Health-related quality of life of salvage prostate reirradiation using stereotactic ablative radiotherapy with urethral-sparing.

Purpose: To explore whether prostate motion mitigation using the rectal distension-mediated technique is safe and effective in stereotactic ablative radiation therapy (SABR) salvage treatment of intraprostatic cancer recurrences following initial radiotherapy for primary prostate cancer. Materials and methods: Between July 2013 and December 2020, 30 patients received salvage SABR for 68Ga- PSMA-11 PET/CT-detected intra-prostatic relapses. Median time from primary RT to salvage reirradiation was 70.2 (IQR, 51.3-116.0) months. Median PSA at retreatment was 3.6 ng/mL (IQR, 1.9-6.2). Rectal distension-mediated SABR was achieved with a 150-cm3 air-inflated endorectal balloon and a Foley catheter loaded with 3 beacon transponders was used for urethra visualization and on-line tracking. MRI-based planning employed a 2-mm expansion around the planned target volume (PTV), reduced to 0-mm at the interface with critical organs at risk (OARs). Volumetric Modulated Arc Therapy (VMAT) permitted a 20% dose reduction of the urethra. VMAT simultaneous integrated boost (SIB) of the dominant intraprostatic lesion was deployed when indicated. Median SABR dose was 35 Gy (7 Gy per fraction over 5 consecutive days; range 35-40 Gy). Toxicity assessment used CTCAE v.4 criteria. Results: Median follow-up was 44 months (IQR, 18-60). The actuarial 3- and 4-year biochemical relapse free survival was 53.4% and 47.5%, respectively. Intraprostatic post-salvage relapse by PSMA PET/CT was 53.3%. Acute grade 2 and 3 genitourinary (GU) toxicities were 20% and 0%, respectively. There were no instances of acute grade ≥2 rectal (GI) toxicity. Late grade 2 and 3 GU toxicities occurred in 13.3% and 0% of patients, respectively. There were no instances of grade ≥2 late rectal toxicity. Patient-reported QOL measures showed an acute transient deterioration in the urinary domain 1 month after treatment but returned to baseline values at 3 months. The median IPSS scores rose over baseline (≥5 points in 53% of patients) between month 6 and 12 post-treatment as a result of urinary symptoms flare, eventually receding at 18 months. The bowel domain metrics had no appreciable changes over time. Conclusion: Pursuit of local control in intraprostatic failures is feasible and can be achieved with an acceptably low toxicity profile associated with effective OAR sparing.

Urethra Sparing With Target Motion Mitigation in Dose-Escalated Extreme Hypofractionated Prostate Cancer Radiotherapy: 7-Year Results From a Phase II Study.

Purpose: To explore whether the rectal distension-mediated technique, harnessing human physiology to achieve intrafractional prostate motion mitigation, enables urethra sparing by inverse dose painting, thus promoting dose escalation with extreme hypofractionated stereotactic ablative radiotherapy (SABR) in prostate cancer. Materials and Methods: Between June 2013 and December 2018, 444 patients received 5 × 9 Gy SABR over 5 consecutive days. Rectal distension-mediated SABR was employed via insertion of a 150-cm3 air-inflated endorectal balloon. A Foley catheter loaded with 3 beacon transponders was used for urethra visualization and online tracking. MRI-based planning using Volumetric Modulated Arc Therapy - Image Guided Radiotherapy (VMAT-IGRT) with inverse dose painting was employed in delivering the planning target volume (PTV) dose and in sculpting exposure of organs at risk (OARs). A 2-mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. All plans fulfilled Dmean ≥45 Gy. Target motion ≥2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of the planned dose delivery. Results: Patient compliance to the rectal distension-mediated immobilization protocol was excellent, achieving reproducible daily prostate localization at a patient-specific retropubic niche. Online tracking recorded ≤1-mm intrafractional target deviations in 95% of treatment sessions, while target realignment in ≥2-mm deviations enabled treatment completion as scheduled in all cases. The cumulative incidence rates of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) toxicities were 5.3% and 1.1%, respectively. The favorable toxicity profile was corroborated by patient-reported quality of life (QOL) outcomes. Median prostate-specific antigen (PSA) nadir by 5 years was 0.19 ng/ml. The cumulative incidence rate of biochemical failure using the Phoenix definition was 2%, 16.6%, and 27.2% for the combined low/favorable-intermediate, unfavorable intermediate, and high-risk categories, respectively. Patients with a PSA failure underwent a 68Ga-labeled prostate-specific membrane antigen (68Ga-PSMA) scan showing a 20.2% cumulative incidence of intraprostatic relapses in biopsy International Society of Urological Pathology (ISUP) grade ≥3. Conclusion: The rectal distension-mediated technique is feasible and well tolerated. Dose escalation to 45 Gy with urethra-sparing results in excellent toxicity profiles and PSA relapse rates similar to those reported by other dose-escalated regimens. The existence of intraprostatic recurrences in patients with high-risk features confirms the notion of a high α/ß ratio in these phenotypes resulting in diminished effectiveness with hypofractionated dose escalation.

