Replacing Manual Planning of Whole Breast Irradiation With Knowledge-Based Automatic Optimization by Virtual Tangential-Fields Arc Therapy.

PURPOSE: To implement Knowledge Based (KB) automatic planning for right and left-sided whole breast treatment through a new volumetric technique (ViTAT, Virtual Tangential-fields Arc Therapy) mimicking conventional tangential fields (TF) irradiation. MATERIALS AND METHOD: A total of 193 clinical plans delivering TF with wedged or field-in-field beams were selected to train two KB-models for right(R) and left(L) sided breast cancer patients using the RapidPlan (RP) tool implemented in the Varian Eclipse system. Then, a template for ViTAT optimization, incorporating individual KB-optimized constraints, was interactively fine-tuned. ViTAT plans consisted of four arcs (6 MV) with start/stop angles consistent with the TF geometry variability within our population; the delivery was completely blocked along the arcs, apart from the first and last 20° of rotation for each arc. Optimized fine-tuned KB templates for automatic plan optimization were generated. Validation tests were performed on 60 new patients equally divided in R and L breast treatment: KB automatic ViTAT-plans (KB-ViTAT) were compared against the original TF plans in terms of OARs/PTVs dose-volume parameters. Wilcoxon-tests were used to assess the statistically significant differences. RESULTS: KB models were successfully generated for both L and R sides. Overall, 1(3%) and 7(23%) out of 30 automatic KB-ViTAT plans were unacceptable compared to TF for R and L side, respectively. After the manual refinement of the start/stop angles, KB-ViTAT plans well fitted TF-performances for these patients as well. PTV coverage was comparable, while PTV D1% was improved with KB-ViTAT by R:0.4/L:0.2 Gy (p < 0.05); ipsilateral OARs Dmean were similar with a slight (i.e., few % volume) improvement/worsening in the 15-35 Gy/2-15 Gy range, respectively. KB-ViTAT better spared contralateral OARs: Dmean of contralateral OARs was 0.1 Gy lower (p < 0.05); integral dose was R:5%/L:8% lower (p < 0.05) than TF. The overall time for the automatic plan optimization and final dose calculation was 12 ± 2 minutes. CONCLUSIONS: Fully automatic KB-optimization of ViTAT can efficiently replace manually optimized TF planning for whole breast irradiation. This approach was clinically implemented in our institute and may be suggested as a large-scale strategy for efficiently replacing manual planning with large sparing of time, elimination of inter-planner variability and of, seldomly occurring, sub-optimal manual plans.

Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized?

AIM: We report molecular subtype impact on 1325 early breast cancer (BCa) patients treated with whole breast hypofractionated (WBH) adjuvant forward-planned intensity modulated radiotherapy (F-IMRT) without boost. METHODS AND MATERIALS: From 02/2009-05/2017 1325 patients with pTis-pT3, pNx-N1aM0 BCa who underwent breast conservation surgery were treated with WBHF-IMRT in our institute, to a total dose of 40 Gy/15 fractions, without boost. Median age: 62 (interquartile range-IQR-:51.14-70.53) years. HISTOLOGY: 8% in situ carcinoma (ISC), 92% invasive tumors. Molecular subtypes (invasive tumors): 49.9% Luminal A, 33.1% Luminal B Her2 negative (-), 6.2% Luminal B Her2 positive (+), 3.6% Hormone Receptor (HR)- Her2+, 7.1% Triple negative (TNBC), and 0.2% HR+. Chemotherapy (CT) was prescribed in 28% of patients, hormonal therapy in 80.3%, monoclonal antibodies (MAb) in 86.8% of Luminal B Her2+ and 97.7% of HR- Her2+ patients. RESULTS: Median follow up was 72.43 (IQR: 44.63-104.13) months. The 5-year Kaplan-Meier estimates of local relapse-free survival (LRFS) was 97.8%, regional-(RRFS) 98.6%, loco-regional- (LRRFS) 96.9%, distant- (DRFS) 96.6%, disease-free survival (DFS) 94.8% and overall survival (OS) 95.5%. Considering molecular subtypes, 5-year LRFS was: 99.8% for Luminal A, 96.7% for Luminal B Her2-, 94.1% for Luminal B Her2+, 87.9% for HR- Her2+, 95.1% for TNBC and 99.1% for in situ carcinoma. CONCLUSION: While the overall estimated probability of LR within 5 years after WBHF-IMRT without boost is good (2.2%), molecular subtypes have a strong impact, despite MAb therapy in Her2+ patients, and CT for TNBC patients, and could be used as a parameter in deciding the boost prescription.

