Amyloid burden identifies neuropsychological phenotypes at increased risk of progression to Alzheimer's disease in mild cognitive impairment patients.

PURPOSE: The extent of amyloid burden associated with cognitive impairment in amnestic mild cognitive impairment is unknown. The primary aim of the study was to determine the extent to which amyloid burden is associated to the cognitive impairment. The secondary objective was to test the relationship between amyloid accumulation and memory or cognitive impairment. MATERIALS AND METHODS: In this prospective study 66 participants with amnestic mild cognitive impairment underwent clinical, neuropsychological and PET amyloid imaging tests. Composite scores assessing memory and non-memory domains were used to identify two clinical classes of neuropsychological phenotypes expressing different degree of cognitive impairment. Detection of amyloid status and definition of optimal amyloid ± cutoff for discrimination relied on unsupervised k-means clustering method. RESULTS: Threshold for identifying low and high amyloid retention groups was of SUVr = 1.3. Aß + participants showed poorer global cognitive and episodic memory performance than subjects with low amyloid deposition. Aß positivity significantly identified individuals with episodic memory impairment with a sensitivity and specificity of 80 and 79%, (χ2 = 21.48; P < 0.00001). Positive and negative predictive values were 82 and 76%, respectively. Amyloid deposition increased linearly as function of memory impairment with a rate of 0.13/ point of composite memory score (R = -44, P = 0.0003). CONCLUSION: The amyloid burden of SUVr = 1.3 allows early identification of subjects with episodic memory impairment which might predict progression from MCI to Alzheimer's disease. TRIAL REGISTRATION: EudraCT 2015-001184-39.

An In-House 3D Voxel Dosimetric Tool to Compare Predictive and Post- Treatment Dosimetry in 90Y Radioembolization: A Proof of Concept.

AIM: The aim of this study was to implement an in-house dosimetric tool to assess tumour- absorbed doses in pre and post-dosimetry for 90Y radioembolization with resin spheres. MATERIALS AND METHODS: To perform dosimetric calculations we set up a dosimetric procedure and developed homemade software to calculate tumour absorbed dose and dose volume histograms (DVHs). The method is based on a simplified voxel dosimetry for an estimated 3D absorbed dose and it can be applied to both 99mTc-MAA SPECT/CT and 90Y PET/CT acquisitions for pre and post-dosimetry. We tested the software performance in a retrospective study using the data of 22 patients with hepatocellular carcinoma who underwent radioembolization with 90Y resin spheres in the period 2016-2021. The software calculates tumour doses (mean, minimum and maximum doses) from voxel counts and dose-volume histograms (DVH_spect, DVH_pet) for both 99mTc-MAA SPECT/CT and 90Y PET/CT imaging. DVH_spect and DVH_pet data were analyzed and compared with the aim to assess an agreement between them. Concordance between dosimetric data were evaluated with the Wilcoxon Signed Ranked test, descriptive statistical analysis and Pearson correlation coefficient. RESULTS: The mean administrated activity was 1313 MBq (range 444 MBq - 2200 MBq). Tumour volumes ranged from 75 mL to 1012 mL. The mean absorbed dose for tumour volume was 161 ± 66 Gy (Dm_spect) and 173 ± 79 Gy (Dm_pet). From Wilcoxon Signed Rank Test the differences between the dosimetric data extrapolated from DVH_spect and DVH_pet results were not significant with α = 0.05 (two-sided test). A good linear correlation was found between 99mTc-MAA and 90Y dosimetric data (Pearson correlation coefficient 0.887 p < 0.001). Generally, DVHs calculated on 99mTc-MAA SPECT/CT and 90Y PET/CT gave comparable results, some discrepancies were observed particularly with those patients where SPECT and PET imaging presented a visual mismatching. CONCLUSION: A simplified 3D dosimetry methodology was implemented and tested retrospectively on patient data treated with 90Y resin spheres. Even if the clinical feasibility of our approach has to be further validated on an extended patient cohort, the preliminary results of our study highlight the potential of the implemented dosimetric tool for tumour dose assessment.