Early PSA density kinetics predicts biochemical and local failure following extreme hypofractionated radiotherapy in intermediate-risk prostate cancer.

PURPOSE: The present study explores PSA density (PSA-D) as predictor of biochemical and local failure in organ-confined prostate cancer at 3-6 months after hypofractionated stereotactic ablative radiotherapy (SABR). METHODS AND MATERIALS: A cohort of 219, hormone-naïve, NCCN intermediate-risk prostate cancer patients were derived from a phase 2 study of 5 × 9 Gy prostate cancer SABR. PSA-D was calculated at 3 and 6 months by dividing serum PSA by the MR-derived prostate CTV, while the slope of the 3-6 months curve was used to express the kinetics of PSA-D decay. RESULTS: The median follow-up was 60.3 (range 46-76) months, and the actuarial 7-year bRFS was 98.0% for intermediate-risk favorable (FIR) patients versus 84.5% for the unfavorable (UIR) subgroup (P = 0.02). Fourteen patients developed a Phoenix-defined biochemical PSA relapse (bRFS) at a median of 34.2 months, 11 confirmed with 68Ga-PSMA PET/CT scan that revealed tracer uptake at the site of dominant intraprostatic pretreatment lesion in 8 patients. The 3-month PSA-D concertation (cut-off 0.08 ng/ml2) and 3-6 months decay slope (cut-off -0.45) values were predictive of long-term bRFS. A dual adverse PSA-D permutation was detected in 25/148 UIR patients, exhibiting 47.5% 7-year bRFS compared with 94.1% for the remaining 123 UIR patients with favorable PSA-D kinetics (P = 0.0006). Intraprostatic local relapse in patients with a 3-month PSA-D > 0.080 ng/ml2 was 11.0% vs. 1.7% for patients with PSA-D ≤ 0.080 ng/ml2 (P = 0.01) and 2.3% vs. 4.3%, respectively, for nodal progression (P = 0.68). CONCLUSIONS: Early post-treatment PSA-D kinetics transcends pre-treatment risk stratification of tumor relapse and adds a nuance in the biological characterization of intermediate-risk prostate cancer phenotypes. The dual adverse PSA-D algorithm may serve as a tool to validate current search of classifiers of radioresistance in prostate cancer with therapeutic implications.

Positron Emission Tomography-Derived Metrics Predict the Probability of Local Relapse After Oligometastasis-Directed Ablative Radiation Therapy.

PURPOSE: Early positron emission tomography-derived metrics post-oligometastasis radioablation may predict impending local relapses (LRs), providing a basis for a timely ablation. METHODS AND MATERIALS: Positron emission tomography data of 623 lesions treated with either 24 Gy single-dose radiation therapy (SDRT) (n = 475) or 3 ×  9 Gy stereotactic body radiation therapy (SBRT) (n = 148) were analyzed in a training data set (n = 246) to obtain optimal cutoffs for pretreatment maximum standardized uptake value (SUVmax) and its 3-month posttreatment decline (ΔSUVmax) in predicting LR risk, validated in a data set unseen to testing (n = 377). RESULTS: At a median of 21.7 months, 91 lesions developed LRs: 39 of 475 (8.2%) after SDRT and 52 of 148 (35.1%) after SBRT. The optimal cutoff values were 12 for SUVmax and -75% for ΔSUVmax. Bivariate SUVmax/ΔSUVmax permutations rendered a 3-tiered LR risk stratification of dual-favorable (low risk), 1 adverse (intermediate risk) and dual-adverse (high risk). Actuarial 5-year local relapse-free survival rates were 93.9% versus 89.6% versus 57.1% (P < .0001) and 76.1% versus 48.3% versus 8.2% (P < .0001) for SDRT and SBRT, respectively. The SBRT area under the ROC curve was 0.71 (95% CI, 0.61-0.79) and the high-risk subgroup yielded a 76.5% true positive LR prediction rate. CONCLUSIONS: The SBRT dual-adverse SUVmax/ΔSUVmax category LR prediction power provides a basis for prospective studies testing whether a timely ablation of impending LRs affects oligometastasis outcomes.