Monitoring skin dose changes during image-guided helical tomotherapy for head and neck cancer patients.

PURPOSE: An increase of skin dose during head and neck cancer (HNC) radiotherapy is potentially dangerous. Aim of this study was to quantify skin dose variation and to assess the need of planning adaptation (ART) to counteract it. METHODS: Planning CTs of 32 patients treated with helical tomotherapy (HT) according to a Simultaneous Integrated Boost (SIB) technique delivering 54/66 Gy in 30 fractions were deformably co-registered to MVCTs taken at fractions 15 and 30; in addition, the first fraction was also considered. The delivered dose-of-the-day was calculated on the corresponding deformed images. Superficial body layers (SL) were considered as a surrogate for skin, considering a layer thickness of 2 mm. Variations of SL DVH (∆SL) during therapy were quantified, focusing on ∆SL95% (i.e., 62.7 Gy). RESULTS: Small changes (within ± 1 cc for ∆SL95%) were seen in 15/32 patients. Only 2 patients experienced ∆SL95% > 1 cc in at least one of the two monitored fractions. Negative ∆SL95% > 1 cc (up to 17 cc) were much more common (15/32 patients). The trend of skin dose changes was mostly detected at the first fraction. Negative changes were correlated with the presence of any overlap between PTV and SL at planning and were explained in terms of how the planning system optimizes the PTV dose coverage near the skin. Acute toxicity was associated with planning DVH and this association was not improved if considering DVHs referring to fractions 15/30. CONCLUSION: About half of the patients treated with SIB with HT for HNC experienced a skin-sparing effect during therapy; only 6% experienced an increase. Our findings do not support skin-sparing ART, while suggesting the introduction of improved skin-sparing planning techniques.

Predictors of radio-induced visual impairment after radiosurgery for uveal melanoma.

AIMS: The aim of the present work is to assess the main predictors of the most clinically relevant radio-induced effects after Gamma Knife stereotactic radiosurgery (GKRS) for uveal melanoma (UM). MATERIALS AND METHODS: Medical records and three-dimensional dosimetry data of critical structures of 66 patients were retrospectively reviewed. Cox's proportional hazard model was used to identify clinical and dosimetric variables as independent risk factor for GKRS-related complications. RESULTS: The fraction of the posterior segment receiving more than 20Gy (V20), Bruch's membrane rupture and tumour thickness were significant prognostic factors for neovascular glaucoma. A clear relationship with the dose received by 1% of the optic nerve (D1%) was found for radiation retinopathy and papillopathy. Multivariables models resulted for visual acuity (VA) reduction >20% of the basal value and for complete VA loss, both including largest tumour diameter and D1% to the optic nerve. The predictive model for complete VA loss includes also Bruch's membrane rupture. An alternative model for complete visual acuity loss, including the optic nerve-prescription isodose minimum distance, was also suggested. CONCLUSIONS: We found clinical and dosimetric variables to clearly predict the risk of the main side effects after GKRS for UM. These results may provide dose constraints to critical structures, potentially able to reduce side effects. Constraining D1% to the optic nerve below 12-13Gy may result in a dramatic reduction of blindness risk, while reducing V20 of the posterior segment of the bulb could limit the neovascular glaucoma onset.