Machine Learning Model to Predict Diagnosis of Mild Cognitive Impairment by Using Radiomic and Amyloid Brain PET.

PURPOSE: The study aimed to develop a deep learning model for predicting amnestic mild cognitive impairment (aMCI) diagnosis using radiomic features and amyloid brain PET. PATIENTS AND METHODS: Subjects (n = 328) from the Alzheimer's Disease Neuroimaging Initiative database and the EudraCT 2015-001184-39 trial (159 males, 169 females), with a mean age of 72 ± 7.4 years, underwent PET/CT with 18 F-florbetaben. The study cohort consisted of normal controls (n = 149) and subjects with aMCI (n = 179). Thirteen gray-level run-length matrix radiomic features and amyloid loads were extracted from 27 cortical brain areas. The least absolute shrinkage and selection operator regression was used to select features with the highest predictive value. A feed-forward neural multilayer network was trained, validated, and tested on 70%, 15%, and 15% of the sample, respectively. Accuracy, precision, F1-score, and area under the curve were used to assess model performance. SUV performance in predicting the diagnosis of aMCI was also assessed and compared with that obtained from the machine learning model. RESULTS: The machine learning model achieved an area under the receiver operating characteristic curve of 90% (95% confidence interval, 89.4-90.4) on the test set, with 80% and 78% for accuracy and F1-score, respectively. The deep learning model outperformed SUV performance (area under the curve, 71%; 95% confidence interval, 69.7-71.4; 57% accuracy, 48% F1-score). CONCLUSIONS: Using radiomic and amyloid PET load, the machine learning model identified MCI subjects with 84% specificity at 81% sensitivity. These findings show that a deep learning algorithm based on radiomic data and amyloid load obtained from brain PET images improves the prediction of MCI diagnosis compared with SUV alone.

Impact of Tracer Retention Levels on Visual Analysis of Cerebral [18F]- Florbetaben Pet Images.

BACKGROUND: To compare visual and semi-quantitative analysis of brain [18F]Florbetaben PET images in Mild Cognitive Impairment (MCI) patients and relate this finding to the degree of ß-amyloid burden. METHODS: A sample of 71 amnestic MCI patients (age 74 ± 7.3 years, Mini Mental State Examination 24.2 ± 5.3) underwent cerebral [18F]Florbetaben PET/CT. Images were visually scored as positive or negative independently by three certified readers blinded to clinical and neuropsychological assessment. Amyloid positivity was also assessed by semiquantitative approach by means of a previously published threshold (SUVr ≥ 1.3). Fleiss kappa coefficient was used to compare visual analysis (after consensus among readers) and semi-quantitative analysis. Statistical significance was taken at P<0.05. RESULTS: After the consensus reading, 43/71 (60.6%) patients were considered positive. Cases that were interpreted as visually positive had higher SUVr than visually negative patients (1.48 ± 0.19 vs 1.11 ± 0.09) (P<0.05). Agreement between visual analysis and semi-quantitative analysis was excellent (k=0.86, P<0.05). Disagreement occurred in 7/71 patients (9.9%) (6 false positives and 1 false negative). Agreement between the two analyses was 90.0% (18/20) for SUVr < 1.1, 83% (24/29) for SUVr between 1.1 and 1.5, and 100% (22/22) for SUVr > 1.5 indicating lowest agreement for the group with intermediate amyloid burden. CONCLUSION: Inter-rater agreement of visual analysis of amyloid PET images is high. Agreement between visual analysis and SUVr semi-quantitative analysis decreases in the range of 1.1

Kidney-sparing radiotherapy by multiple-field three-dimensional technique in the postoperative management of patients with gastric cancer: comparison with standard two-field conformal technique.