Reproducibility and accuracy of a target motion mitigation technique for dose-escalated prostate stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: To quantitate the accuracy, reproducibility and prostate motion mitigation efficacy rendered by a target immobilization method used in an intermediate-risk prostate cancer dose-escalated 5×9Gy SBRT study. MATERIAL AND METHODS: An air-inflated (150 cm3) endorectal balloon and Foley catheter with three electromagnetic beacon transponders (EBT) were used to mitigate and track intra-fractional target motion. A 2 mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. EBT-detected ≥ 2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of planned dose delivery. Geometrical uncertainties were measured with an in-house ESAPI script. RESULTS: Quantitative data were obtained in 886 sessions from 189 patients. Mean PTV dose was 45.8 ± 0.4 Gy (D95 = 40.5 ± 0.4 Gy). A mean of 3.7 ± 1.7 CBCTs were acquired to reach reference position. Mean treatment time was 19.5 ± 12 min, 14.1 ± 11 and 5.4 ± 5.9 min for preparation and treatment delivery, respectively. Target motion of 0, 1-2 and >2 mm/10 min were observed in 59%, 30% and 11% of sessions, respectively. Temporary beam-on hold occurred in 7.4% of sessions, while in 6% a new reference CBCT was required to correct deviations. Hence, all sessions were completed with application of the planned dose. Treatment preparation time > 15 min was significantly associated with the need of a second reference CBCT. Overall systematic and random geometrical errors were in the order of 1 mm. CONCLUSION: The prostate immobilization technique explored here affords excellent accuracy and reproducibility, enabling normal tissue dose sculpting with tight PTV margins.

Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in Patients With Intermediate-Risk Prostate Cancer: Results From the PROSINT Phase 2 Randomized Clinical Trial.

IMPORTANCE: Ultra-high single-dose radiotherapy (SDRT) represents a potential alternative to curative extreme hypofractionated stereotactic body radiotherapy (SBRT) in organ-confined prostate cancer. OBJECTIVE: To compare toxic effect profiles, prostate-specific antigen (PSA) responses, and quality-of-life end points of SDRT vs extreme hypofractionated SBRT. DESIGN, SETTING, AND PARTICIPANTS: The PROSINT single-institution phase 2 randomized clinical trial accrued, between September 2015 and January 2017, 30 participants with intermediate-risk prostate cancer to receive SDRT or extreme hypofractionated SBRT. Androgen deprivation therapy was not permitted. Data were analyzed from March to May 2020. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive 5 × 9 Gy SBRT (control arm) or 24 Gy SDRT (test arm). MAIN OUTCOMES AND MEASURES: The primary end point was toxic effects; the secondary end points were PSA response, PSA relapse-free survival, and patient-reported quality of life measured with the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaires. RESULTS: A total of 30 men were randomized; median (interquartile range) age was 66.3 (61.2-69.9) and 73.6 (64.7-75.9) years for the SBRT and SDRT arms, respectively. Time to appearance and duration of acute and late toxic effects were similar in the 2 trial arms. Cumulative late actuarial urinary toxic effects did not differ for grade 1 (hazard ratio [HR], 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57). Actuarial grade 1 late gastrointestinal (GI) toxic effects were comparable (HR, 0.37; 90% CI, 0.07-1.94) and there were no grade 2 or greater late GI toxic effects. Declines in PSA level to less than 0.5 ng/mL occurred by 36 months in both study arms. No PSA relapses occurred in favorable intermediate-risk disease, while in the unfavorable category, the actuarial 4-year PSA relapse-free survival values were 75.0% vs 64.0% (HR, 0.76; 90% CI, 0.17-3.31) for SBRT vs SDRT, respectively. The EPIC-26 median summary scores for the genitourinary and GI domains dropped transiently at 1 month and returned to pretreatment scores by 3 months in both arms. The IPSS-derived transient late urinary flare symptoms occurred at 9 to 18 months in 20% (90% CI, 3%-37%) of patients receiving SDRT. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial among patients with intermediate-risk prostate cancer, SDRT was safe and associated with low toxicity, and the tumor control and quality-of-life end points closely match the SBRT arm outcomes. Further studies are encouraged to explore indications for SDRT in the cure of prostate cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02570919.