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.

Dose-volume effects for pelvic bone marrow in predicting hematological toxicity in prostate cancer radiotherapy with pelvic node irradiation.

PURPOSE: To prospectively identify clinical/dosimetric predictors of acute/late hematologic toxicity (HT) in chemo-naÏve patients treated with whole-pelvis radiotherapy (WPRT) for prostate cancer. MATERIAL AND METHODS: Data of 121 patients treated with adjuvant/salvage WPRT were analyzed (static-field IMRT n=19; VMAT/Rapidarc n=57; Tomotherapy n=45). Pelvic bone marrow (BM) was delineated as ilium (IL), lumbosacral, lower and whole pelvis (WP), and the relative DVHs were calculated. HT was graded both according to CTCAE v4.03 and as variation in percentage relative to baseline. Logistic regression was used to analyze association between HT and clinical/DVHs factors. RESULTS: Significant differences (p<0.005) in the DVH of BM volumes between different techniques were found: Tomotherapy was associated with larger volumes receiving low doses (3-20 Gy) and smaller receiving 40-50 Gy. Lower baseline absolute values of WBC, neutrophils and lymphocytes (ALC) predicted acute/late HT (p ⩽ 0.001). Higher BM V40 was associated with higher risk of acute Grade3 (OR=1.018) or late Grade2 lymphopenia (OR=1.005). Two models predicting lymphopenia were developed, both including baseline ALC, and BM WP-V40 (AUC=0.73) and IL-V40+smoking (AUC=0.904) for acute/late respectively. CONCLUSIONS: Specific regions of pelvic BM predicting acute/late lymphopenia, a risk factor for viral infections, were identified. The 2-variable models including specific constraints to BM may help reduce HT.

Second Tumor Induction Risk in IMRT for Prostate Cancer: An Unbalanced Comparison Between Surgery and Radiotherapy?

The aim of this study was to evaluate the risk of second tumor induction for prostate patients treated with volumetric modulated arc therapy in age classes 50-70. Based on both age-dependent models and doses to critical organs, the risk of second tumor induction was evaluated simulating the small field (prostate and seminal vesicles) and large field (whole pelvis) for Helical Tomotherapy and Rapid Arc. The doses to the organs closest to the treatment volume were derived from treatment planning system data. Whereas, due to the lack of calculation algorithms where leakage and internal radiation scattering are unreliable at a large distance from target, the doses to the organs outside the treatment volume were measured in an anthropomorphic phantom. Doses from Image Guided Radiotherapy (IGRT) were also assessed on phantom measurements. The Lifetime Attributable Risk (LAR) for second tumor induction increases from 2.2 to 13.7% as irradiated volume increases and age decreases. IGRT could add a non-negligible factor to the risk when daily set-up verification with high-resolution modality is included. As prostate cancer is detected earlier, the probability of an increase in early stage patients rises, and life expectancy thus increases. Radiotherapy has improved its capability in the tailoring of the dose around the target at the cost of a greater dose to surrounding organs, thus increasing the risk of second tumor induction, especially for those patients expected to survive 15 y or more.

Static and rotational intensity modulated techniques for head-neck cancer radiotherapy: a planning comparison.

