Skin dose-volume predictors of moderate-severe late side effects after whole breast radiotherapy.

BACKGROUND: Toxicity after whole breast Radiotherapy is a relevant issue, impacting the quality-of-life of a not negligible number of patients. We aimed to develop a Normal Tissue Complication Probability (NTCP) model predicting late toxicities by combining dosimetric parameters of the breast dermis and clinical factors. METHODS: The skin structure was defined as the outer CT body contour's 5 mm inner isotropic expansion. It was retrospectively segmented on a large mono-institutional cohort of early-stage breast cancer patients enrolled between 2009 and 2017 (n = 1066). Patients were treated with tangential-field RT, delivering 40 Gy in 15 fractions to the whole breast. Toxicity was reported during Follow-Up (FU) using SOMA/LENT scoring. The study endpoint was moderate-severe late side effects consisting of Fibrosis-Atrophy-Telangiectasia-Pain (FATP G ≥ 2) developed within 42 months after RT completion. A machine learning pipeline was designed with a logistic model combining clinical factors and absolute skin DVH (cc) parameters as output. RESULTS: The FATP G2 + rate was 3.8 %, with 40/1066 patients experiencing side effects. After the preprocessing of variables, a cross-validation was applied to define the best-performing model. We selected a 4-variable model with Post-Surgery Cosmetic alterations (Odds Ratio, OR = 7.3), Aromatase Inhibitors (as a protective factor with OR = 0.45), V20 Gy (50 % of the prescribed dose, OR = 1.02), and V42 Gy (105 %, OR = 1.09). Factors were also converted into an adjusted V20Gy. CONCLUSIONS: The association between late reactions and skin DVH when delivering 40 Gy/15 fr was quantified, suggesting an independent role of V20 and V42. Few clinical factors heavily modulate the risk.

Knowledge-based automatic plan optimization for left-sided whole breast tomotherapy.

Background/Purpose: Tomotherapy may deliver high-quality whole breast irradiation at static angles. The aim of this study was to implement Knowledge-Based (KB) automatic planning for left-sided whole breast using this modality. Materials/Methods: Virtual volumetric plans were associated to the dose distributions of 69 Tomotherapy (TT) clinical plans of previously treated patients, aiming to train a KB-model using a commercial tool completely implemented in our treatment planning system. An individually optimized template based on the resulting KB-model was generated for automatic plan optimization. Thirty patients of the training set and ten new patients were considered for internal/external validation. Fully-automatic plans (KB-TT) were generated and compared using the same geometry/number of fields of the corresponding clinical plans. Results: KB-TT plans were successfully generated in 26/30 and 10/10 patients of the internal/external validation sets; for 4 patients whose original plans used only two fields, the manual insertion of one/two fields before running the automatic template was sufficient to obtain acceptable plans. Concerning internal validation, planning target volume V95%/D1%/dose distribution standard deviation improved by 0.9%/0.4Gy/0.2Gy (p < 0.05) against clinical plans; Organs at risk mean doses were also slightly improved (p < 0.05) by 0.07/0.4/0.2/0.01 Gy for left lung/heart/right breast/right lung respectively. Similarly satisfactory results were replicated in the external validation set. The resulting treatment duration was 8 ± 1 min, consistent with our clinical experience. The active planner time per patient was 5-10 minutes. Conclusion: Automatic TT left-sided breast KB-plans are comparable to or slightly better than clinical plans and can be obtained with limited planner time. The approach is currently under clinical implementation.

Toxicity of Hypofractionated Whole Breast Radiotherapy Without Boost and Timescale of Late Skin Responses in a Large Cohort of Early-Stage Breast Cancer Patients.