Target motion mitigation promotes high-precision treatment planning and delivery of extreme hypofractionated prostate cancer radiotherapy: Results from a phase II study.

BACKGROUND AND PURPOSE: While favourable long-term outcomes have been reported in organ-confined prostate cancer treated with 5 × 7-8 Gy extreme hypofractionation, dose escalation to 5 × 9-10 Gy improved local control but was associated with unacceptable rates of late rectal and urinary toxicities. The purpose of this study was to explore the feasibility of intra-fractional prostate immobilization in reducing toxicity, to promote dose escalation with extreme hypofractionated radiotherapy in prostate cancer. MATERIAL AND METHODS: 207 patients received 5 consecutive fractions of 9 Gy. An air-inflated (150 cm3) endorectal balloon and an intraurethral Foley catheter with 3 beacon transponders were used to immobilize the prostate and monitor intra-fractional target motion. VMAT-IGRT with inverse dose-painting was employed in delivering the PTV dose and in sculpting exposure of normal organs at risk to fulfil dose-volume constraints. RESULTS: Introduction of air-filled balloon induced repeatable rectum/prostate complex migration from its resting position to a specific retropubic niche, affording the same 3D anatomical configuration daily. Intra-fractional target deviations ≤1 mm occurred in 95% of sessions, while target realignment in ≥2 mm deviations enabled treatment completion as scheduled. Nadir PSA at median 54 months follow-up was 0.19 ng/mL, and bRFS was 100%, 92.4% and 71.4% in low-, intermediate- and high-risk categories, respectively. Late Grade 2 GU and GI toxicities were 2.9% and 2.4%, respectively. No adverse changes in patient-reported quality of life scores were observed. CONCLUSION: The unique spatial configuration of this prostate motion mitigation protocol enabled precise treatment planning and delivery that optimized outcomes of ultra-high 5 × 9 Gy hypofractionated radiotherapy of organ-confined prostate cancer.

The evolving role of external beam radiotherapy in localized prostate cancer.

Primary organ-confined prostate cancer is curable with external-beam radiotherapy. However, prostate cancer expresses a unique radiobiological phenotype, and its ablation requires doses at the high-end range of clinical radiotherapy. At this dose level, normal tissue radiosensitivity restricts the application of curative treatment, and mandates the use of the most advanced high-precision treatment delivery techniques to spare critical organs at risk. The efficacy and tolerance of dose-escalated conventional fractionated radiotherapy and of the biological equivalent doses of moderate and extreme hypofractionation are reviewed. Current studies indicate that novel risk-adapted techniques to spare normal organs at risk are still required to deploy high-biological equivalent dose extreme hypofractionation, while affording preservation of quality of life and cost-effectiveness.

Phenotype-Oriented Ablation of Oligometastatic Cancer with Single Dose Radiation Therapy.

