Proton FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases: The FAST-01 Nonrandomized Trial.

Importance: To our knowledge, there have been no clinical trials of ultra-high-dose-rate radiotherapy delivered at more than 40 Gy/sec, known as FLASH therapy, nor first-in-human use of proton FLASH. Objectives: To assess the clinical workflow feasibility and treatment-related toxic effects of FLASH and pain relief at the treatment sites. Design, Setting, and Participants: In the FAST-01 nonrandomized trial, participants treated at Cincinnati Children's/UC Health Proton Therapy Center underwent palliative FLASH radiotherapy to extremity bone metastases. Patients 18 years and older with 1 to 3 painful extremity bone metastases and life expectancies of 2 months or more were eligible. Patients were excluded if they had foot, hand, and wrist metastases; metastases locally treated in the 2 weeks prior; metal implants in the treatment field; known enhanced tissue radiosensitivity; and implanted devices at risk of malfunction with radiotherapy. One of 11 patients who consented was excluded based on eligibility. The end points were evaluated at 3 months posttreatment, and patients were followed up through death or loss to follow-up for toxic effects and pain assessments. Of the 10 included patients, 2 died after the 2-month follow-up but before the 3-month follow-up; 8 participants completed the 3-month evaluation. Data were collected from November 3, 2020, to January 28, 2022, and analyzed from January 28, 2022, to September 1, 2022. Interventions: Bone metastases were treated on a FLASH-enabled (≥40 Gy/sec) proton radiotherapy system using a single-transmission proton beam. This is consistent with standard of care using the same prescription (8 Gy in a single fraction) but on a conventional-dose-rate (approximately 0.03 Gy/sec) photon radiotherapy system. Main Outcome and Measures: Main outcomes included patient time on the treatment couch, device-related treatment delays, adverse events related to FLASH, patient-reported pain scores, and analgesic use. Results: A total of 10 patients (age range, 27-81 years [median age, 63 years]; 5 [50%] male) underwent FLASH radiotherapy at 12 metastatic sites. There were no FLASH-related technical issues or delays. The average (range) time on the treatment couch was 18.9 (11-33) minutes per patient and 15.8 (11-22) minutes per treatment site. Median (range) follow-up was 4.8 (2.3-13.0) months. Adverse events were mild and consistent with conventional radiotherapy. Transient pain flares occurred in 4 of the 12 treated sites (33%). In 8 of the 12 sites (67%) patients reported pain relief, and in 6 of the 12 sites (50%) patients reported a complete response (no pain). Conclusions and Relevance: In this nonrandomized trial, clinical workflow metrics, treatment efficacy, and safety data demonstrated that ultra-high-dose-rate proton FLASH radiotherapy was clinically feasible. The treatment efficacy and the profile of adverse events were comparable with those of standard-of-care radiotherapy. These findings support the further exploration of FLASH radiotherapy in patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT04592887.

FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases (FAST-01): Protocol for the First Prospective Feasibility Study.

BACKGROUND: In preclinical studies, FLASH therapy, in which radiation delivered at ultrahigh dose rates of ≥40 Gy per second, has been shown to cause less injury to normal tissues than radiotherapy delivered at conventional dose rates. This paper describes the protocol for the first-in-human clinical investigation of proton FLASH therapy. OBJECTIVE: FAST-01 is a prospective, single-center trial designed to assess the workflow feasibility, toxicity, and efficacy of FLASH therapy for the treatment of painful bone metastases in the extremities. METHODS: Following informed consent, 10 subjects aged ≥18 years with up to 3 painful bone metastases in the extremities (excluding the feet, hands, and wrists) will be enrolled. A treatment field selected from a predefined library of plans with fixed field sizes (from 7.5 cm × 7.5 cm up to 7.5 cm × 20 cm) will be used for treatment. Subjects will receive 8 Gy of radiation in a single fraction-a well-established palliative regimen evaluated in prior investigations using conventional dose rate photon radiotherapy. A FLASH-enabled Varian ProBeam proton therapy unit will be used to deliver treatment to the target volume at a dose rate of ≥40 Gy per second, using the plateau (transmission) portion of the proton beam. After treatment, subjects will be assessed for pain response as well as any adverse effects of FLASH radiation. The primary end points include assessing the workflow feasibility and toxicity of FLASH treatment. The secondary end point is pain response at the treated site(s), as measured by patient-reported pain scores, the use of pain medication, and any flare in bone pain after treatment. The results will be compared to those reported historically for conventional dose rate photon radiotherapy, using the same radiation dose and fractionation. RESULTS: FAST-01 opened to enrollment on November 3, 2020. Initial results are expected to be published in 2022. CONCLUSIONS: The results of this investigation will contribute to further developing and optimizing the FLASH-enabled ProBeam proton therapy system workflow. The pain response and toxicity data acquired in our study will provide a greater understanding of FLASH treatment effects on tumor responses and normal tissue toxicities, and they will inform future FLASH trial designs. TRIAL REGISTRATION: : ClinicalTrials.gov NCT04592887; http://clinicaltrials.gov/ct2/show/NCT04592887. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41812.