AIM: To report toxicity of hypofractionated whole-breast radiotherapy in a large cohort of early-stage breast cancer (BCaients. MATERIALS AND METHODS: From 02/2009-05/2017, 1325 consecutive BCa patients were treated with 40.05 Gy/15 fractions, without boost. Median age was 62 (IQR:51.1-70.5) years. Chemotherapy was prescribed for 28% of patients, hormonal therapy for 80.3%, monoclonal antibodies for 8.2%. RESULTS: Median follow-up was 72.4 (IQR: 44.6-104.1) months. Acute RTOG toxicity was: 69.8% Grade (G) 1, 14.3% G2 and 1.7% G3. Late SOMA-LENT toxicities were: edema-hyperpigmentation (E-H): G1 28.67%, G2 4.41%, G3 0.15%; fibrosis-atrophy-telangiectasia-pain (F-A-T-P): G1 14.6%, G2 3.2%, G3 0.8%, G4 0.1%. Median time to first occurrence was 6 and 18 months, respectively. Aesthetic result after surgery was excellent in 28.7%, good in 41.5%, acceptable in 20.3% and poor in 9.5% of patients. Change in breast appearance after radiotherapy was mild in 6.9%, moderate in 2.3% and marked in 1.3% of patients. Concomitant chemotherapy, obesity, smoking, use of bolus and planning target volume (PTV) were associated with higher acute toxicity. Patients ≥55 years old were less likely to experience acute toxicity. PTV and acute G2 toxicity were associated with ≥G2 E-H. PTV, concomitant chemotherapy, hypertension and ≥G2 acute toxicity were associated with increased risk of F-A-T-P. CONCLUSION: Hypofractionated whole-breast radiotherapy without boost demonstrated mild acute and late toxicity in a large cohort of consecutive patients. Moderate and marked changes in breast appearance were registered for 3.6% of patients and occurred between 18 to 42 months.

Ten Year Results of Extensive Nodal Radiotherapy and Moderately Hypofractionated Simultaneous Integrated Boost in Unfavorable Intermediate-, High-, and Very High-Risk Prostate Cancer.

AIMS: To report 10-year outcomes of WPRT and HD moderately hypofractionated SIB to the prostate in UIR, HR, and VHR PCa. METHODS: From 11/2005 to 12/2015, 224 UIR, HR, and VHR PCa patients underwent WPRT at 51.8 Gy/28 fractions and SIB at 74.2 Gy (EQD2 88 Gy) to the prostate. Androgen deprivation therapy (ADT) was prescribed in up to 86.2% of patients. RESULTS: Median follow-up was 96.3 months (IQR: 71-124.7). Median age was 75 years (IQR: 71.3-78.1). At last follow up, G3 GI-GU toxicity was 3.1% and 8%, respectively. Ten-year biochemical relapse-free survival (bRFS) was 79.8% (95% CI: 72.3-88.1%), disease-free survival (DFS) 87.8% (95% CI: 81.7-94.3%), overall survival (OS) 65.7% (95% CI: 58.2-74.1%), and prostate cancer-specific survival (PCSS) 94.9% (95% CI: 91.0-99.0%). Only two patients presented local relapse. At univariate analysis, VHR vs. UIR was found to be a significant risk factor for biochemical relapse (HR: 2.8, 95% CI: 1.17-6.67, p = 0.021). After model selection, only Gleason Score ≥ 8 emerged as a significant factor for biochemical relapse (HR = 2.3, 95% CI: 1.12-4.9, p = 0.023). Previous TURP (HR = 3.5, 95% CI: 1.62-7.54, p = 0.001) and acute toxicity ≥ G2 (HR = 3.1, 95% CI = 1.45-6.52, p = 0.003) were significant risk factors for GU toxicity ≥ G3. Hypertension was a significant factor for GI toxicity ≥ G3 (HR = 3.63, 95% CI: 1.06-12.46, p = 0.041). ADT (HR = 0.31, 95% CI: 0.12-0.8, p = 0.015) and iPsa (HR = 0.37, 95% CI: 0.16-0.83, p = 0.0164) played a protective role. CONCLUSIONS: WPRT and HD SIB to the prostate combined with long-term ADT, in HR PCa, determine good outcomes with acceptable toxicity.

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.

Co-Culture System of Human Enteroids/Colonoids with Innate Immune Cells.

