endpoints. DVHs of bowel loops for patients with/without toxicity were compared for each endpoint, having excluded patients with baseline scores <5 (rate ranging between 2% and 7% according to the endpoint): the resulting best dosimetric predictors were combined with selected clinical parameters through multivariate logistic regression (MVA) to derive predictive models. RESULTS: ΔIBDQ ranged between 0.2-1.5 points considering separately each IBDQ symptom. Only four symptoms (IBDQ1 = frequency, IBDQ5 = diarrhea, IBDQ17 = gas passage, IBDQ24 = urgency) showed a median worsening ≥ 1; DVH predicted the risk of worse symptoms for IBDQ5, IBDQ24 and overall Bowel Domain. At multivariable analysis DVHs (best cut-off: V46Gy ≥80 cc) and baseline scores (Odd-Ratio:0.35-0.65) were independently associated to the three end-points. The resulting models were reliable (H&L test: 0.453-0.956), well calibrated (calibration plot: slope = 0.922-1.069, R2 = 0.725-0.875) and moderately discriminative (Area Under the Curve:0.628-0.669). A bootstrap-based validation confirmed their robustness. CONCLUSION: Constraining the bowel loops (V46 < 80 cc) may reduce the risk of several moderate intestinal symptoms, with a much greater impact for patients with lower IBDQ baseline scores.

Prostate cancer dose-response, fractionation sensitivity and repopulation parameters evaluation from 25 international radiotherapy outcome data sets.

OBJECTIVE: This study was undertaken to model the biochemical free survival at 5 years and to evaluate the parameters defining dose-response curve, dose-fractionation radiosensitivity and repopulation. METHODS: It was carried out a literature search on Pubmed to retrieve data sets of patients treated with external beam radiation therapy of 1.8-4.0 Gy per fraction and overall treatment time of 3 to 10 weeks. 10 groups were identified, based on risk class and androgen deprivation therapy (ADT). Dose-response curve D50 (dose at 50% probability of control) and g50 (steepness), α/ß (dose-fractionation radiosensitivity), and repopulation parameters, dprolif and Tprolif , were calculated. Bootstrap-based cross-validation was performed and median and 95% CI (confidence interval) were evaluated. RESULTS: 25 data sets, including 20,310 patients, were considered. The median (95% CI) D50 and g50 values were 62 (CI 53 - 66) Gy and 1.6 (0.8 - 2.4). ADT patients showed lower values of D50 and g50 (57 ± 5 Gy and 1.1 ± 0.4) compared to no-ADT patients (65 ± 2 Gy and 2.3 ± 0.6), with p < 0.0001 and p = 0.002. If we did not consider any dependence on overall treatment time, the median (95% CI) value of α/ß was 1.4 (1.0 - 1.9) Gy with p < 0.0001 for all patients. The median values of dproli f and Tprolif were 0.0 to 0.3 Gy/d and 18-40 days. CONCLUSION: Dose-response curve resulted dependent on risk class and ADT, with higher steepness for no-ADT patients. Low values of dose-fractionation radiosensitivity were found, supporting the use of moderate hypofractionated radiotherapy in each risk class. A limited dependence on repopulation was observed. ADVANCES IN KNOWLEDGE: Prostate cancer response to moderate hypofractionated radiotherapy was reliably quantified considering risk class and androgen deprivation therapy.

Salvage radiation therapy after radical prostatectomy: survival analysis.