PURPOSE: The current oligometastatic (OM) model postulates that the disease evolves dynamically with sequential emergence of OM (SOM) lesions requiring successive rounds of SOM ablation to afford tumor cure. The present phase 2 study explores the ablative efficacy of 24 Gy single-dose radiation therapy (SDRT), its feasibility in diverse OM settings, and the impact of radioablation on polymetastatic (PM) dissemination. METHODS AND MATERIALS: One hundred seventy-five consecutive patients with 566 OM or SOM lesions underwent periodic positron emission tomography/computed tomography (PET/CT) imaging to stage the disease before treatment, determine tumor response, and monitor timing of PM conversion after SDRT. When 24 Gy SDRT was restricted by dose or volume constraints of serial normal organs, radioablation was diverted to a nontoxic 3×9 Gy SBRT schedule. RESULTS: SOM/SOMA occurred in 42% of the patients, and 24 Gy SDRT was feasible in 76% of the lesions. Despite 92% actuarial 5-year OM ablation by 24 Gy SDRT, respective PM-free survival (PMFS) was 26%, indicating PM conversion dominates over effective OM radioablation in many patients. Multivariate analysis of OM metrics derived from staging PET/CT scanning before first treatment predicted PMFS outcome after SDRT. Bivariate analysis of dichotomized high versus low baseline metric combinations of CT-derived tumor load (cutoff at 14.8 cm3) and PET-derived metabolic SUVmax (cutoff at 6.5) yielded a 3-tiered PMFS categorization of 89%, 58% and 17% actuarial 5-year PMFS in categories 1, 2, and 3, respectively (P < .001), defining OM disease as a syndrome of diverse clinical and prognostic phenotypes. CONCLUSION: Long-term risk of PM dissemination, predicted by preablation PET/CT staging, provides guidelines for phenotype-oriented OM therapy. In categories 1 and 2, radioablation should be a primary therapeutic element when pursuing tumor cure, whereas in the PM-prone category 3, radioablation should be a component of multimodal trials addressing primarily the risk of PM dissemination. PET/CT baseline staging also provides a platform for discovery of pharmacologically accessible PM drivers as targets for new phenotype-oriented treatment protocols.

Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer.

Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

In silico comparison of photons versus carbon ions in single fraction therapy of lung cancer.

PURPOSE: Stereotactic body image guided radiation therapy (SBRT) shows good results for lung cancer treatment. Better normal tissue sparing might be achieved with scanned carbon ion therapy (PT). Therefore an in silico trial was conducted to find potential advantages of and patients suited for PT. METHODS: For 19 patients treated with SBRT, PT plans were calculated on 4D-CTs with simulated breathing motion. Prescribed single fraction dose was 24Gy and OAR constraints used for photon planning were respected. Motion was mitigated by rescanning and range-adapted ITVs. Doses were compared to the original SBRT plans. RESULTS: CTV coverage was the same in SBRT and PT. The field-specific PTV including range margins for PT was 1.5 (median, 25-75% 1.3-2.1) times larger than for SBRT. Nevertheless, maximum point dose and mean dose in OARs were higher in SBRT by 2.8 (1.6-3.7) Gy and 0.7 (0.3-1.6) Gy, respectively. Patients with a CTV >2.5cc or with multiple lung lesions showed larger differences in OAR doses in favor of PT. CONCLUSIONS: Patients receive less dose in critical OARs such as heart, spinal cord, esophagus, trachea and aorta with PT, while maintaining the same target coverage. Patients with multiple or larger lesions are particularly suited for PT.

Spinal metastases: From conventional fractionated radiotherapy to single-dose SBRT.

AIM: To review the recent evolution of spine SBRT with emphasis on single dose treatments. BACKGROUND: Radiation treatment of spine metastases represents a challenging problem in clinical oncology, because of the high risk of inflicting damage to the spinal cord. While conventional fractionated radiation therapy still constitutes the most commonly used modality for palliative treatment, notwithstanding its efficacy in terms of palliation of pain, local tumor control has been approximately 60%. This limited effectiveness is due to previous lack of technology to precisely target the tumor while avoiding the radiosensitive spinal cord, which constitutes a dose-limiting barrier to tumor cure. MATERIALS AND METHODS: A thorough review of the available literature on spine SBRT has been carried out and critically assessed. RESULTS: Stereotactic body radiotherapy (SBRT) emerges as an alternative, non-invasive high-precision approach, which allows escalation of tumor dose, while effectively sparing adjacent uninvolved organs at risk. Engaging technological advances, such as on-line Cone Beam Computed Tomography (CBCT), coupled with Dynamic Multi-Leaf Collimation (DMLC) and rapid intensity-modulated (IMRT) beam delivery, have promoted an interactive image-guided (IGRT) approach that precisely conforms treatment onto a defined target volume with a rapid dose fall-off to collateral non-target tissues, such as the spinal cord. Recent technological developments allow the use of the high-dose per fraction mode of hypofractionated SBRT for spinal oligometastatic cancer, even if only a few millimeters away from the tumor. CONCLUSION: Single-dose spine SBRT, now increasingly implemented, yields unprecedented outcomes of local tumor ablation and safety, provided that advanced technology is employed.