Human intestinal enteroids derived from adult stem cells offer a relevant ex vivo system to study biological processes of the human gut. They recreate cellular and functional features of the intestinal epithelium of the small intestine (enteroids) or colon (colonoids) albeit limited by the lack of associated cell types that help maintain tissue homeostasis and respond to external challenges. In the gut, innate immune cells interact with the epithelium, support barrier function, and deploy effector functions. We have established a co-culture system of enteroid/colonoid monolayers and underlying macrophages and polymorphonuclear neutrophils to recapitulate the cellular framework of the human intestinal epithelial niche. Enteroids are generated from biopsies or resected tissue from any segment of the human gut and maintained in long-term cultures as three-dimensional structures through supplementation of stem cell growth factors. Immune cells are isolated from fresh human whole blood or frozen peripheral blood mononuclear cells (PBMC). Monocytes from PBMC are differentiated into macrophages by cytokine stimulation prior to co-culture. The methods are divided into the two main components of the model: (1) generating enteroid/colonoid monolayers and isolating immune cells and (2) assembly of enteroid/colonoid-immune cell co-cultures with separate apical and basolateral compartments. Co-cultures containing macrophages can be maintained for 48 hr while those involving neutrophils, due to their shorter life span, remain viable for 4 hr. Enteroid-immune co-cultures enable multiple outcome measures, including transepithelial resistance, production of cytokines/chemokines, phenotypic analysis of immune cells, tissue immunofluorescence imaging, protein or mRNA expression, antigen or microbe uptake, and other cellular functions. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Seeding enteroid fragments onto Transwells for monolayer formation Alternate Protocol: Seeding enteroid fragments for monolayer formation using trituration Basic Protocol 2: Isolation of monocytes and derivation of immune cells from human peripheral blood Basic Protocol 3: Isolation of neutrophils from human peripheral blood Basic Protocol 4: Assembly of enteroid/macrophage or enteroid/neutrophil co-culture.

Virtual Tangential-fields Arc Therapy (ViTAT) for whole breast irradiation: Technique optimization and validation.

PURPOSE: To test the performances of a volumetric arc technique named ViTAT (Virtual Tangential-fields Arc Therapy) mimicking tangential field irradiation for whole breast radiotherapy. METHODS: ViTAT plans consisted in 4 arcs whose starting/ending position were established based on gantry angle distribution of clinical plans for right and left-breast. The arcs were completely blocked excluding the first and last 20°. Different virtual bolus densities and thicknesses were preliminarily evaluated to obtain the best plan performances. For 40 patients with tumor laterality equally divided between right and left sides, ViTAT plans were optimized considering the clinical DVHs for OARs (resulting from tangential field manual planning) to constrain them: ViTAT plans were compared with the clinical tangential-fields in terms of DVH parameters for both PTV and OARs. RESULTS: Distal angle values were suggested in the ranges [220°,240°] for the right-breast and [115°,135°] for the left-breast cases; medial angles were [60°,40°] for the right side and [295°,315°] for the left side, limiting the risk of collision. The optimal virtual bolus had -500 HU density and 1.5 cm thickness. ViTAT plans generated dose distributions very similar to the tangential-field plans, with significantly improved PTV homogeneity. The mean doses of ipsilateral OARs were comparable between the two techniques with minor increase of the low-dose spread in the range 2-15 Gy (few % volume); contralateral OARs were slightly better spared with ViTAT. CONCLUSION: ViTAT dose distributions were similar to tangential-fields. ViTAT should allow automatic plan optimization by developing knowledge-based DVH prediction models of patients treated with tangential-fields.

Personalized Risk-Benefit Ratio Adaptation of Breast Cancer Care at the Epicenter of COVID-19 Outbreak.

Northern Italy has been one of the European regions reporting the highest number of COVID-19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of most of the available health care resources to treat COVID-19-positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID-19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer-related outcome. In this article, we attempt to estimate the individual risk-benefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID-19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources. IMPLICATIONS FOR PRACTICE: Managing patients with breast cancer during the COVID-19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID-19-related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients' and health workers' psychological distress.

Sentinel node biopsy after primary systemic therapy in node positive breast cancer patients: Time trend, imaging staging power and nodal downstaging according to molecular subtype.

BACKGROUND: The management of axilla after Primary Systemic Therapy (PST) for breast cancer is a highly debated field. Despite the proven axillary downstaging occurring after PST, there is still some degree of reluctance in applying sentinel node biopsy (SNB) in the neoadjuvant setting. PATIENTS AND METHODS: We performed a retrospective analysis on 181 PST patients with axillary positive nodes at presentation treated between 2005 and 2017 at San Raffaele Hospital in Milan. The aim was to observe the application time trend of SNB, to determine the imaging staging power and the axillary downstaging according to molecular subtypes. RESULTS: Median follow-up after surgery was 32.5(IQR: 12-59) months. After PST, 119 (65.7%) patients had no clinically palpable nodes, 72 (39.7%) converted to N0 on final imaging and 34 (18.8%) underwent SNB with an increasing application trend. Axillary-US showed the highest accuracy (69.3%) in re-staging axilla after PST. Staging power of preoperative testing varied with tumour biology: Positive Predictive Value was higher in Luminal A (80% for clinical examination and 100% for axillary-US) and Luminal B (72% and 70.5%) tumours, whilst Negative Predictive Value was higher in HER2 positive (100% and 93.3%), and triple negative (71.4% and 93.3%) tumours. Ninety five (52.5%) patients experienced axillary downstaging after PST, by molecular subtype 15% (3/20) in Luminal A, 46.4% (45/97) in Luminal B, 90.9% (20/22) in HER2+ and 70.3% (26/37) in triple negative breast tumours. CONCLUSION: SNB application after PST for breast cancer in node positive patients at presentation is increasing. Pre-operative axillary imaging and tumour biology help identify patients who might be candidates for SNB as a single staging procedure.