BACKGROUND: To evaluate the outcome of patients treated with salvage radiotherapy after radical prostatectomy and to investigate the effects of independent predictors on survival. METHODS: From January 2000 to December 2015, 234 patients with biochemical/clinical recurrences after radical prostatectomy were submitted to salvage radiotherapy (SRT). One hundred and fifty-seven patients (67%) received three-dimensional (3D) conformal radiotherapy while 77 patients (33%) were treated with intensity-modulated radiotherapy (IMRT) or IMRT/image-guided radiotherapy by tomotherapy. The median RT dose to prostate bed was 70.2 Gy (range: 66-79 Gy). The investigated endpoints were biochemical relapse-free survival (BRFS), clinical relapse-free survival (CRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS). Different covariates were considered to investigate predictors of survival. RESULTS: With a median follow-up of 117 months the BRFS, CRFS, DMFS and PCSS at 10 years were 54%, 84%, 90%, and 94%, respectively. In multivariate analysis (MVA), the pathological Gleason Score (pGS) was the most important factor affecting BRFS, CRFS, DMFS and PCSS (P<0.007, HR>1.55); pathological stage (pT) was predictor of BRFS (P=0.007, HR=1.7) and PCSS (P=0.02, HR=4.2), and the last prostate-specific antigen during follow-up was an important survival predictor of CRFS (P=0.004, HR=1.26) and PCSS (P<0.0001, HR=1.04). The time between surgery and the start of SRT was correlated with BRFS (P<0.0001, HR=0.987) and CRFS (P=0.047, HR=0.989). In univariate analysis (UVA), positive surgical margins at the prostatectomy specimen improved BRFS (P=0.01, HR=0.54), CRFS (P=0.05, HR=0.46) and DMFS (P=0.005, HR=0.13) after SRT. CONCLUSIONS: At long-term follow-up, excellent outcome results of SRT on BRFS, CRFS, DMFS, and PCSS were obtained. Several prognostic factors such as pGS, pT and surgical margin status were found to be predictors of survival.

Comparison of two different EPID-based solutions performing pretreatment quality assurance: 2D portal dosimetry versus 3D forward projection method.

PURPOSE: The aim of this paper is to characterize two different EPID-based solutions for pre-treatment VMAT quality assurance, the 2D portal dosimetry and the 3D projection technique. Their ability to catch the main critical delivery errors was studied. METHODS: Measurements were performed with a linac accelerator equipped with EPID aSi1000, Portal Dose Image Prediction (PDIP), and PerFRACTION softwares. Their performances were studied simulating perturbations of a reference plan through systematic variations in dose values and micromultileaf collimator position. The performance of PDIP, based on 2D forward method, was evaluated calculating gamma passing rate (%GP) between no-error and error-simulated measurements. The impact of errors with PerFRACTION, based on 3D projection technique, was analyzed by calculating the difference between reference and perturbed DVH (%ΔD). Subsequently pre-treatment verification with PerFRACTION was done for 27 patients of different pathologies. RESULTS: The sensitivity of PerFRACTION was slightly higher than sensitivity of PDIP, reaching a maximum of 0.9. Specificity was 1 for PerFRACTION and 0.6 for PDIP. The analysis of patients' DVHs indicated that the mean %ΔD was (1.2 ±â€¯1.9)% for D2%, (0.6 ±â€¯1.7)% for D95% and (-0.0 ±â€¯1.2)% for Dmean of PTV. Regarding OARs, we observed important discrepancies on DVH but that the higher dose variations were in low dose area (<10 Gy). CONCLUSIONS: This study supports the introduction of the new 3D forward projection method for pretreatment QA raising the claim that the visualization of the delivered dose distribution on patient anatomy has major advantages over traditional portal dosimetry QA systems.

Patient-reported intestinal toxicity from whole pelvis intensity-modulated radiotherapy: First quantification of bowel dose-volume effects.