AIMS AND BACKGROUND: The opposed two-field technique is the standard approach for delivering adjuvant radiotherapy to patients with resected gastric cancer. Since a considerable radiation dose may reach both kidneys with this beam arrangement, with a potential risk of late effects, we investigated whether the CT-based multiple-field (M-F) approach was superior in terms of sparing critical organs at risk. METHODS: From March 2001 to March 2004, 19 patients with radically resected gastric cancer entered the study. They were treated with adjuvant chemoradiotherapy according to the INT 0116 protocol. For each patient dose-volume histograms were calculated and the volume values of both kidneys and liver receiving 25 Gy (V25), 30 Gy (V30) and 40 Gy (V40) individually estimated with the M-F and two-field techniques were compared in detail. RESULTS: Right kidney median V25, V30 and V40 values for the two-field and M-F techniques were 1.50%, 0%, 0% and 0%, 0% and 0%, respectively (P < 0.005, P < 0.01, P < 0.05). Left kidney median V25, V30 and V40 values for the M-F and two-field technique were 16%, 9.80%, 0.90% and 33.20%, 30.20%, 21.40% (P < 0.001, P < 0.0005, P < 0.0005). Liver median V25, V30 and V40 values for the M-F and two-field techniques were 51.30%, 22.30%, 8.90% and 13.30%, 11.60%, 8.10%, respectively (P < 0.0001, P < 0.0005 and P = 0.18). CONCLUSIONS: Our comparison revealed that with the multiple-field technique the right kidney may be largely spared from irradiation; with respect to the two-field technique, the left kidney may receive a significantly reduced dose; however, the liver receives an increased dose that warrants careful long-term monitoring of hepatic function.

Very late nonfatal consequences of fractionated TBI in children undergoing bone marrow transplant.

PURPOSE: To describe long-term late consequences in children who received total body irradiation (TBI) for hematopoietic stem cell transplantation 10 years earlier. METHODS AND MATERIALS: A cohort of 42 children treated with TBI between 1985 and 1993, still alive at least 10 years after fractionated TBI (FTBI), was evaluated. Twenty-five patients received FTBI at 330 cGy/day for 3 days (total dose 990 cGy), whereas 17 children were administered fractions of 200 cGy twice daily for 3 days (total dose 1200 cGy). Twenty-seven patients received autologous and 16 allogeneic hematopoietic stem cell transplantation. Median age at TBI was 6.3 years, and 18.4 years at most recent follow-up. RESULTS: Cataract was diagnosed in 78% of patients after a median of 5.7 years. Hypothyroidism was detected in 12%, whereas thyroid nodules were observed in 60% of our population after a median interval of 10.2 years. Patients treated with 990 cGy developed thyroid nodules more frequently than those treated with 1200 cGy (p = 0.0002). Thyroid carcinoma was diagnosed in 14% of the total population. Females who received FTBI after menarche more frequently developed temporary ovarian dysfunction than those treated before menarche, but cases of persistent ovarian dysfunction did not differ between the two groups. Indirect signs of germinal testicular dysfunction were detected in 87% of males. Restrictive pulmonary disease was observed in 74% of patients. Osteochondroma was found in 29% of patients after a median interval of 9.2 years. This latter complication appeared more frequently in patients irradiated before the age of 3 years (p < 0.001). CONCLUSIONS: This study shows that late effects that are likely permanent, although not fatal, are frequent in survivors 10 years after TBI. However, some of the side effects observed shortly after TBI either disappeared or remained unchanged without signs of evolution. Monitoring is recommended to pursue secondary prevention strategies and counseling on family planning.

Rectal and bladder motion during conformal radiotherapy after radical prostatectomy.