Evaluating Proton Dose and Associated Range Uncertainty Using Daily Cone-Beam CT.

Purpose: This study aimed to quantitatively evaluate the range uncertainties that arise from daily cone-beam CT (CBCT) images for proton dose calculation compared to CT using a measurement-based technique. Methods: For head and thorax phantoms, wedge-shaped intensity-modulated proton therapy (IMPT) treatment plans were created such that the gradient of the wedge intersected and was measured with a 2D ion chamber array. The measured 2D dose distributions were compared with 2D dose planes extracted from the dose distributions using the IMPT plan calculated on CT and CBCT. Treatment plans of a thymoma cancer patient treated with breath-hold (BH) IMPT were recalculated on 28 CBCTs and 9 CTs, and the resulting dose distributions were compared. Results: The range uncertainties for the head phantom were determined to be 1.2% with CBCT, compared to 0.5% for CT, whereas the range uncertainties for the thorax phantom were 2.1% with CBCT, compared to 0.8% for CT. The doses calculated on CBCT and CT were similar with similar anatomy changes. For the thymoma patient, the primary source of anatomy change was the BH uncertainty, which could be up to 8 mm in the superior-inferior (SI) direction. Conclusion: We developed a measurement-based range uncertainty evaluation method with high sensitivity and used it to validate the accuracy of CBCT-based range and dose calculation. Our study demonstrated that the CBCT-based dose calculation could be used for daily dose validation in selected proton patients.

A Prospective Study of a Resorbable Intravesical Fiducial Marker for Bladder Cancer Radiation Therapy.

Purpose: We conducted a prospective pilot study to evaluate safety and feasibility of TraceIT, a resorbable radiopaque hydrogel, to improve image guidance for bladder cancer radiation therapy (RT). Methods and Materials: Patients with muscle invasive bladder cancer receiving definitive RT were eligible. TraceIT was injected intravesically around the tumor bed during maximal transurethral resection of bladder tumor. The primary endpoint was the difference between radiation treatment planning margin on daily cone beam computed tomography based on alignment to TraceIT versus standard-of-care pelvic bone anatomy. The Van Herk margin formula was used to determine the optimal planning target volume margin. TraceIT visibility, recurrence rates, and survival were estimated by Kaplan-Meier method. Toxicity was measured by Common Terminology Criteria for Adverse Events version 4.03. Results: The trial was fully accrued and 15 patients were analyzed. TraceIT was injected in 4 sites/patient (range, 4-6). Overall, 94% (95% confidence interval [CI], 90%-98%) of injection sites were radiographically visible at RT initiation versus 71% (95% CI, 62%-81%) at RT completion. The median duration of radiographic visibility for injection sites was 106 days (95% CI, 104-113). Most patients were treated with a standard split-course approach with initial pelvic radiation fields, then midcourse repeat transurethral resection of bladder tumor followed by bladder tumor bed boost fields, and 14/15 received concurrent chemotherapy. Alignment to fiducials could allow for reduced planning target volume margins (0.67 vs 1.56 cm) for the initial phase of RT, but not for the boost (1.01 vs 0.96 cm). This allowed for improved target coverage (D95% 80%-83% to 91%-94%) for 2 patients retrospectively planned with both volumetric-modulated arc therapy and 3-dimensional conformal RT. At median follow-up of 22 months, no acute or late complications attributable to TraceIT placement occurred. No patients required salvage cystectomy. Conclusions: TraceIT intravesical fiducial placement is safe and feasible and may facilitate tumor bed delineation and targeting in patients undergoing RT for localized muscle invasive bladder cancer. Improved image guided treatment may facilitate strategies to improve local control and minimize toxicity.