Moderately Hypofractionated Helical IMRT, FDG-PET/CT-guided, for Progressive Malignant Pleural Mesothelioma in Patients With Intact Lungs.

INTRODUCTION: The objective of this study was to present the outcomes of moderately hypofractionated helical intensity-modulated radiation therapy (HT) with/without simultaneous integrated boost (SIB) on fluorodeoxyglucose-positron emission tomography (FDG-PET) positive areas (gross tumor volume [GTV]-PET) for patients with progressive malignant pleural mesothelioma (MPM) after previous treatments. METHODS AND MATERIALS: From May 2006 to April 2014, 51 patients with a median age of 68.8 years (range, 38.6-82 years) were treated. There were 41 men and 10 women; 43 epithelioid MPM and 8 sarcomatoid, involving the left pleura in 25 patients and the right pleura in 26 patients. The initial stage was: I, 11 patients; II, 14 patients; III, 17 patients; and IV, 9 patients. Chemotherapy was prescribed for 46 patients, for 6 cycles (range, 0-18 cycles). Eighteen patients had pleurectomy/decortication, and 33 had talc pleurodesis. FDG-PET was used for target identification. A median dose of 56 Gy/25 fractions was prescribed to the involved pleura, and SIB to 62.5 Gy to GTV-PET was added in 38 patients. RESULTS: The median survival from diagnosis was 25.8 months (range, 8.4-99.0 months). One patient, treated with SIB, was alive at the October 2017 follow-up. Two cases of grade 5 radiation pneumonitis were registered. A GTV-PET ≤ 205 cc was predictive of late ≥ grade 2 lung toxicity, but also of better survival in stage III and IV disease: 5.9 versus 11.7 months (P = .04). A GTV-PET ≥ 473 cc was predictive of early death (P = .001). CONCLUSIONS: Moderately hypofractionated, FDG-PET guided salvage HT in patients with progressive MPM after previous treatments showed acceptable toxicity and outcome results similar to adjuvant radiotherapy after pleurectomy/decortication, suggesting that the delay of radiotherapy is not detrimental to survival, and has the associated benefit of postponing inherent toxicity.

Clinical implementation of low-dose total body irradiation using topotherapy technique.

BACKGROUND AND PURPOSE: The topotherapy technique was recently suggested as a robust alternative to helical radiation delivery for total body irradiation (TBI). It allows to deliver a discrete number of beams with fixed gantry. A Topotherapy-based low-dose TBI technique was optimized and clinically implemented. MATERIALS AND METHODS: TBI delivery was split in two parts: the first treating from the head to half thigh and the second the remaining legs. An in-silico investigation aimed to optimize plan parameters was first carried out on four patients. For the upper plan, field width and pitch were fixed to 5 cm and 0.5: the combined impact of five modulation factor (MF) values and different field configurations (6/8/12 fields) was investigated. For the lower plan, two anterior/posterior beams (field width: 5 cm; pitch: 0.5; MF:1.5) were used. After assessing the optimal technique, set-up/quality assurance/image-guidance procedures were defined and the technique clinically implemented: 23 patients were treated up to now. RESULTS: The best compromise between treatment time and planning target volume (PTV) coverage/homogeneity was found for MF = 1.5 and 8 fields. All clinical plans were automatically optimized using an "ad-hoc" plan template: excellent PTV coverage (PTV95%>98.5%) and homogeneity (median SD:4%) were found with a median beam-on time of 17/9 min for the upper/lower plan. All patients were successfully treated and transplanted. CONCLUSIONS: TBI delivered with the topotherapy approach robustly guarantees adequate coverage and dose homogeneity. Semi-automatic clinical plans can be quickly generated and efficiently delivered.

Toxicity and efficacy of salvage carbon 11-choline positron emission tomography/computed tomography-guided radiation therapy in patients with lymph node recurrence of prostate cancer.