PURPOSE: To compare helical Tomotherapy (HT), two volumetric-modulated arc techniques and conventional fixed-field intensity modulated techniques (S-IMRT) for head-neck (HN) cancers. METHODS AND MATERIALS: Eighteen HN patients were considered. Four treatment plans were generated for each patient: HT, S-IMRT optimised with Eclipse treatment planning system and two volumetric techniques using Elekta-Oncentra approach (VMAT) and Varian-RapidArc (RA), using two full arcs. All techniques were optimised to simultaneously deliver 66Gy to PTV1 (GTV and enlarged nodes) and 54Gy to PTV2 (subclinical and electively treated nodes). Comparisons were assessed on several dosimetric parameters and, secondarily, on planned MUs and delivery time. RESULTS: Concerning PTV coverage, significantly better results were found for HT and RA. HT significantly improved the target coverage both compared to S-IMRT and VMAT. No significant differences were found between S-IMRT and volumetric techniques in terms of dose homogeneity. For OARs, all the techniques were able to satisfy all hard constraints; significantly better results were found for HT, especially in the intermediate dose range (15-30 Gy). S-IMRT reached a significantly better OARs sparing with respect to VMAT and RA. No significant differences were found for body mean dose, excepting higher values of V5-V10 for HT. A reduction of planned MUs and delivery treatment time was found with volumetric techniques. CONCLUSIONS: The objectives of satisfying target coverage and sparing of critical structures were reached with all techniques. S-IMRT techniques were found more advantageous compared to RA and VMAT for OARs sparing. HT reached the best overall treatment plan quality.

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).

Correlation between surrogates of bladder dosimetry and dose-volume histograms of the bladder wall defined on MRI in prostate cancer radiotherapy.

The correlation between bladder dose-wall-histogram (DWH) and dose-volume-histogram (DVH), dose-surface-histogram (DSH), and DVH-5/10 was investigated in a group of 28 patients; bladder walls were drawn on T2-MRI. DVH showed the poorest correlation with DWH; DSH or DVH-5/10 should be preferred in planning; absolute DVH may be used for radical patients, although less robust.

Contouring variability of the penile bulb on CT images: quantitative assessment using a generalized concordance index.

PURPOSE: Within a multicenter study (DUE-01) focused on the search of predictors of erectile dysfunction and urinary toxicity after radiotherapy for prostate cancer, a dummy run exercise on penile bulb (PB) contouring on computed tomography (CT) images was carried out. The aim of this study was to quantitatively assess interobserver contouring variability by the application of the generalized DICE index. METHODS AND MATERIALS: Fifteen physicians from different Institutes drew the PB on CT images of 10 patients. The spread of DICE values was used to objectively select those observers who significantly disagreed with the others. The analyses were performed with a dedicated module in the VODCA software package. RESULTS: DICE values were found to significantly change among observers and patients. The mean DICE value was 0.67, ranging between 0.43 and 0.80. The statistics of DICE coefficients identified 4 of 15 observers who systematically showed a value below the average (p value range, 0.013 - 0.059): Mean DICE values were 0.62 for the 4 "bad" observers compared to 0.69 of the 11 "good" observers. For all bad observers, the main cause of the disagreement was identified. Average DICE values were significantly worse from the average in 2 of 10 patients (0.60 vs. 0.70, p < 0.05) because of the limited visibility of the PB. Excluding the bad observers and the "bad" patients," the mean DICE value increased from 0.67 to 0.70; interobserver variability, expressed in terms of standard deviation of DICE spread, was also reduced. CONCLUSIONS: The obtained values of DICE around 0.7 shows an acceptable agreement, considered the small dimension of the PB. Additional strategies to improve this agreement are under consideration and include an additional tutorial of the so-called bad observers with a recontouring procedure, or the recontouring by a single observer of the PB for all patients included in the DUE-01 study.

Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcinoma: a single-institute analysis of 742 patients.