Patterns and Predictors of First-Line Taxane Use in Patients with Metastatic Triple-Negative Breast Cancer in US Clinical Practice.

We investigated first-line (1L) treatment patterns and predictors of taxane use to better understand the evolving metastatic triple-negative breast cancer (mTNBC) treatment landscape. This retrospective analysis of the Truven Health MarketScan® (Somers, NY, USA) Database included women with mTNBC who received 1L therapy within six months of diagnosis (January 2005-June 2015). Multivariate logistic regression models identified predictors of taxane use, adjusting for prognostic factors. A total of 2,271 women with newly diagnosed mTNBC received 1L treatment during the study period. Half received a 1L taxane (53%), more often in combination than as monotherapy (58% versus 42%), though this varied by specific taxane. Nab-Paclitaxel monotherapy increased substantially after 2010. More recent treatment year (odds ratio, 2.16 (95% CI 1.69-2.76]) and number of metastases (≥3 versus 1: 1.73 (1.25-2.40)) predicted taxane monotherapy versus combination. Having a health maintenance organization versus a preferred provider organization plan predicted less nab-paclitaxel versus paclitaxel (0.32 (0.13-0.80)) or docetaxel (0.30 (0.10-0.89)) use. More recent index year (2011-2015 vs 2005-2010) was the only predictor favoring nab-paclitaxel versus paclitaxel (2.01 (1.26-3.21)) or docetaxel (3.63 (2.11-6.26)). Taxane-containing regimens remained the most common 1L mTNBC treatments. Paclitaxel and nab-paclitaxel use changed substantially over time, with nab-paclitaxel use associated with insurance coverage.

High-grade serous peritoneal cancer follows a high stromal response signature and shows worse outcome than ovarian cancer.

In the era of personalized medicine, where transition from organ-based to individualized genetic diagnosis takes place, the tailoring of treatment in cancer becomes increasingly important. This is particularly true for high-grade, advanced FIGO stage serous adenocarcinomas of the ovary (OC), fallopian tube (TC), and peritoneum (PC), which are currently all treated identically. We analyzed three independent patient cohorts using histopathologically classified diagnosis and various molecular approaches (transcriptomics, immunohistochemistry, next-generation sequencing, fluorescent and chromogenic in situ hybridization). Using multivariate Cox regression model, we found that PC is more aggressive compared with advanced-stage OC independent of residual disease as shown by an earlier relapse-free survival in two large cohorts (HR: 2.63, CI: 1.59-4.37, P < 0.001, and HR: 1.66, CI: 1.04-2.63, P < 0.033). In line with these findings, transcriptomic data revealed differentially expressed gene signatures identifying PC as high stromal response tumors. The third independent cohort (n = 4054) showed a distinction between these cancer types for markers suggested to be predictive for chemotherapy drug response. Our findings add additional evidence that ovarian and peritoneal cancers are epidemiologically and molecularly distinct diseases. Moreover, our data also suggest consideration of the tumor-sampling site for future diagnosis and treatment decisions.

Rectal Hydrogel Spacer Improves Late Gastrointestinal Toxicity Compared to Rectal Balloon Immobilization After Proton Beam Radiation Therapy for Localized Prostate Cancer: A Retrospective Observational Study.

PURPOSE: Our purpose was to compare dosimetric parameters and late gastrointestinal outcomes between patients treated with proton beam therapy (PBT) for localized prostate cancer with rectal balloon immobilization versus a hydrogel rectal spacer. METHODS AND MATERIALS: Patients with localized, clinical stage T1-4 prostate adenocarcinoma were treated at a single institution using conventionally fractionated, dose-escalated PBT from 2013 to 2018. Patient-reported gastrointestinal toxicity was prospectively collected, and the incidence of rectal bleeding was retrospectively reviewed from patient records. RESULTS: One hundred ninety-two patients were treated with rectal balloon immobilization, and 75 were treated with a rectal spacer. Rectal hydrogel spacer significantly improved rectal dosimetry while maintaining excellent target coverage. The 2-year actuarial rate of grade 2+ late rectal bleeding was 19% and 3% in the rectal balloon and hydrogel spacer groups, respectively (P = .003). In univariable analysis, the probability of grade 2+ rectal bleeding was significantly correlated with increasing rectal dose. In multivariable analysis, only receipt of spacer hydrogel (hazard ratio, 0.145; P = .010) and anticoagulation use (hazard ratio, 5.019; P < .001) were significantly associated with grade 2+ bleeding. At 2-year follow-up, patient-reported Expanded Prostate Cancer Index Composite bowel quality of life composite scores were less diminished in the hydrogel spacer group (absolute mean difference, 5.5; P = .030). CONCLUSIONS: Use of rectal hydrogel spacer for prostate PBT is associated with a significantly lower incidence of clinically relevant, late rectal bleeding and lower decrement in long-term, patient-reported bowel quality of life compared with rectal balloon immobilization. Our results suggest that hydrogel spacer may improve rectal sparing compared with rectal balloon immobilization during PBT for prostate cancer.