BACKGROUND AND PURPOSE: Intestinal toxicity is commonly experienced during whole-pelvis intensity-modulated radiotherapy (WPRT) for prostate cancer. The aim of the current study was to assess bowel dose-volume relationships for acute patient-reported intestinal symptoms of patients treated with WPRT for prostate cancer. MATERIALS AND METHODS: Complete data of 206 patients were available; the median dose to pelvic nodes was 51.8Gy (range 50.4-54.4, 1.7-2Gy/fr). Intestinal symptoms were assessed as changes in the Inflammatory Bowel Disease Questionnaire scores relative to the Bowel Domain (IBDQ-B) between baseline and radiotherapy mid-point/end. The 25th percentiles of the most severe worsening from baseline (ΔIBDQ-B) were set as end-points. The impact of bowel loops and sigmoid colon dose-volume/surface parameters as well as selected clinical parameters were investigated using multivariate logistic regression. RESULTS: Analyses were focused on the four questions showing a median ΔIBDQ-B>0. No dose volume/surface parameters were predictive, other than ΔIBDQ5≥3 (loose stools): when grouping patients according to bowel DVHs (high risk: V20>470cc, V30>245cc, V42>110cc; low risk: all the remaining patients), a two-variable model including high-risk DVH-shape (OR: 9.3) and age (protective, OR: 0.94) was assessed. The model showed good calibration (slope: 1.003, R2=0.92) and was found to be robust after bootstrap-based internal validation. CONCLUSIONS: Constraining the bowel loops may reduce the risk of loose stools. The risk is higher for younger patients.

Prognostic factors in prostate cancer patients treated by radical external beam radiotherapy.

BACKGROUND: The aim of this paper was to analyze, retrospectively, in prostate cancer patients treated in our Centre with external beam radiotherapy, the prognostic factors and their impact on the outcome in terms of cancer-specific survival (CSS), biochemical disease-free survival (BDFS) and clinical disease-free survival (CDFS). METHODS: From October 1999 and March 2012, 1080 patients were treated with radiotherapy at our Institution: 87% of them were classified as ≤cT2, 83% had a Gleason Score (GS) ≤7, their mean of iPSA was 18 ng/mL, and the rate of clinical positive nodes was 1%. The mean follow-up was 81 months. RESULTS: The statistically significant prognostic factors for all groups of patients at both, univariate and multivariate analysis, were the GS and the iPSA. In intermediate- and high- or very-high-risk patients at multivariate analysis other prognostic factors for CSS were positive nodes on computed tomography (CT) scan and rectal preparation during the treatment; for BDFS, the prognostic factors were patient risk classification, positive lymph nodes on CT scan and rectal/bladder preparation; for CDFS, the prognostic factors were the number of positive core on biopsy (P=0.003), positive lymph nodes on CT scan, and radiotherapy (RT) dose. In high/very-high risk patient group at multivariate analysis other prognostic factors for CSS were clinical/radiological stage and RT dose, for BDFS they were adjuvant hormone therapy, clinical/radiological stage, and RT dose >77.7 Gy, and for CDFS they were clinical/radiological stage and RT dose >77.7 Gy. CONCLUSIONS: The results of this study confirm the prognostic factors described in the recent literature, with the addition of rectal/bladder preparation, generally known for its effect on toxicity but not yet on outcome.

External beam radiotherapy with dose escalation in 1080 prostate cancer patients: definitive outcome and dose impact.