OBJECTIVE: To report the 3-year toxicity and outcomes of carbon 11 (11C)-choline-positron emission tomography (PET)/computed tomography (CT)-guided radiotherapy (RT), delivered via helical tomotherapy (HTT; Tomotherapy® Hi-Art II® Treatment System, Accuray Inc., Sunnyvale, CA, USA) after lymph node (LN) relapses in patients with prostate cancer. PATIENTS AND METHODS: From January 2005 to March 2013, 81 patients with biochemical recurrence after surgery, with or without adjuvant/salvage RT or radical RT, and with evidence of LN 11C-choline-PET/CT pathological uptake, underwent HTT (median [range] prostate-specific antigen level 2.59 [0.61-187] ng/mL). Of the 81 patients, 72 were treated at the pelvic and/or lumbar-aortic LN chain with HTT at 51.8 Gy/28 fr and with simultaneous integrated boost to a median dose of 65.5 Gy on the pathological uptake sites detected by 11C-choline-PET/CT. Nine patients were treated without simultaneous integrated boost (50-65.5 Gy, 25-30 fr). RESULTS: With a median (range) follow-up of 36 (9-116) months, 91.4% of the patients had a PSA reduction 3 months after HTT. The 3-year overall, local relapse-free and clinical relapse-free survival rates were 80.0, 89.8 and 61.8%, respectively. The 3-year actuarial incidences of ≥grade 2 rectal and ≥grade 2 genitourinary toxicity were 6.6% (±2.9%) and 26.3% (±5.5%), respectively. A PSA nadir of ≥0.26 ng/mL (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.7-7.7; P = 0.001), extrapelvic 11C-choline-PET/CT-positive LN location (HR 2.4, 95% CI 0.9-6.4; P = 0.07), RT previous to HTT (HR 2.7; 95% CI 1.07-6.9, P = 0.04) and number of positive LNs (HR 1.13, 95% CI 1.04-1.22; P = 0.003) were the main predictors of clinical relapse after HTT. CONCLUSIONS: 11C-choline-PET/CT-guided HTT is safe and effective in the treatment of LN relapses of prostate cancer in previously treated patients.

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.

PET-guided dose escalation tomotherapy in malignant pleural mesothelioma.

PURPOSE: To test the feasibility of salvage radiotherapy using PET-guided helical tomotherapy in patients with progressive malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: A group of 12 consecutive MPM patients was treated with 56 Gy/25 fractions to the planning target volume (PTV); FDG-PET/CT simulation was always performed to include all positive lymph nodes and MPM infiltrations. Subsequently, a second group of 12 consecutive patients was treated with the same dose to the whole pleura adding a simultaneous integrated boost of 62.5 Gy to the FDG-PET/CT positive areas (BTV). RESULTS: Good dosimetric results were obtained in both groups. No grade 3 (RTOG/EORTC) acute or late toxicities were reported in the first group, while 3 cases of grade 3 late pneumonitis were registered in the second group: the duration of symptoms was 2-10 weeks. Median overall survival was 8 months (1.2-50.5 months) and 20 months (4.3-33.8 months) from the beginning of radiotherapy, for groups I and II, respectively (p=0.19). A significant impact on local relapse from radiotherapy was seen (median time to local relapse: 8 vs 17 months; 1-year local relapse-free rate: 16% vs 81%, p=0.003). CONCLUSIONS: The results of this pilot study support the planning of a phase III study of combined sequential chemoradiotherapy with dose escalation to BTV in patients not able to undergo resection.

Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC.