PURPOSE: To investigate the clinical factors independently predictive of long-term severe urinary sequelae after postprostatectomy radiotherapy. PATIENTS AND METHODS: Between 1993 and 2005, 742 consecutive patients underwent postoperative radiotherapy with either adjuvant (n = 556; median radiation dose, 70.2 Gy) or salvage (n = 186; median radiation dose, 72 Gy) intent. RESULTS: After a median follow-up of 99 months, the 8-year risk of Grade 2 or greater and Grade 3 late urinary toxicity was almost identical (23.9% vs. 23.7% and 12% vs. 10%) in the adjuvant and salvage cohorts, respectively. On univariate analysis, acute toxicity was significantly predictive of late Grade 2 or greater sequelae in both subgroups (p <.0001 in both cases), and hypertension (p = .02) and whole-pelvis radiotherapy (p = .02) correlated significantly in the adjuvant cohort only. The variables predictive of late Grade 3 sequelae were acute Grade 2 or greater toxicity in both groups and whole-pelvis radiotherapy (8-year risk of Grade 3 events, 21% vs. 11%, p = .007), hypertension (8-year risk, 18% vs. 10%, p = .005), age ≤ 62 years at RT (8-year risk, 16% vs. 11%, p = .04) in the adjuvant subset, and radiation dose >72 Gy (8-year risk, 19% vs. 6%, p = .007) and age >71 years (8-year risk, 16% vs. 6%, p = .006) in the salvage subgroup. Multivariate analysis confirmed the independent predictive role of all the covariates indicated as statistically significant on univariate analysis. CONCLUSIONS: The risk of late Grade 2 or greater and Grade 3 urinary toxicity was almost identical, regardless of the RT intent. In the salvage cohort, older age and greater radiation doses resulted in a worse toxicity profile, and younger, hypertensive patients experienced a greater rate of severe late sequelae in the adjuvant setting. The causes of this latter correlation and apparently different etiopathogenesis of chronic damage in the two subgroups were unclear and deserve additional investigation.

Inter-observer variability in contouring the penile bulb on CT images for prostate cancer treatment planning.

Several investigations have recently suggested the existence of a correlation between the dose received by the penile bulb (PB) and the risk of erectile dysfunction (ED) after radical radiotherapy for clinically localized prostate carcinoma. A prospective multi-Institute study (DUE-01) was implemented with the aim to assess the predictive parameters of ED. Previously, an evaluation of inter-observer variations of PB contouring was mandatory in order to quantify its impact on PB dose-volume parameters by means of a dummy run exercise. Fifteen observers, from different Institutes, drew the PB on the planning CT images of ten patients; inter-observer variations were analysed in terms of PB volume variation and cranial/caudal limits. 3DCRT treatment plans were simulated to evaluate the impact of PB contouring inter-variability on dose-volume statistics parameters. For DVH analysis the values of PB mean dose and the volume of PB receiving more than 50 Gy and 70 Gy (V50 and V70, respectively) were considered. Systematic differences from the average values were assessed by the Wilcoxon test. Seven observers systematically overestimated or underestimated the PB volume with deviations from the average volumes ranging between -48% and +34% (p < 0.05). The analysis of the cranial and caudal borders showed a prevalence of random over systematic deviations. Inter-observer contouring variability strongly impacts on DVH parameters, although standard deviations of inter-patient differences were larger than inter-observer variations: 14.5 Gy versus 6.8 Gy for mean PB dose, 23.0% versus 11.0% and 16.8% versus 9.3% for V50 and V70 respectively. In conclusion, despite the large inter-observer variation in contouring PB, a large multi-centric study may have the possibility to detect a possible correlation between PB % dose-volume parameters and ED. The impact of contouring uncertainty could be reduced by "a posteriori" contouring from a single observer or by introducing Magnetic Resonance Imaging (MRI) in the planning procedures and/or in improving the skill of observers through post-dummy run tutoring of those observers showing large systematic deviations from the mean.

Anatomical and clinical predictors of acute bowel toxicity in whole pelvis irradiation for prostate cancer with Tomotherapy.