Should MMMT still be treated with adjuvant taxane-based combination chemotherapy?

BACKGROUND: Malignant mixed Mullerian tumors of endometrial (MMMT-E) and ovarian (MMMT-O) origin are associated with poor prognosis. Suggestively epithelial-driven tumors, their treatment has shifted from anthracycline or ifosfamide-based towards taxane-based chemotherapy. It remains unclear whether this change associates with better outcomes. PATIENTS AND METHODS: A conjoined Australian and Swiss patient cohort of MMMT-E (N = 103) and MMMT-O (N = 17) was compared to patients with adenocarcinoma of the endometrium (EC, N = 172) and ovary (OC, N = 189). Clinicopathological characteristics, FIGO stage, first-line treatment, and patient outcomes were analyzed. The generated hypothesis was verified in an US-American cohort with high-grade serous ovarian cancer (HGSOC, N = 1290) and MMMT-O (N = 450) using immunohistochemistry and next-generation sequencing. RESULTS: Early stage I/II MMMT-E showed a survival plateau after 2.5 years, with no recurrence or death observed afterwards. Relapse-free survival was significantly worse in MMMT-E treated with platinum/taxanes (P = 0.024) compared to non-taxane regimen. Hypothesizing that also MMMT-O might benefit from an adjuvant non-paclitaxel regimen, a second independent cohort of MMMT-O and HGSOC patients was examined. p53 mutations dominated in both cancers with comparable frequency. PI3KCA and KRAS mutations were less frequent: they were more frequent in MMMT-O than in HGSOC (P = 0.015 and P = 0.018, respectively). MMMT-O responded better to a combination of carboplatin with anthracyclines than with taxanes (73.9% vs. 39.4%). CONCLUSION: Early stage I/II MMMT-E patients have excellent prognosis if no recurrence has appeared within the first 2.5 years. In MMMT-E, platinum/anthracycline or ifosfamide regimen associated with better outcomes than platinum/taxanes regimens. This might also apply to MMMT-O.

Impact of Double- or Triple-Hit Pathology on Rates and Durability of Radiation Therapy Response Among Patients With Relapsed or Refractory Large B-Cell Lymphoma.

PURPOSE: Double-hit lymphomas and triple-hit lymphomas (DHL/THL), also known as high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, are associated with chemoresistance and inferior survival. However, whether radiation therapy (RT) efficacy is altered in DHL/THL is less well characterized. Among patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), we compared rates and durability of response between patients with and without DHL/THL. METHODS AND MATERIALS: We retrospectively reviewed consecutive R/R LBCL patients who were irradiated at a single institution from January 2008 to June 2017. Patients in whom c-MYC rearranged status was known were evaluated for response to RT, in-field control, progression-free, and overall survival. RESULTS: Among 245 irradiated patients with LBCL, 41 patients with confirmed c-MYC status were treated for R/R disease (14 DHL/THL, 27 non-DHL/THL) and formed our cohort. Compared with non-DHL/THL, more DHL/THL patients had progressive disease at RT (71% vs 48%), had larger gross tumor volumes (GTV; median 696 mL vs 117 mL), and were treated with palliative intent (71% vs 41%). Despite similar RT doses (median 35 Gy), radiographic complete response rate was lower among DHL/THL patients: 14.3% versus 64.7% (P = .01). With a median 2 years of follow-up, one in-field failure was observed in each group. DHL/THL patients had inferior progression-free survival (7% vs 46%; P = .02) and overall survival (14% vs 68%; P = .03) at 6 months. CONCLUSIONS: R/R LBCL is responsive to RT, although rates of response are lower among DHL/THL patients. Given poor survival after RT, in-field control was hard to evaluate in this cohort. Larger cohorts are required to better elucidate whether differences in response rates are driven by larger disease burden at RT versus tumor biology. These findings are of increasing pertinence in light of use of RT as bridging therapy to cellular immunotherapies.