Information for decision making by patients with early-stage prostate cancer: a comparison across 9 countries.

PURPOSE: To describe decisional roles of patients with early-stage prostate cancer in 9 countries and to compare the information they rated important for decision making (DM). METHOD: A survey of recently treated patients was conducted in Canada, Italy, England, Germany, Poland, Portugal, Netherlands, Spain, and Turkey. Participants indicated their decisional role in their actual decision and the role they would prefer now. Each participant also rated (essential/desired/no opinion/avoid) the importance of obtaining answers, between diagnosis and treatment decision, to each of 92 questions. For each essential/desired question, participants specified all purposes for that information (to help them: understand/decide/plan/not sure/other). RESULTS: A total of 659 patients participated with country-specific response rates between 58%-77%. Between 83%-96% of each country's participants recalled actually taking an active decisional role and, in most countries, that increased slightly if they were to make the decision today; there were no significant differences among countries. There was a small reliable difference in the mean number of questions rated essential for DM across countries. More striking, however, was the wide variability within each country: no question was rated essential for DM by even 50% of its participants but almost every question was rated essential by some. CONCLUSIONS: Almost all participants from each country want to participate in their treatment decisions. Although there are country-specific differences in the amount of information required, wide variation within each country suggests that information that patients feel is essential or desired for DM should be addressed on an individual basis in all countries.

Information needs of early-stage prostate cancer patients: a comparison of nine countries.

BACKGROUND AND PURPOSE: Providing information to patients can improve their medical and psychological outcomes. We sought to identify core information needs common to most early-stage prostate cancer patients in participating countries. MATERIAL AND METHODS: Convenience samples of patients treated 3-24 months earlier were surveyed in Canada, England, Italy, Germany, Poland, Portugal, Netherlands, Spain, and Turkey. Each participant rated the importance of addressing each of 92 questions in the diagnosis-to-treatment decision interval (essential/desired/no opinion/avoid). Multivariate modelling determined the extent of variance accounted by covariates, and produced an unbiased prediction of the proportion of essential responses for each question. RESULTS: Six hundred and fifty-nine patients responded (response rates 45-77%). On average, 35-53 questions were essential within each country; similar questions were essential to most patients in most countries. Beyond cross-country similarities, each country showed wide variability in the number and which questions were essential. Multivariate modelling showed an adjusted R-squared with predictors country, age, education, and treatment group of only 6% of the variance. A core of 20 questions were predicted to be essential to >2/3 of patients. CONCLUSIONS: Core information can be identified across countries. However, providing the core should only be a first step; each country should then provide information tailored to the needs of the individual patient.

Gene expression profiling to predict outcome after chemoradiation in head and neck cancer.

PURPOSE: The goal of the present study was to improve prediction of outcome after chemoradiation in advanced head and neck cancer using gene expression analysis. MATERIALS AND METHODS: We collected 92 biopsies from untreated head and neck cancer patients subsequently given cisplatin-based chemoradiation (RADPLAT) for advanced squamous cell carcinomas (HNSCC). After RNA extraction and labeling, we performed dye swap experiments using 35k oligo-microarrays. Supervised analyses were performed to create classifiers to predict locoregional control and disease recurrence. Published gene sets with prognostic value in other studies were also tested. RESULTS: Using supervised classification on the whole series, gene sets separating good and poor outcome could be found for all end points. However, when splitting tumors into training and validation groups, no robust classifiers could be found. Using Gene Set Enrichment analysis, several gene sets were found to be enriched in locoregional recurrences, although with high false-discovery rates. Previously published signatures for radiosensitivity, hypoxia, proliferation, "wound," stem cells, and chromosomal instability were not significantly correlated with outcome. However, a recently published signature for HNSCC defining a "high-risk" group was shown to be predictive for locoregional control in our dataset. CONCLUSION: Gene sets can be found with predictive potential for locoregional control after combined radiation and chemotherapy in HNSCC. How treatment-specific these gene sets are needs further study.