BACKGROUND AND PURPOSE: To investigate the impact of Helical Tomotherapy (HT) upon the dose distribution when compared to our routinely delivered 3D conformal radiotherapy (CRT) in the case of patients affected by stage III non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: Thirteen stage III inoperable NSCLC patients were scheduled to receive 61.2-70.2Gy, 1.8Gy/fraction. Two treatment techniques (HT and CRT) were considered, and in the case of CRT the dose calculation was performed using both the pencil beam (PB) and Anisotropic Analytical Algorithm (AAA) available on the Varian Eclipse planning system. Dose volume constraints for PTV coverage and OAR sparing were assessed for the HT inverse planning with the highest priority upon PTV coverage and spinal cord sparing. The three plans were compared in terms of dose-volume histograms (DVHs) and normal tissue complication probability (NTCP). A statistical analysis was performed using non-parametric Wilcoxon matched pairs tests. RESULTS: In CRT the use of a less accurate algorithm (PB) decreased the monitor unit number by 2.4%. HT significantly improved dose homogeneity within PTV compared with CRT_AAA. For lung parenchyma V20-V40 were lower with HT, corresponding to a decrease of 7% in the risk of radiation pneumonitis. The volume of the heart and esophagus irradiated to >45-60Gy were reduced using HT plans. For eight PTs with an esophagus-PTV overlap >5%, HT significantly reduced both late and acute esophageal complication probability. CONCLUSIONS: Our findings obtained in stage III NSCLC patients underline that HT guarantees an important sparing of lungs and esophagus, thus HT has the potential to improve therapeutic ratio, when compared with CRT, by means of dose escalation and/or combined treatment strategy. In CRT of locally advanced lung cancers, the use of a more advanced algorithm would give significantly better modeling of target dose and coverage.

Tetracaine oral gel in patients treated with radiotherapy for head-and-neck cancer: final results of a phase II study.

PURPOSE: We performed a phase II study to assess feasibility, pain relief, and toxicity of a tetracaine-based oral gel in the treatment of radiotherapy (RT)-induced mucositis. METHODS AND MATERIALS: Fifty patients treated with RT for head-and-neck cancer with clinical evidence of acute oral mucositis of grade>or=2 were scheduled to receive the tetracaine gel. A questionnaire evaluating the effect of the gel was given to all subjects. RESULTS: In 38 patients (79.2%), a reduction in oral cavity pain was reported. Thirty-four patients (82.9%) reported no side effect. Seventy-one percent of patients had no difficulties in gel application. Unpleasant taste of the gel and interference with food taste were noticed in 5 (12%) and 16 patients (39%), respectively. Planned RT course was interrupted less frequently in patients who reported benefit from gel application than in patients who did not (p=0.014). None of the patients who experienced pain relief needed a nasogastric tube, opposite to the patients who did not report any benefit from gel application (p=0.001). CONCLUSION: Tetracaine oral gel administration seemed feasible and safe while reducing RT-induced mucositis-related oral pain in a sizeable proportion of treated head-and-neck cancer patients. A trial designed to compare efficacy of this gel vs. standard treatment is warranted.

Hyperfractionated radiotherapy in locally advanced nasopharyngeal cancer. An analysis of 43 consecutive patients.

BACKGROUND: Despite numerous randomized trials suggesting a benefit of unconventional fractionation in locally advanced head and neck cancer, the role of this approach in nasopharyngeal carcinoma is debatable. Based on the current clinical experience, the authors introduced hyperfractionated irradiation in the treatment of locally advanced head and neck cancer, including nasopharyngeal tumors. The preliminary results of this treatment approach in nasopharyngeal cancer patients are presented, with special focus on the pattern of failure and toxicity. PATIENTS AND METHODS: 43 patients with nasopharyngeal cancer (stage II-IV, TNM 1997) underwent hyperfractionated irradiation. In 34 cases, radiotherapy was preceded by a median of three cycles of cisplatin-based induction chemotherapy. Irradiation was delivered using a shrinking-field technique up to a total dose of 74.4 Gy in 62 fractions of 1.2 Gy twice daily (minimum 6-h interval)/5 days/week. RESULTS: Acute toxicity of hyperfractionated radiotherapy was significant but tolerable. Mucositis proved the most common side effect (grade 3: 24 patients, grade 4: three patients). Severe late toxicity was not observed. 30 of 34 patients (88%) responded to induction chemotherapy. At 6 weeks after completion of radiotherapy, complete response was seen in 35 patients (81%), partial response in five (12%), stable disease in one, and progressive disease in two. After a median follow-up of 32 months, 18 patients (41%) developed progressive disease. Primary tumor progression was observed in three patients, and seven patients each showed regional lymph node progression and distant metastases. In one case both regional lymph node progression and distant metastases were diagnosed. The 2-year progression-free survival and overall survival rates were 58% and 84%, respectively. CONCLUSION: Hyperfractionated radiotherapy seems a feasible and active regimen in locally advanced nasopharyngeal carcinoma. Accompanying acute and late toxicity is acceptable and does not compromise delivery of the planned irradiation dose. This regimen is associated with a high local control rate; relatively high nodal and distant failure, however, call for further treatment modifications, e. g., optimization of irradiation technique and/or dose escalation as well as improved systemic therapies.