BACKGROUND: The aim of this paper was to report definitive outcome of prostate cancer patients treated with dose escalation during a period of 12.5 years. METHODS: From October 1999 to March 2012 we treated 1080 patients affected by prostate cancer, using External Beam Radiotherapy (EBRT). The mean age was 69.2 years. Most of the patients (69%) were staged as cT2, Gleason Score (GS)<7; the mean iPSA 18 ng/mL; the rate of clinical positive nodes was 1%. Our intention to treat was the following: for low risk patients 72 Gy; for intermediate risk patients 75.6 Gy and for high-very high risk patients 79.2 Gy in 1.8 Gy/day fractions. From 2008 we changed the fractionation scheme and the doses were the following: for low risk patients 74 Gy and for intermediate and high-very high risk patients 78 Gy in 2.0 Gy/day fractions. Whole pelvis irradiation was performed in high-very high risk patients with 43.2-50.4 Gy in 1.8 Gy per day. The mean follow-up was 81 months. RESULTS: For the whole population at 5 and 10 years, the prostate cancer specific overall survival (CSOS) was 96.7% and 92.2% respectively; the clinical disease free survival (CDFS) 88% and 77%; the biochemical disease free survival (BDFS) 75% and 58.5%. The 5 and 10 years CSOS was 98% and 96% respectively for low risk, 96% and 92% for intermediate risk and 89% and 82% for high-very high risk patients. In intermediate and high-very high risk groups at 5 and 10 years the CSOS was 95.2% and 89.2% respectively, the CDFS 84.5% and 70% and the BDFS 70% and 51% respectively. In high-very high risk patients at 5 and 10 years the CSOS were respectively 89% and 82% the CDFS was 78% and 61% and BDFS was 61% and 34%. In whole patient population the BDFS was related with the dose level (P=0.006) as well as the CDFS (P=0.003) with a cut off of 75.6 Gy. In the subgroup of intermediate plus high-very high risk patients the BDFS and the CDFS were dose-related with a cut off of 75.6 Gy (P=0.007 and P=0.0018 respectively). Finally, in the subgroup of high-very high risk patients we found that the CSOS, the BDFS and the CDFS were related to the dose level with a cut-off of 77.7 Gy (P=0.017; P=0.006 and P=0.038, respectively). Overall gastrointestinal (GI) acute and late G2 toxicities were respectively 5 % and 3.8%; GI acute and late >G3 toxicities were respectively 0.5% and 0.9%; acute and late >G2 genitourinary (GU) toxicities were respectively 10.5% and 2.6%; finally GU acute and late >G3 toxicities were respectively 0.6% and 0.5%. CONCLUSIONS: The dose escalation is not relevant for the outcome in low risk patients that can benefit from relatively moderate doses (72-74 Gy). For intermediate and high-very high risk patients the dose becomes significant to levels above 75.6 Gy; particularly in high-very high risk doses >77.7 Gy correlate with an improved outcome. Patients receiving dose >77.7 Gy presented a higher rate of overall GI and GU toxicity, but the number of grade >2 remains low. Our results, consolidated by a long follow-up, corroborate the literature data, confirming that 3D-CRT can allow a safe dose escalation without significantly increasing the severe toxicity.

Multi-variable models of large International Prostate Symptom Score worsening at the end of therapy in prostate cancer radiotherapy.

PURPOSE/OBJECTIVE: Prospectively assessing clinical/dosimetry factors affecting the acute worsening of urinary functionality after radiotherapy for prostate cancer. MATERIAL/METHODS: DUE01 population was considered, including patients treated with conventional or moderate hypo-fractionation (2.2-2.7 Gy/fr). Relevant clinical factors were collected, urinary symptoms were self-reported through the International Prostate Symptom Score (IPSS) before and at the end of radiotherapy; while absolute weekly dose-surface histograms (DSHw) were chosen as dosimetry descriptors. An IPSS increase of at least 10 and 15 points (ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15) were chosen as endpoints. Patients with baseline IPSS>20 were excluded. Relevant factors were chosen through a bootstrap-based in silico methodology. RESULTS: Complete information was available for 380 patients: 77/380 (20%) and 28/380 (7%) with ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15, respectively. Neoadjuvant hormone was protective (OR=0.49 and 0.69). DSHw at 8.5 Gy/week and 12 Gy/week were risk factors, with additional risk for patients who use cardiovascular drugs and anti-hypercholesterolemia drugs. In the hypo-fractionated subgroup (n=209) the role of cardiovascular drugs (OR=2.16) for ΔIPSS ⩾ 10 and anti-hypercholesterolemia drugs (OR=2.80) for ΔIPSS⩾15, together with DSHw (10 Gy/week and 12.5 Gy/week, respectively), was confirmed. CONCLUSION: Current study shows a dose-surface/volume effect for acute large worsening of urinary functionality; several clinical variables largely impact the risk and especially all the factors related with vascular diseases.

A pre-treatment quality assurance survey on 384 patients treated with helical intensity-modulated radiotherapy.

The gamma index pass rate (%GP) of 384 helical Tomotherapy pre-patient quality assurance, acquired with ArcCHECK, is presented, analyzed, and correlated to plan characteristics. Average %GP was higher than 90% and correlated strongly with gamma method, irradiated length, pitch, maximum dose to diodes, and dose per fraction.