BACKGROUND AND PURPOSE: To investigate the extent and the impact of rectum and bladder motion during adjuvant conformal radiotherapy (3DCRT) after radical prostatectomy (RP). MATERIALS AND METHODS: Nine patients previously operated with RP and treated with early adjuvant 3DCRT were considered for this investigation. Weekly CT scans were collected during treatment (CT1-CTn, n=4-6) and were 3D matched using bony anatomy with the planning CT (CT0). A single observer drew the contours of rectum and bladder on all CTs. The CTV (prostate+/-seminal vesicles surgical bed) was contoured on CT0 by a single observer and a 4-field 3DCRT technique was planned: dose statistics/dose-volume histograms (DVH) of the rectum and bladder were calculated for each contour referred to CT0, CT1...CTn. Average DVHs during the treatment were then calculated and compared with the planned DVH. Cranial, caudal, anterior and posterior shifts of rectum and bladder were also assessed by lateral BEV projections. NTCP values for the rectum were also calculated using the Lyman-Kutcher model. RESULTS: Random variations of volume and DVHs due to variable filling content were found for the bladder; a trend of the bladder to be more empty during therapy with respect to CT0 was also found (median values: 45 cm3 vs. 79 cm3, P=0.02). Regarding the rectum, 6/9 patients showed an average DVH 'worse' than the planned one (up to 10-20%). BEV and volume analyses showed that the rectal volume decreased in 3/9 patients after the first week. In 6/9 patients a systematic anterior shift of the cranial half of the rectum was detected and found to be correlated with a corresponding shift of the posterior border of CTV contoured by five different observers. The average rectal NTCP during therapy was systematically higher than the NTCP referred to CT0 (average increase 1.2%; range 0.0-3.7%, for a 70 Gy ICRU dose, P=0.01). CONCLUSIONS: The impact of systematic uncertainty due to rectal wall motion seems to be relatively high for patients treated with adjuvant 3DCRT after RP. The detected trend of the rectum in migrating anteriorly during therapy is consistent with post-surgery settlement effects and/or some modification of rectum mobility due to irradiation. Rectal motion (and consequent shifts of CTV) was large at the half cranial portion of the rectum while it was very small below the flexure.

The impact of contouring uncertainty on rectal 3D dose-volume data: results of a dummy run in a multicenter trial (AIROPROS01-02).

PURPOSE: To estimate the impact of the uncertainty in contouring the rectum on rectal dose-volume parameters and normal tissue complication probability (NTCP) in a prospective (AIROPROS01-02) investigation about rectal toxicity. METHODS AND MATERIALS: The participants in a prospective trial (18 observers) were asked to draw the external contour of the rectum of 4 sample patients (3 patients undergoing radical conformal radiotherapy, 1 patient undergoing post-prostatectomy) on CT images (0.5 cm spacing) using a 3D treatment planning system. A previously accepted definition of cranial and caudal borders of the rectum was applied. For each patient, four- and six-field 3D-conformal techniques (70-76 Gy, ICRU dose) were planned and DVH/dose statistics of the rectum were calculated. The impact of interobserver variability on rectal volume, cranial and caudal borders, mean, maximum, and median rectal dose, percentage of rectum receiving more than 40, 45, 50, 55, 60, 65, 70, and 75 Gy (V(40)-V(75)), and NTCP were investigated. RESULTS: Concerning DVHs, 9/18 observers tended to have some systematic deviation. However, deviations from the mean values greater than 5% were found only in 1/9 because of a systematic discrepancy in the caudal limit assessment (mean deviation from the most frequently chosen slice: 8 mm). No other observers showed a mean deviation in the cranial or the caudal limit definition greater than 5.8 mm. For another observer, it was possible to clearly assess the cause of a relatively large systematic deviation for DVH parameters. In both cases, the observers were contacted to avoid these systematic deviations. When considering the remaining 16/18 observers, the average values of SD for V(40)-V(75) ranged between 1% and 4% and were found to be lower (<3%) for the 3 nonoperated patients. The average values of the SD were around 1.5-2 Gy and less than 1.5% for mean/median dose and NTCPs, respectively. CONCLUSIONS: Concerning the uncertainty in rectum definition, the collection of rectal dose-volume data in multicenter investigations seems to be feasible after a clear and previously accepted definition of rectum is assessed. However, even with a general agreement on rectum definition, contouring appears to be a quite significant source of uncertainty. A dummy run procedure is useful in identifying possible discrepancies among single observers and in assessing reliable confidence levels on dose-volume constraints because of contouring uncertainty, making the dummy run mandatory in multicenter trials evaluating 3D dose-volume data.

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%.