Polyunsaturated fatty acid food frequency questionnaire validation in people with end stage renal disease on dialysis.

AIM: To validate the polyunsaturated food frequency questionnaire (PUFA FFQ) and test for reproducibility in people with end stage renal disease on dialysis treatment. METHODS: Participants (n = 32) completed the PUFA FFQ and three 24-hour recalls. Erythrocyte samples (n = 29) were used for erythrocyte fatty acid analysis. The triangular relationship between the PUFA FFQ, 24-hour recalls and the biomarker was assessed using the method of triads. Agreement between the two dietary methods was also assessed using Bland-Altman plots and classification by quintiles. Reproducibility was tested on a subset of the group (n = 8). RESULTS: The PUFA FFQ was a valid measure of all PUFA except for docosapentaenoic acid (DPA) and arachidonic acid (AA). Strong validity coefficients were found for n-3 long-chain PUFA (LCPUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of 0.914 (95% CI: 0.665, 0.997) and 0.889 (95% CI: 0.706, 0.994), respectively. In the Bland-Altman plots 91-100% of observations fell between the limits of agreement for all PUFA. There were significant correlations between the initial FFQ and the repeat FFQ for all PUFA except DPA and AA. CONCLUSIONS: The PUFA FFQ is a valid tool for assessing PUFA intake in people with end stage renal disease.

A prospective evaluation of whole brain volume loss and neurocognitive decline following hippocampal-sparing prophylactic cranial irradiation for limited-stage small-cell lung cancer.

INTRODUCTION: This study evaluated an association between whole brain volume loss and neurocognitive decline following prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC). METHODS: This was a secondary analysis of a prospective clinical trial that accrued patients at a single institution from 2013 to 2016. Patients with limited-stage SCLC treated with standard chemo-radiation received PCI 25 Gy/10 fractions, with mean hippocampal dose limited to < 8 Gy. Whole brain volumes were measured using MR imaging obtained before and at 6, 12, 18, and 24 months after PCI. Verbal memory was measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) before and at 6 and 12 months after PCI. Univariate and multivariate linear regression evaluated associations between changes in whole brain volume and verbal memory. RESULTS: Twenty-two patients enrolled. The median whole brain volume before PCI was 1301 mL. Subsequent reduction in whole brain volume was greatest at 18 months after PCI (median change - 23 mL, range - 142 to 20, p = 0.03). At 6 months after PCI, reduction in volume was independently associated with decline in verbal memory, measured by two components of the HVLT-R (Delayed Recall: 0.06/mL volume change, p = 0.046; Percent Retained: 0.66/mL volume change, p = 0.030), when controlling for education and global cognitive function at baseline. CONCLUSION: This is the first study to correlate reduction in whole brain volume and decline in neurocognitive function following whole brain radiation therapy (WBRT). This suggests that loss of brain volume after WBRT may be clinically significant and subsequently impact cognition and quality of life.

Analysis of Gastrointestinal Toxicity in Patients Receiving Proton Beam Therapy for Prostate Cancer: A Single-Institution Experience.

PURPOSE: We characterized both physician- and patient-reported rates of gastrointestinal (GI) toxicity in patients treated with proton beam therapy (PBT) at our institution for prostate adenocarcinoma and identified factors associated with toxicity. METHODS AND MATERIALS: We treated 192 patients with PBT between July 2013 and July 2016. Included patients had ≥1 year of follow-up. Potential preexisting clinical and treatment-related risk factors for GI toxicity were recorded. Common Terminology Criteria for Adverse Events version 4.0 was used to score toxicity. Expanded Prostate Cancer Index Composite (EPIC) bowel domain questionnaires assessed patient-reported quality of life. Associations between grade (GR) 2+ toxicity and clinical, treatment, and dosimetric factors were assessed using Cox models and corresponding hazard ratios. RESULTS: The median follow-up was 1.7 years. Most of the observed GI toxicity (>90%) was in the form of rectal bleeding (RB). GR2+ GI toxicity and RB actuarial rates specifically at 2 years were 21.3% and 20.4%, respectively. GR3 toxicity was rare, with only 1 observed RB event. No GR4/5 toxicity was seen. The EPIC bowel domain median score was 96 (range, 61-100) pretreatment, 93 (range, 41-100) at 1 year, 89 (range, 57-100) at 1.5 years, and 89 (range, 50-100) at 2 years. Anticoagulation use was the only factor selected during multivariate analysis for predicting GR2+ RB, with a resulting concordance index of 0.59 (95% confidence interval, 0.48-0.68; P = .088). Type of proton technology (pencil beam scanning vs uniform scanning) and number of fields treated per day (1 vs 2) showed no significant difference in toxicity rate. CONCLUSIONS: PBT was associated with acceptable rates of GR2+ transient GI toxicity, mostly in the form of RB, which correlated with anticoagulation use. High EPIC bowel domain quality of life was maintained in the 2 years after treatment.