Tomotherapy PET-guided dose escalation: A dosimetric feasibility study for patients with malignant pleural mesothelioma.

AIM: The aim of this study was to investigate whether a safe escalation of the dose to the pleural cavity and PET/CT-positive areas in patients with unresectable malignant pleural mesothelioma (MPM) is possible using helical tomotherapy (HT). MATERIAL AND METHODS: We selected 12 patients with MPM. Three planning strategies were investigated. In the first strategy (standard treatment), treated comprised a prescribed median dose to the planning target volume (PTV) boost (PTV1) of 64.5 Gy (range: 56 Gy/28 fractions to 66 Gy/30 fractions) and 51 Gy (range: 50.4 Gy/28 fractions to 54 Gy/30 fractions) to the pleura PTV (PTV2). Thereafter, for each patient, two dose escalation plans were generated prescribing 62.5 and 70 Gy (2.5 and 2.8 Gy/fraction, respectively) to the PTV1 and 56 Gy (2.24 Gy/fraction) to the PTV2, in 25 fractions. Dose-volume histogram (DVH) constraints and normal tissue complication probability (NTCP) calculations were used to evaluate the differences between the plans. RESULTS: For all plans, the 95 % PTVs received at least 95 % of the prescribed dose. For all patients, it was possible to perform the dose escalation in accordance with the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) constraints for organs at risk (OARs). The average contralateral lung dose was < 8 Gy. NTCP values for OARs did not increase significantly compared with the standard treatment (p > 0.05), except for the ipsilateral lung. For all plans, the lung volume ratio was strongly correlated with the V20, V30, and V40 DVHs of the lung (p < 0.0003) and with the lung mean dose (p < 0.0001). CONCLUSION: The results of this study suggest that by using HT it is possible to safely escalate the dose delivery to at least 62.5 Gy in PET-positive areas while treating the pleural cavity to 56 Gy in 25 fractions without significantly increasing the dose to the surrounding normal organs.

Erratum to: Tomotherapy PET-guided dose escalation--A dosimetric feasibility study for patients with malignant pleural mesothelioma.

Unfortunately, erroneous author affiliations were published in the article "Tomotherapy PET-guided dose escalation ­ A dosimetric feasibility study for patients with malignant pleural mesothelioma". The correct list of author affiliations reads as follows: Angelo Maggio 1, Claudia Cutaia 1, Amalia Di Dia 1, Sara Bresciani 1, Anna Miranti 1, Matteo Poli 1, Elena Delmastro 2, Elisabetta Garibaldi 2, Pietro Gabriele 2 and Michele Stasi 1. 1: Medical Physics Department, Candiolo Cancer Institute ­ FPO, IRCCS, Turin, Italy. 2: Radiotherapy Department, Candiolo Cancer Institute ­ FPO, IRCCS, Turin, Italy. We apologize for any inconveniences caused.

Technical and clinical description of a case of extensive anogenital Paget's disease associated with anal cancer treated by tomotherapy.

In this paper we describe a case of extramammary Paget's disease associated with anal cancer, which was successfully treated by intensity-modulated radiotherapy using tomotherapy with a simultaneous integrated boost and daily image guidance. The main pitfall in this report is the relatively short follow-up (1 year), which means that the evaluated data is promising but not conclusive. Considering the rarity and wide extension of our patient's Paget's disease in the anogenital region, and the lack of literature reports about curative radiotherapy in this particular setting, this case report may be considered the first related to extensive extramammary Paget's disease treated by tomotherapy.

Daily sodium butyrate enema for the prevention of radiation proctitis in prostate cancer patients undergoing radical radiation therapy: results of a multicenter randomized placebo-controlled dose-finding phase 2 study.