Neoadjuvant androgen deprivation and prostate gland shrinkage during conformal radiotherapy.

PURPOSE: The shrinking effect of 3-month neoadjuvant androgen deprivation (NAD) on preradiotherapy prostate gland volume is well documented. However, recently, it has been shown that the cancerous prostate gland keeps shrinking up to 12 months after NAD start. Thus, if such a reduction is not taken into account, a larger than planned portion of the surrounding normal tissues might shift in the high-dose region during conformal radiotherapy (3DCRT) course. The present study was undertaken to quantify this issue. MATERIALS AND METHODS: Prostate gland volume reduction between planning CT (plCT) and the last week of 3DCRT (tmtCT) was prospectively assessed in 33 consecutive patients with localized prostate carcinoma. The median time interval between plCT and tmtCT was 2.5 months (2.1-2.7 months). A single observer was asked to draw on each slice prostate gland volume as appropriate. The observer was 'blind' to the timing of CT (plCT vs. tmtCT). In order to estimate intra-observer variability, prostate gland delineation was repeated twice for each data set. Mean prostate gland change, plCT and tmtCT cumulative dose volume histogram (DVH) calculations for the rectum were analyzed for each patient. Results were correlated to AD status and its duration before plCT. Means were compared by non-parametric rank tests. RESULTS: Based on an internal protocol, 14 patients (42%) did not receive AD, while 19 patients (58%) had undergone neoadjuvant and concomitant AD. The median duration of AD before plCT ranged from 0.2 to 6 months (median: 2.9 months). Although individual data were highly variable, compared to plCT volume, mean prostate gland volume change at the end of 3DCRT was similar for patients receiving (-7.3%) or not (-7%) androgen deprivation (P=0.77). However, within the group of patients treated with hormones, patients starting AD within 3 months from plCT had a significantly larger reduction in prostate volume (-14.2%) than patients with longer NAD duration (-1.1%, P=0.03). At tmtCT, on average, patients undergoing 3DCRT within 3 months from AD start showed an increase of the amount of rectum receiving 40-75 Gy compared to plCT values. At 40 Gy (V40) the mean difference between tmtCT and plCT was +7.5%. In the other two groups, average variations of V40-70 were within +/-2% of plCT values. However, these differences are not significant. CONCLUSION: For patients who undergo plCT and 3DCRT shortly after AD start, prostate gland shrinkage may be substantial. In some of these patients, this might lead to an unexpected increase of the percentage of rectal wall exposed to intermediate doses.

Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions.

BACKGROUND: Accurate modeling of late rectal reactions needs the collection of individual 3D dose-volume data (i.e. DVH) as well as clinical information of large cohorts of patients. The possibility of collecting a large number of patients with many different dose-volume combinations is very suitable for this purpose. PURPOSE: The purpose of the study is to search for significant correlation between dose-volume histograms/dose statistics of the rectum and late rectum bleeding. MATERIALS AND METHODS: Data from three institutions for 402 patients previously treated for prostate cancer with three to four field techniques, were retrospectively pooled and were collected with a number of clinical and physical parameters, including DVHs of the rectum (including filling). Patients with large air/fecal content in the rectum during planning computerized tomography (CT) scan were excluded from the analysis (n = 74). Out of 328 patients, 229 patients received an ICRU dose between 70 and 76Gy and the current analysis is referred to this subgroup of patients (median follow up: 30 months, range: 12-85 months). Out of these 229 patients, 189 patients were treated with conformal techniques. Rectum was contoured from the anal verge up to the sigmoid flessure by one observer for each institution. Dosimetric and contouring consistencies between the three institutions were previously investigated and the impact on DVHs was found to be quite modest for the purposes of the study. Median/quartile values of all parameters were considered as cut-off values for statistical analysis. We considered as bleeders those patients who experienced grades II-III late bleeding (modified RTOG scoring scale). RESULTS: Twenty two of 229 patients experienced > or =grade II late bleeding (30 months actuarial incidence: 10.7%). Significant correlation between a number of parameters and late bleeding was found (log-rank test). With regard to DVH, all median and third quartile values for V50-V70 were found to be significantly associated with an increased risk of rectal bleeding, if excepting the median value of V70. Based on the results of univariate analysis, the patients were divided into two groups: 'high risk', with at least one value above quartiles in the range V50-V60 (V50: 70%, V55: 64%, V60: 55%); 'low risk', the remaining patients. The 30 months actuarial rates of bleeding were 19.2 and 5.9% for the 'high' and the 'low' risk group, respectively (P = 0.0003 log-rank test). A multivariate analysis (Cox regression model) including 'DVH grouping' and the main remaining variables (age, previous prostatectomy, diabetes, hypertension, adjuvant hormonal therapy, rectum volume and ICRU dose) showed that 'DVH grouping' is the most predictive parameter (P = 0.005) together with adjuvant hormonal therapy (P = 0.025) and ICRU dose (P = 0.06). CONCLUSIONS: Our data confirm the role of the rectal DVH in separating groups of patients having prostate radiotherapy in low and high risk of developing late bleeding. Based on these results, V50 below 60-65% and V60 below 50-55% seem to be the robust cut-off values to keep the risk of developing late rectal bleeding reasonably low. However, due to the 'heterogeneity' of the considered population, the results found should be applied with caution in 'more homogeneous' groups of patients. The association of adjuvant hormone deprivation seems to be associated with an increased risk of rectal toxicity; the mechanism for this effect should be a focus of further research.