Early toxicity and patient reported quality-of-life in patients receiving proton therapy for localized prostate cancer: a single institutional review of prospectively recorded outcomes.

BACKGROUND: We report prospectively captured clinical toxicity and patient reported outcomes in a single institutional cohort of patients treated for prostate cancer with proton beam therapy (PBT). This is the largest reported series of patients treated mostly with pencil beam scanning PBT. METHODS: We reviewed 231 patients treated on an IRB approved institutional registry from 2013 to 2016; final analysis included 192 patients with > 1-year of follow-up. Toxicity incidence was prospectively captured and scored using CTCAE v4.0. International Prostate Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) score, and Expanded Prostate Cancer Index Composite (EPIC) bowel domain questionnaires were collected at each visit. Univariate Cox regression was used to explore associations of grade 2+ toxicity with clinical, treatment, and dosimetric variables. RESULTS: Median follow-up was 1.7 years. Grade 3 toxicity was seen in 5/192 patients. No grade 4 or 5 toxicity was seen. Patient reported quality-of-life showed no change in urinary function post-radiation by IPSS scores. Median SHIM scores declined by 3.7 points at 1-year post-treatment without further decrease beyond year 1. On univariate analysis, only younger age (HR = 0.61, p = 0.022) was associated with decreased sexual toxicity. EPIC bowel domain scores declined from 96 at baseline (median) by an average of 5.4 points at 1-year post-treatment (95% CI: 2.5-8.2 points, p < 0.001), with no further decrease over time. Bowel toxicity was mostly in the form of transient rectal bleeding and was associated with anticoagulation use (HR = 3.45, p = 0.002). CONCLUSIONS: Grade 3 or higher toxicity was rare at 2-years after treatment with PBT for localized prostate cancer. Longer follow-up is needed to further characterize late toxicity and biochemical control. TRIAL REGISTRATION: NCT, NCT01255748 . Registered 1 January 2013.

Biomarker-Driven Therapy in Metastatic Gastric and Esophageal Cancer: Real-Life Clinical Experience.

BACKGROUND: Precision treatment of cancer uses biomarker-driven therapy to individualize and optimize patient care. OBJECTIVE: To evaluate real-life clinical experience with biomarker-driven therapy in metastatic gastric and esophageal cancer in Israel. PATIENTS AND METHODS: This multicenter retrospective cohort study included patients with metastatic gastric or esophageal cancer who were treated in the participating institutions and underwent biomarker-driven therapy. Treatment was considered to have a benefit if the ratio between the longest progression-free survival (PFS) post biomarker-driven therapy and the last PFS before the biomarker-driven therapy was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. RESULTS: The analysis included 46 patients (61% men; median age, 58 years; 57% with poorly-differentiated tumors). At least one actionable (i.e., predictive of response to a specific therapy) biomarker was identified for each patient. Immunohistochemistry was performed on all samples and identified 1-8 (median: 3) biomarkers per patient (most commonly: low TS, high TOPO1, high TOP2A). Twenty-eight patients received therapy after the biomarker analysis (1-4 lines). In the 1st line after biomarker analysis, five patients (18%) achieved a partial response and five (18%) stable disease; the median (range) PFS was 129 (12-1155) days. Twenty-four patients were evaluable for PFS ratio analysis; in seven (29.2%), the ratio was ≥1.3. In a one-sided exact binomial test vs. the null hypothesis, p = 0.019; therefore, the null hypothesis was rejected. CONCLUSIONS: Our findings demonstrated that implementing biomarker-driven analysis is feasible and could provide clinical benefit for a considerable proportion (~30%) of patients with metastatic gastric or esophageal cancer.