PURPOSE: Assessing predictors of acute bowel toxicity after whole-pelvis irradiation (WPRT) Image-guided Tomotherapy with simultaneous integrated boost on prostate/prostate bed. METHODS AND MATERIALS: In the period March 2005-April 2009, 178 patients were treated with radical or adjuvant/salvage intent with WPRT Tomotherapy. Median dose to the pelvic nodes was 51.8 Gy/28 fractions while concomitantly delivering 65.5-74.2 Gy to prostate/prostatic bed. The impact of many anatomical and clinical parameters on ≥ Grade 2 acute bowel toxicity was investigated by logistic analyses. RESULTS: Only 15/178 patients (8.4%) experienced Grade 2 toxicity (none Grade 3). Main predictors at univariate analysis were nodal CTV (CTVN ≥ 380 cc; OR: 3.7, p=0.017), treatment duration (< 40 days; OR: 6.2, p=0.006) and Grade 2 acute rectal toxicity (OR: 6.5, p=0.015). A multivariate analysis including only pre-treatment variables revealed an independent role of CTVN and age; if including treatment-related factors the best predictors were age, treatment duration and Grade 2 rectal toxicity. This last was correlated with the overlap between PTVN and loops (OVPN ≥ 51 cc; OR: 14.4, p=0.0003) that is representative of the volume of loops receiving the prescribed dose (51.8 Gy, 1.85 Gy/fr). CONCLUSIONS: Acute bowel toxicity after WPRT Tomotherapy is mild, relatively rare and associated to larger CTVN and older age. While efforts to further reduce it do not appear to be relevant, the pre-treatment assessment of "high-risk" patients may help physicians in better managing symptoms. A prospective validation would be very important in confirming these results and in better refining dose-volume bowel effects including symptoms milder that the ones here investigated and retrospectively assessed.

Gamma knife radiosurgery for treatment of cerebral metastases from non-small-cell lung cancer.

PURPOSE: To evaluate clinical and physico-dosimetric variables affecting clinical outcome of patients treated with Gamma Knife radiosurgery (GKRS) for brain metastases from non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Between 2001 and 2006, 373 patients (298 men and 75 women, median age 65 years) with brain metastases from NSCLC underwent GKRS. All of them had KPS ≥ 60%, eight or fewer brain metastases, confirmed histopathological diagnosis and recent work-up (<3 months). Thirty-five patients belonged to recursive partitioning analysis (RPA) Class I, 307 patients were in RPA Class II, 7 patients were in RPA Class III. Median tumor volume was 3.6 cm(3). Median marginal dose was 22.5 Gy at 50% isodose.; median 10 Gy and 12 Gy isodose volumes were 30.8 cm(3) and 15.8 cm(3), respectively. Follow-up with MRI was performed every 3 months. Overall survival data were collected from internal database, telephone interviews, and identifying registries. RESULTS: Mean follow-up after GKRS was 51 months (range, 6 to 96 months); mean overall survival was 14.2 months. Of 373 patients, 29 were alive at time of writing, 104 had died of cerebral progression, and 176 had died of systemic progression. In 64 cases it was not possible to ascertain the cause. Univariate and multivariate analysis were adjusted for the following: RPA class, surgery, WBRT, age, gender, number of lesions, median tumor volume, median peripheral dose, and 10 Gy and 12 Gy volumes. Identified RPA class and overall tumor volume >5 cc were the only two covariates independently predictive of overall survival in patients who died of cerebral progression. CONCLUSIONS: Global volume of brain disease should be the main parameter to consider for performing GKRS, which is a first-line therapy for patient in good general condition and controlled systemic disease.

Time course of hypothalamic-pituitary deficiency in adults receiving cranial radiotherapy for primary extrasellar brain tumors.

BACKGROUND: No longitudinal data on hypothalamic-pituitary (HP) function are available in patients who had received cranial radiation therapy (CRT) for primary extrasellar brain tumors (PBT). PURPOSE: To investigate the effects of CRT on HP function in adults with PBT. PATIENTS AND METHODS: Twenty-six adults irradiated for PBT and six CRT naive controls were studied. CRT was delivered with 6 MV X-ray by a linear accelerator (2 Gy fraction schedule). Gross Tumor Volume (GTV) excluded the HP region that was contoured on the planning CT. Median dose to the HP region was 41.8 Gy (IQR: 30.7-49.8). RESULTS: All controls maintained normal HP function. Hypopituitarism developed in 38% of CRT patients (GH deficiency 29%, ACTH 22%, TSH 14%, gonadotropin 4%, no abnormal prolactin level or diabetes insipidus). All HP failures occurred within 32 months after CRT. CONCLUSIONS: Adults undergoing CRT for PBT are at increased risk for HP dysfunction within 3 years from CRT. Endocrine surveillance is recommended also in adults patients exposed to CRT for primary brain tumors distant from HP region.