Contralateral parotid-sparing radiotherapy in patients with unilateral squamous cell carcinoma of the head and neck: technical methodology and preliminary results.

AIMS AND BACKGROUND: Radiation-induced permanent xerostomia occurs frequently in patients affected by squamous cell carcinoma of the head and neck treated by parallel opposed lateral fields. An ipsilateral technique by using co-planar multiple-field arrangement was designed to restrict treatment to the primary tumor and neck on the same side for patients with selected lateralized squamous cell carcinoma of the head and neck. METHODS: From November 2001 till December 2002, 30 patients affected by squamous cell carcinoma of tonsillar fossa, retromolar trigone, alveolar ridge and oropharyngeal lateral wall were included in this investigational trial and treated with an ipsilateral multiple field technique: in detail, oblique opposed two upper half fields were planned ipsilaterally to the squamous cell carcinoma site to cover PTV1 and PTV2, whereas an anterior-lower half field was planned to encompass the lower neck node area above clavicles. On CT scans, the contralateral parotid gland was outlined as organ at risk and the contralateral upper lymph node area was contoured as volume of interest. In selected cases, convergent oblique two wedge-pair half fields were added to opposed oblique two-field technique in order to cover only PTV2: generally, in these patients, PTV1 received 1.8 Gy per fraction and PTV2 2.2 Gy per fraction up to total doses of 54 Gy and 66 Gy, respectively. RESULTS: Ten patients received radical radiotherapy, 9 patients radical alternating chemo-radiotherapy, and 11 patients adjuvant radiotherapy. At the end of treatment, unilateral confluent mucositis was recorded in 13 (43%) patients and unilateral moist skin epidermolysis in 14 (46%) patients. Six months after the end of radiotherapy, grade 0 xerostomia was recorded in 20 (67%) patients. No patient experienced grade 2+ xerostomia. At a median follow-up of 12 months, 26 (86%) patients were alive and well; 2 patients (6%) developed contralateral neck node failure, both 4 months after the end of ipsilateral radiotherapy. CONCLUSIONS: These results, although preliminary, suggest that by using an ipsilateral radiotherapy technique, symptomatic xerostomia may be avoided in selected patients with lateralized squamous cell carcinoma of the head and neck without an increased short-term risk of contralateral nodal failure.

Late local treatment morbidity after accelerated radiotherapy or alternating chemoradiotherapy for advanced head and neck carcinoma.