PURPOSE: To evaluate the efficacy of sodium butyrate enemas (NABUREN) in prostate cancer radiation therapy (RT) in reducing the incidence, severity, and duration of acute RT-induced proctitis. METHODS AND MATERIALS: 166 patients, randomly allocated to 1 of 4 groups (rectal sodium butyrate 1 g, 2 g, or 4 g daily or placebo), were treated with NABUREN during and 2 weeks after RT. The grade of proctitis was registered in a daily diary. The correlation between NABUREN and proctitis was investigated through χ(2) statistics. The toxicity endpoints considered were as follows: total number of days with grade ≥1 proctitis (≥G1); total number of days with grade ≥2 proctitis (≥G2); ≥G1 and ≥G2 proctitis lasting at least 3 and 5 consecutive days starting from week 4 (≥G1+3d, ≥G2+3d); damaging effects of RT on rectal mucosa as measured by endoscopy. The relationship between endpoints and pretreatment morbidities, hormonal therapy, presence of diabetes or hypertension, abdominal surgery, or hemorrhoids was investigated by univariate analysis. RESULTS: The patients were randomly allocated to the 4 arms. No difference in the distribution of comorbidities among the arms was observed (P>.09). The mean ≥G1 and ≥G2 proctitis were 7.8 and 4.9 for placebo and 8.9 and 4.7 for the NABUREN group, respectively. No favorable trend in reduction of incidence, severity, and duration of ≥G1 and ≥G2 proctitis was observed with NABUREN use. In univariate analysis, ≥G1+3d toxicity was found to be related to hemorrhoids (P=.008), and a slight correlation was found between ≥G2 proctitis and hormonal therapy (P=.06). The RT effects on rectal mucosa as based on endoscopic assessment were mainly related to diabetes (P<.01). Endoscopy data at 6 week showed no significant difference between the placebo and butyrate arms. The other investigated endpoints were not correlated with any of the clinical risk factors analyzed. CONCLUSION: There was no evidence of efficacy of NABUREN in reducing the incidence, severity, and duration of acute radiation proctitis. There was a correlation between some endpoints and clinical risk factors.

Relationships between bladder dose-volume/surface histograms and acute urinary toxicity after radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: DUE01 is an observational study aimed at developing predictive models of genito-urinary toxicity of patients treated for prostate cancer with conventional (1.8-2Gy/fr, CONV) or moderate hypo-fractionation (2.35-2.7Gy/fr, HYPO). The current analysis focused on the relationship between bladder DVH/DSH and the risk of International Prostate Symptoms Score (IPSS)⩾15/20 at the end of radiotherapy. MATERIALS AND METHODS: Planning and relevant clinical parameters were prospectively collected, including DVH/DSH, LQ-corrected (DVHc/DSHc) and weekly (DVHw/DSHw) histograms. Best parameters were selected by the differences between patients with/without IPSS⩾15/20 at the end of radiotherapy. Logistic uni- and backward multi-variable (MVA) analyses were performed. RESULTS: Data of 247 patients were available (CONV: 116, HYPO: 131). Absolute DVHw/DSHw and DVHc/DSHc predicted the risk of IPSS⩾15 at the end of radiotherapy (n=77/247); an MVA model including baseline IPSS, anti-hypertensive, T stage, the absolute surface receiving ⩾8.5Gy/week and ⩾12.5Gy/week was developed (AUC=0.78, 95% CI: 0.72-0.83). Similar AUC values were found if replacing DSHw with DVHw/DVHc/DSHc parameters. The impact of dose-volume/surface parameters remained when excluding patients with baseline IPSS⩾15 and in HYPO. IPSS⩾20 at the end of radiotherapy (n=27/247) was mainly correlated to baseline IPSS and T stage. CONCLUSIONS: Although the baseline IPSS was the main predictor, constraining v8.5w<56cc and v12.5w<5cc may significantly reduce acute GU toxicity.

Tomotherapy treatment plan quality assurance: the impact of applied criteria on passing rate in gamma index method.