Consolidation radiotherapy in primary central nervous system lymphomas: impact on outcome of different fields and doses in patients in complete remission after upfront chemotherapy.

PURPOSE: Avoidance radiotherapy or reduction of irradiation doses in patients with primary central nervous system lymphoma (PCNSL) in complete remission (CR) after high-dose methotrexate (HD-MTX)-based chemotherapy has been proposed to minimize the neurotoxicity risk. Nevertheless, no study has focused on the survival impact of radiation parameters, as far as we know, and the optimal radiation schedule remains to be defined. METHODS AND MATERIALS: The impact on outcome and neurologic performance of different radiation fields and doses was assessed in 33 patients with PCNSL who achieved CR after MTX-containing chemotherapy and were referred to consolidation whole-brain irradiation (WBRT). Patterns of relapse were analyzed on computed tomography-guided treatment planning, and neurologic impairment was assessed by the Mini Mental Status Examination. RESULTS: At a median follow-up of 50 months, 21 patients are relapse-free (5-year failure-free survival [FFS], 51%). WBRT doses ≥ 40 Gy were not associated with improved disease control in comparison with a WBRT dose of 30 to 36 Gy (relapse rate, 46% vs. 30%; 5-year FFS, 51% vs. 50%; p = 0.26). Disease control was not significantly different between patients irradiated to the tumor bed with 45 to 54 Gy or with 36 to 44 Gy, with a 5-year FFS of 35% and 44% (p = 0.43), respectively. Twenty patients are alive (5-year overall survival, 54%); WB and tumor bed doses did not have an impact on survival. Impairment as assessed by the Mini Mental Status Examination was significantly more common in patients treated with a WBRT dose ≥ 40 Gy. CONCLUSION: Consolidation with WBRT 36 Gy is advisable in patients with PCNSL in CR after HD-MTX-based chemotherapy. Higher doses do not change the outcome and could increase the risk of neurotoxicity.

Predictors of acute bowel toxicity in patients treated with IMRT whole pelvis irradiation after prostatectomy.

PURPOSE/OBJECTIVE: Whole pelvis irradiation with IMRT (WPRT-IMRT) after prostatectomy is efficient in reducing acute toxicity: however, a number of patients still experience moderate acute bowel toxicity. MATERIALS AND METHODS: Ninety-six patients treated with WPRT-IMRT after prostatectomy with adjuvant or salvage intent were analysed. A number of parameters were individually recovered, including the DVHs of the intestinal cavity outside PTV and of the loops referred to both the WPRT phase and the whole treatment. Correlation between clinical-dosimetric parameters and acute bowel toxicity was investigated by logistic analyses. Best predictive cut-off values for continuous variables were assessed by ROC curves. RESULTS: 15/96 (15.6%) Patients experienced grade 2 toxicity (no grade 3). Best dose-volume predictors were the fraction of loops receiving more than 45, 50 and 55 Gy (respectively, V45TL ≥ 50cc, V50TL ≥ 13cc, V55TL ≥ 3cc; p-values ranging from 0.005 to 0.027). Age, GU acute toxicity, rectal acute toxicity and time between prostatectomy and IMRT were also predictors of acute bowel toxicity. Multivariate analysis showed that the most predictive independent parameters were age (OR: 1.13; 95%CI: 1.02-1.25; p=0.021) and V50TL (≥ 13cc, OR: 8.2; 95%CI: 1.7-40; p=0.009). CONCLUSIONS: The risk of moderate acute uGI toxicity during WPRT-IMRT for post-operatively treated patients increases with age; the risk is substantially reduced in patients with small overlap between PTV and loops.