BACKGROUND: To report local long-term morbidity after concomitant boost radiotherapy (AFRT) or alternating chemoradiotherapy (CTRT), we analyzed the toxicity data recorded in 168 patients with advanced head and neck squamous cell carcinoma treated at our institution within phase II-III studies. PATIENTS AND METHODS: All patients enrolled in three consecutive phase II-III studies and followed for a minimum of three months after the end of treatment were included in the present analysis. Local late reactions were scored prospectively. The actuarial incidence of grade 2 or more (2-4) late local toxicity according to RTOG/EORTC was taken as endpoint. The median follow-up is 32.0 months (range, 3.3-138.1 months). For living patients the minimum and median follow-up are 12.1 and 69.3 months, respectively. RESULTS: The five-year actuarial incidence of grade 2+ and grade 3+ toxicity are 56.7 +/- 5% and 21 +/- 4%, respectively. At multivariate analysis, acute mucositis grade, complementary surgery, primary site and performance status proved to be independent predictive factors of grade 2+ late toxicity with P values of <0.001, 0.009, 0.022 and 0.033, respectively. No effect was found for treatment itself on the incidence of late toxicity, although patients treated with accelerated radiotherapy had a higher probability of confluent mucositis than patients treated with alternating chemoradiotherapy (68% vs 32%, P <0.01). CONCLUSIONS: A substantial proportion of surviving patients develops late complications, although severe irreversible reactions occur in a minority of patients. Acute local toxicity can be used to predict local late toxicity that arises within five years of the end of treatment.

Does treatment of the pelvic nodes with IMRT increase late rectal toxicity over conformal prostate-only radiotherapy to 76 Gy?

PURPOSE: To compare late rectal toxicity rates after three-dimensional conformal radiotherapy to the prostate alone (P-3D-CRT) and whole-pelvis intensity-modulated radiotherapy along with a prostate boost (WP-IMRT/PB) to the same nominal total dose to the prostate. PATIENTS AND METHODS: 68 patients treated with conformal radiotherapy to the prostate only to 76 Gy at the National Institute for Cancer Research, Genoa, Italy, represented the first group (P-3D-CRT). The second group consisted of 45 patients treated at the University of Texas Medical Branch (UTMB), Galveston, TX, USA, with IMRT covering the pelvic nodes and seminal vesicles to 54 Gy at 1.8 Gy per fraction and the prostate to 60 Gy in the same 30 fractions. A separate phase boosted the prostate to 76 Gy (WP-IMRT/PB). Major aspects of planning were remarkably similar at both institutions leaving the inclusion or not of pelvic nodes as the main treatment-related difference between the two groups. Late rectal toxicity was prospectively scored according to the RTOG scale. All patients have a 12-month minimum follow-up, and mean follow-up, similar in both groups, is 25.9 months (SD [standard deviation]: 8.4 months). RESULTS: At 2 years, the estimated cumulative incidence of grade 2 late rectal toxicity is 6%+/-4% for WP-IMRT/PB and 21.2%+/-6% for P-3D-CRT (p=0.06). The difference became significant (HR [hazard ratio]=0.1, 95% CI [confidence interval]: 0.0-0.6; p=0.01) at multivariate analysis. None of the patients developed grade 3+ toxicity. CONCLUSION: Despite the larger treated volume, WP-IMRT/PB allows more rectal sparing than P-3D-CRT.

Sucralfate versus mesalazine versus hydrocortisone in the prevention of acute radiation proctitis during conformal radiotherapy for prostate carcinoma. A randomized study.