Heterogeneity of gene expression profiles in head and neck cancer.

BACKGROUND: Results of gene expression profiling studies from different institutes often lack consistency. This could be due to the use of different microarray platforms and protocols, or to intratumoral heterogeneity in mRNA expression. The aim of our study was to quantify intratumoral heterogeneity in head and neck cancer. METHODS: Forty-four fresh frozen biopsies were taken from 22 patients, 2 per tumor. RNA was extracted, tested for quality, amplified, labeled, and hybridized to a 35k oligoarray. RESULTS: Unsupervised clustering analyses using all genes, the most variable genes, or random gene sets showed that 80% to 90% of biopsy pairs clustered together. A within-pair-between-pair scatter ratio analysis showed that the similarity between matching pairs was significantly greater than that between random pairs (p <.00001). CONCLUSIONS: Two biopsies from the same tumor show far greater similarity in gene expression than biopsies from different tumors, supporting the use of 1 biopsy for expression profiling.

New evidence of shared dinosaur across Upper Jurassic Proto-North Atlantic: Stegosaurus from Portugal.

More than one century after its original description by Marsh in 1877, we report in this paper the first uncontroversial evidence of a member of the genus Stegosaurus out of North America. The specimen consists of a partial skeleton from the Upper Jurassic of Portugal, herein considered as Stegosaurus cf. ungulatus. The presence of this plated dinosaur in the upper Kimmeridgian-lower Tithonian Portuguese record and synchronic levels of the Morrison Formation of North America reinforces previous hypothesis of a close relationship between these two areas during the Late Jurassic. This relationship is also supported by geotectonic evidences indicating high probability of an episodic corridor between the Newfoundland and Iberian landmasses. Together, Portuguese Stegosaurus discovery and geotectonic inferences could provide a scenario with episodical faunal contact among North Atlantic landmasses during the uppermost Kimmeridgian-lowermost Tithonian (ca. 148-153 Ma ago).

Low-dose hyperradiosensitivity of human glioblastoma cell lines in vitro does not translate into improved outcome of ultrafractionated radiotherapy in vivo.

PURPOSE: Low dose hyperradiosensitivity (HRS) has been observed in HGL21- and T98G human glioblastoma cells in vitro. The present study investigates whether these effects translate into improved outcome of ultrafractionated irradiation (UF) in vivo. MATERIAL AND METHODS: T98G or HGL21 were transplanted on the hind leg of nude mice. Tumours were irradiated with UF (3 fractions of 0.4 Gy per day, interval 4 h, 7 days per week) or with conventional fractionation (CF; 1 fraction of 1.68 Gy per day, 5 days per week) over 2 or 4 weeks in HGL21 and 2,4 or 6 weeks in T98G. In HGL21, graded top-up doses under clamped hypoxia were applied after 4 weeks of fractionated irradiation. Additional groups of animals were irradiated with single doses under clamp hypoxic conditions with or without whole body irradiation (WBI) before tumour transplantation. Experimental endpoints were growth delay (time to 5-fold starting volume, GD(V5)) and local tumour control. RESULTS: In T98G tumours median relative GD(V5) was 1.2 [95% C.I. 0.96; 8] in the CF and 0.8 [0.7; 1.02] in the UF arm (p = 0.009) indicating that ultrafractionation is less efficient than conventional fractionation. The TCD50 value of 33.5 Gy [22; 45] after UF was higher than TCD50 of 23.6 Gy [16; 31] after CF (p = 0.15). In HGL21 the median relative GD(V5) was not significantly different between CF and UF. The top-up TCD50 value of 16.1 Gy [95% C.I. 9; 23 Gy] after CF was significantly lower than the corresponding value of 33.2 Gy [23; 44] after UF irradiation (p = 0.007), indicating a higher efficacy of CF compared to UF. CONCLUSION: The results on human T98G and HGL21 glioblastoma do not support the hypothesis that HRS in vitro translates into improved outcome of ultrafractionated irradiation in vivo.