IMRT significantly reduces acute toxicity of whole-pelvis irradiation in patients treated with post-operative adjuvant or salvage radiotherapy after radical prostatectomy.

PURPOSE: To investigate the role of IMRT in reducing the risk of acute genito-urinary (GU), upper gastrointestinal (uGI) and lower gastrointestinal (lGI) toxicity following whole-pelvis irradiation (WPRT) after radical prostatectomy. PATIENTS AND METHODS: 172 consecutive patients with prostate cancer were post-operatively irradiated to the prostatic bed (PB) and pelvic lymph-nodal area with adjuvant (n=100) or salvage (n=72) intent. Eighty-one patients underwent three-dimensional conformal (3DCRT) WPRT, while the remaining 91 underwent IMRT (54/91 with helical tomotherapy (HTT); 37/91 with Linac intensity-modulated RT (LinacIMRT)). RESULTS: Patients treated with IMRT experienced a decreased risk of acute toxicity. The crude incidence of grade > or =2 toxicity was GU 12.3% vs. 6.6% (p=0.19); lGI 8.6% vs. 3.2% (p=0.14); uGI 22.2% vs. 6.6% (p=0.004), for 3DCRT and IMRT, respectively. With respect to uGI and lGI, the acute toxicity profile of the HTT patients was even better when compared to that of 3DCRT patients (crude incidence:1.8% and 0.0%, respectively). Treatment interruptions due to uGI toxicity were 11/81 in the 3DCRT group vs. 2/91 in the IMRT group (p=0.006). CONCLUSIONS: The risk of acute toxicity following post-operative WPRT delivered by means of IMRT was reduced compared to that of 3DCRT. The most significant reduction concerned uGI, mainly owing to better bowel sparing with IMRT.

Dose-volume relationships for acute bowel toxicity in patients treated with pelvic nodal irradiation for prostate cancer.

PURPOSE: To find correlation between dose-volume histograms (DVHs) of the intestinal cavity (IC) and moderate-severe acute bowel toxicity in men with prostate cancer treated with pelvic nodal irradiation. METHODS AND MATERIALS: The study group consisted of 191 patients with localized prostate cancer who underwent whole-pelvis radiotherapy with radical or adjuvant/salvage intent during January 2004 to November 2007. Complete planning/clinical data were available in 175 of these men, 91 of whom were treated with a conventional four-field technique (50.4 Gy, 1.8 Gy/fraction) and 84 of whom were treated with IMRT using conventional Linac (n = 26, 50.4 Gy, 1.8 Gy/fraction) or Helical TomoTherapy (n = 58, 50-54 Gy, 1.8-2 Gy/fraction). The IC outside the planning target volume (PTV) was contoured and the DVH for the first 6 weeks of treatment was recovered in all patients. The correlation between a number of clinical and DVH (V10-V55) variables and toxicity was investigated in univariate and multivariate analyses. The correlation between DVHs for the IC outside the PTV and DVHs for the whole IC was also assessed. RESULTS: Twenty-two patients experienced toxicity (3/22 in the IMRT/tomotherapy group). Univariate analyses showed a significant correlation between V20-V50 and toxicity (p = 0.0002-0.001), with a higher predictive value observed for V40-V50. Previous prostatectomy (p = 0.066) and abdominal/pelvic surgery (p = 0.12) also correlated with toxicity. Multivariate analysis that included V45, abdominal/pelvic surgery, and prostatectomy showed that the most predictive parameters were V45 (p = 0.002) and abdominal/pelvic surgery (p = 0.05, HR = 2.4) CONCLUSIONS: Our avoidance IMRT approach drastically reduces the incidence of acute bowel toxicity. V40-V50 of IC and, secondarily, previous abdominal/pelvic surgery were the main predictors of acute bowel toxicity.