PURPOSE: To assess whether the topical use of steroids or 5-aminosalicylic acid (5-ASA) is superior to sucralfate in preventing acute rectal toxicity during three-dimensional conformal radiotherapy (3DCRT) to 76 Gy. PATIENTS AND METHODS: Patients undergoing 3DCRT for prostate carcinoma at our institution were offered to be randomized to sucralfate 3 g in 15 ml suspension enema (Antepsin, mesalazine 4 g gel enema (Enterasyn, or hydrocortisone 100 mg foam enema (Colifoam. Randomization was blind to the treating physician but not to the patient. Sucralfate was chosen as control arm. Topical treatment had to be performed once daily, starting on day 1 of 3DCRT. Acute rectal toxicity was scored weekly according to RTOG criteria. Time to occurrence of grade 2+ acute rectal toxicity was taken as endpoint. RESULTS: The trial was opened in August 1999, and after the first 24 patients had been treated, arm 2 was discontinued because of eight patients receiving mesalazine, seven actually developed acute rectal toxicity (five patients grade 3 and two patients grade 2). Until May 2001, 134 consecutive patients were randomly assigned to sucralfate (63 patients), mesalazine (eight patients) or hydrocortisone (63 patients). The cumulative incidence of acute rectal toxicity at the end of treatment by arm is 61.9 +/- 6.1%, 87.5 +/- 11.7%, and 52.4 +/- 6.2% for arms 1, 2, and 3, respectively. The difference between the mesalazine group and the sucralfate group is highly significant (hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.1-5.7; p = 0.03). At both uni- and multivariate analysis taking into account several patients and treatment covariates, the difference between hydrocortisone and sucralfate is not significant (HR 0.7, 95% CI 0.5-1.2; p = 0.2). CONCLUSION: Topical mesalazine is contraindicated during radiotherapy. Hydrocortisone enema is not superior to sucralfate in preventing acute rectal toxicity.

Anatomic variations due to radical prostatectomy. Impact on target volume definition and dose-volume parameters of rectum and bladder.

BACKGROUND AND PURPOSE: A quantitative estimate of the impact of prostatectomy on pelvic anatomy is unavailable, even if it would be an important prerequisite for a precise definition of clinical target volume (CTV) in post-prostatectomy radiotherapy. The purpose of this study was to investigate the impact of prostatectomy on the definition of CTV, on the position of bladder and rectum and their implications for three-dimensional conformal radiotherapy (3-D CRT). PATIENTS AND METHODS: Six patients eligible for radical retropubic prostatectomy were considered. Each patient underwent a planning CT between 1 week and 1 month before surgery (CTpre), and then CT was repeated in the same positioning 1-2 months after surgery (CTpost). For each patient the CT(pre/post) scans were matched; rectum, bladder and CTV were contoured on both CT scans for each patient by one observer. Two different CTVs were contoured: CTV1: prostate + seminal vesicles in CTpre; prostate + seminal vesicles surgical bed in CTpost; CTV2: prostate in CTpre; prostate surgical bed in CT(post). After image registration, the contours of rectum, bladder and CTV1/2 drawn on CTpost were transferred on CTpre. The corresponding planning target volumes (PTVs) were generated, and for each PTV, a conformal four field technique using 18-MV X-rays was planned. The volumes of CTV1, CTV2, PTV1, PTV2, rectum and bladder pre- and post-surgery were compared. Differences in 3-D position of these structures before and after surgery were analyzed by beam's eye view (BEV) images. Pre- and post-surgery dose-volume histograms (DVHs) of rectum and bladder were compared together with the fraction of rectum/bladder receiving at least 95% of the ICRU dose (V95), the treated volume (TV, body included in the 95% isodose) and the irradiated volume (IV, body included in the 50% isodose). RESULTS: For both CTV1 and CTV2, the volumes were significantly reduced after prostatectomy (average reduction around 30 cm3 for both; range 0-60 cm3). This reduction was mainly due to a more caudal definition of the cranial edge of CTV after prostatectomy (average difference for CTV2: 1.5 cm; range 0-2.5 cm). Concerning the bladder, a systematic posterior shift of the bladder base (average: 1.5 cm) was found and was correlated with a significant reduction of V95 for bladder (around 10 cm3; p = 0.03). V95 of the rectum, TV and IV also resulted to be significantly lower after surgery. The average reduction of V95 for the rectum was relatively small (2.5 cm3 of rectal wall). CONCLUSION: The impact of prostatectomy on CTV definition is high. A significant reduction of CTV, PTV, TV and IV may be expected after surgery with a consequent reduction of the portions of rectum/bladder irradiated with adjuvant radiotherapy.