PURPOSE: Pretreatment patient plan verification with gamma index (GI) metric analysis is standard procedure for intensity modulated radiation therapy (IMRT) treatment. The aim of this paper is to evaluate the variability of the local and global gamma index obtained during standard pretreatment quality assurance (QA) measurements for plans performed with Tomotherapy unit. The QA measurements were performed with a 3D diode array, using variable passing criteria: 3%∕3 mm, 2%∕2 mm, 1%∕1 mm, each with both local and global normalization. METHODS: The authors analyzed the pretreatment QA results for 73 verifications; 37 were prostate cancer plans, 16 were head and neck plans, and 20 were other clinical sites. All plans were treated using the Tomotherapy Hi-Art System. Pretreatment QA plans were performed with the commercially available 3D diode array ArcCHECK™. This device has 1386 diodes arranged in a helical geometry spaced 1 cm apart. The dose measurements were acquired on the ArcCHECK™ and then compared with the calculated dose using the standard gamma analysis method. The gamma passing rate (%GP), defined as the percentage of points satisfying the condition GI < 1, was calculated for different criteria (3%∕3 mm, 2%∕2 mm, 1%∕1 mm) and for both global and local normalization. In the case of local normalization method, the authors set three dose difference threshold (DDT) values of 2, 3, and 5 cGy. Dose difference threshold is defined as the minimum absolute dose error considered in the analysis when using local normalization. Low-dose thresholds (TH) of 5% and 10% were also applied and analyzed. RESULTS: Performing a paired-t-test, the authors determined that the gamma passing rate is independent of the threshold values for all of the adopted criteria (5%TH vs 10%TH, p > 0.1). Our findings showed that mean %GPs for local (or global) normalization for the entire study group were 93% (98%), 84% (92%), and 66% (61%) for 3%∕3 mm, 2%∕2 mm, and 1%∕1 mm criteria, respectively. DDT was equal to 2 cGy for the local normalization analysis cases. The authors observed great variability in the resulting %GP. With 3%∕3 mm gamma criteria, the overall passing rate with local normalization was 4.6% less on the average than with global one, as expected. The wide difference between %GP calculated with global or local approach is also confirmed by an unpaired t-test statistical analysis. CONCLUSIONS: The variability of %GP obtained confirmed the necessity to establish defined agreement criteria that could be universal and comparable between institutions. In particular, while the gamma passing rate does not depend on the choice of threshold, the choice of DDT strongly influences the gamma passing rate for local calculations. The difference between global and local %GP was statistically significant for prostate and other treatment sites when DDT was changed from 2 to 3 cGy.

Dose to organs at risk in the upper abdomen in patients treated with extended fields by helical tomotherapy: a dosimetric and clinical preliminary study.

BACKGROUND: The aim of this work was to determine the technical feasibility and safety of extended-field radiotherapy (EF), performed by Helical TomoTherapy, in patients with positive pelvic and/or para-aortic nodes. Dosimetric data were collected and acute and sub-acute toxicities of the upper abdominal organs at risk (OAR) were evaluated. METHODS: Twenty-nine patients suitable for EF irradiation for local disease and/or nodal disease in the pelvic or para-aortic area were treated. The prescription dose was 50.4/54 Gy (1.7-1.8 Gy/fraction) for prophylactic lymph nodes (N-) and 60-70.5 Gy (2-2.35 Gy/fraction) for clinically evident gross disease (N+). Modulation factor (MF), pitch and field width (FW) were chosen to optimize dose distribution and treatment duration. Dose values of PTVs and OAR were analysed. The length of the treatment field, the N + and N- volumes, and treatment duration were reported. To evaluate the safety of treatment, haematological, hepatic, renal and pancreatic functions were assessed before, during and after treatment. The median follow-up time was 17.6 months (range: 6-22 months). RESULTS: The treatment was well tolerated and all patients but one completed treatment without interruption. Four of the 29 patients experienced G3 haematological acute toxicity (13.8%), but no patient experienced sub-acute grade G3 toxicity. Ten patients experienced G1 and three G2 acute gastrointestinal toxicity (nausea). No sub-acute gastrointestinal or renal toxicity was observed. Only one (3.7%) patient had a persistent slight increase of pancreatic enzymes and two (7.4%) patients a slight increase of hepatic enzymes six months after radiotherapy (G1 toxicity). CONCLUSIONS: With our treatment design and dose regimen, we found that EF treatment by TomoTherapy could be safely and effectively delivered with minimal acute and sub-acute toxicities in the upper abdomen area.

Helical tomotherapy and intensity modulated proton therapy in the treatment of dominant intraprostatic lesion: a treament planning comparison.

PURPOSE: To compare helical tomotherapy (HT) and intensity modulated proton therapy (IMPT) for prostate cancer irradiation while concomitantly boosting dominant intraprostatic lesions (DILs). METHODS AND MATERIALS: Treatment plans of seven patients were designed for HT and IMPT (pencil beam size: 3mm sigma). The prescribed median PTV/DIL doses were 71.4/100 Gy in 28 fractions, while satisfying "safe" dose constraints for organs at risks (OARs) including rectum, bladder, femoral heads, penile bulb and urethra. The planner could further reduce the dose to OARs if PTV/DIL constraints were reached. RESULTS: IMPT achieved better dose conformity (CI=1.11 vs 1.31, p<0.05) and coverage (V95%=97.3% vs 95.3%, p<0.05) in PTV. Concerning DIL volumes, both techniques delivered the prescribed dose (D median: HT=100 Gy, IMPT=102.1 Gy) with similar dose conformity (CI: HT=1.49, IMPT=1.44) and same dose homogeneity, D99%, D1%, while satisfying the OARs constraints. Excepting urethra, the sparing of OARs was significantly better with IMPT; in general, the lower the dose, the greater the benefit of IMPT. Normal tissue complication probabilities for the rectum were in favor of IMPT with an absolute reduction of 3-8%, depending on the NTCP model (p<0.05). CONCLUSIONS: Both techniques allowed delivering 100 Gy to DILs, while complying with the OARs constraints. IMPT was superior in sparing OARs for doses up to approximately 70 Gy, with larger benefit at lower doses.

Impact of the radiotherapy technique on the correlation between dose-volume histograms of the bladder wall defined on MRI imaging and dose-volume/surface histograms in prostate cancer patients.

The aim of this study was to evaluate the correlation between the 'true' absolute and relative dose-volume histograms (DVHs) of the bladder wall, dose-wall histogram (DWH) defined on MRI imaging and other surrogates of bladder dosimetry in prostate cancer patients, planned both with 3D-conformal and intensity-modulated radiation therapy (IMRT) techniques. For 17 prostate cancer patients, previously treated with radical intent, CT and MRI scans were acquired and matched. The contours of bladder walls were drawn by using MRI images. External bladder surfaces were then used to generate artificial bladder walls by performing automatic contractions of 5, 7 and 10 mm. For each patient a 3D conformal radiotherapy (3DCRT) and an IMRT treatment plan was generated with a prescription dose of 77.4 Gy (1.8 Gy/fr) and DVH of the whole bladder of the artificial walls (DVH-5/10) and dose-surface histograms (DSHs) were calculated and compared against the DWH in absolute and relative value, for both treatment planning techniques. A specific software (VODCA v. 4.4.0, MSS Inc.) was used for calculating the dose-volume/surface histogram. Correlation was quantified for selected dose-volume/surface parameters by the Spearman correlation coefficient. The agreement between %DWH and DVH5, DVH7 and DVH10 was found to be very good (maximum average deviations below 2%, SD < 5%): DVH5 showed the best agreement. The correlation was slightly better for absolute (R = 0.80-0.94) compared to relative (R = 0.66-0.92) histograms. The DSH was also found to be highly correlated with the DWH, although slightly higher deviations were generally found. The DVH was not a good surrogate of the DWH (R < 0.7 for most of parameters). When comparing the two treatment techniques, more pronounced differences between relative histograms were seen for IMRT with respect to 3DCRT (p < 0.0001).