Dosimetric comparison of single-beam multi-arc and 2-beam multi-arc VMAT optimization in the Monaco treatment planning system.

The purpose of this study was to evaluate the dosimetric and practical effects of the Monaco treatment planning system "max arcs-per-beam" optimization parameter in pelvic radiotherapy treatments. We selected for this study a total of 17 previously treated patients with a range of pelvic disease sites including prostate (9), bladder (1), uterus (3), rectum (3), and cervix (1). For each patient, 2 plans were generated, one using an arc-per-beam setting of "1" and another with an arc-per-beam setting of "2" using the volumes and constraints established from the initial clinical treatments. All constraints and dose coverage objects were kept the same between plans, and all plans were normalized to 99.7% to ensure 100% of the planning target volume (PTV) received 95% of the prescription dose. Plans were evaluated for PTV conformity, homogeneity, number of monitor units, number of control points, and overall plan acceptability. Treatment delivery time, patient-specific quality assurance procedures, and the impact on clinical workflow were also assessed. We found that for complex-shaped target volumes (small central volumes with extending arms to cover nodal regions), the use of 2 arc-per-beam (2APB) parameter setting achieved significantly lower average dose-volume histogram values for the rectum V20 (p = 0.0012) and bladder V30 (p = 0.0036) while meeting the high dose target constraints. For simple PTV shapes, we found reduced monitor units (13.47%, p = 0.0009) and control points (8.77%, p = 0.0004) using 2APB planning. In addition, we found a beam delivery time reduction of approximately 25%. In summary, the dosimetric benefit, although moderate, was improved over a 1APB setting for complex PTV, and equivalent in other cases. The overall reduced delivery time suggests that the use of mulitple arcs per beam could lead to reduced patient-on-table time, increased clinical throughput, and reduced medical physics quality assurance effort.

Molecular Profiling of Clear Cell Ovarian Cancers: Identifying Potential Treatment Targets for Clinical Trials.

BACKGROUND: Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets. PATIENTS AND METHODS: Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis. RESULTS: The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%). CONCLUSIONS: This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.

Treatment of patients with refractory metastatic cancer according to molecular profiling on tumor tissue in the clinical routine: an interim-analysis of the ONCO-T-PROFILE project.

INTRODUCTION: Patients with refractory metastatic cancer have been shown to benefit from molecular profiling of tumor tissue. The ONCO-T-PROFILE project was launched in March 2014 at the Innsbruck Medical University. Within 2 years our project aims to recruit 110 patients with stage IV cancer refractory to standard therapy. Our data presented here are based on an interim-analysis. METHODS: Tumor tissue specimens were submitted for molecular profiling to the certified laboratory (Caris Life Science, USA). Druggable tumor targets were selected based on biomarker status to agents with potential clinical benefit. Clinical benefit was defined as a PFS ratio (=PFS upon treatment according to the molecular profile/ PFS upon the last prior therapy) ≥ 1.3. RESULTS: As of April 2015, tumors from 50 patients have been molecularly profiled and one or more targets were detectable in 48 specimens (98%). So far, 19 (38%) patients have been treated according to their molecular tumor profile. To date, 8 (42%) patients have reached a PFS ratio of ≥ 1.3. CONCLUSIONS: We could show that molecular profiling is feasible in the clinical routine. A proportion of patients might benefit from an individualized treatment approach based on molecular profiling. As a result, we will proceed to enroll patients in ONCO-T-PROFILE.

Information Needs of Men with Localized Prostate Cancer During Radiation Therapy.

The purpose of this study was to describe how patient information needs change over the course of receiving radiation therapy for prostate cancer. Convenience sampling was utilized to recruit men with stage I-III prostate cancer. A longitudinal repeated measures design was implemented for this pilot study. Patients were presented with 36 paired comparisons, each asking the participant to choose the most important information topic(s) for today. Following completion of the survey instruments, the clinic nurse delivered the four top-ranked information topic handouts to each patient with brief instruction on how to use the handouts. Over the course of 6 months, we were able to recruit 35 men. The four highest priority topics across all four sessions were prognosis, stage of disease, treatment options, and side effects. Our results suggest trends in the information priorities that men hold over the course of radiation treatment. The information priorities do appear to shift over time, notably prognosis concerns and risk for family members continued to rise over time, while side effect information declined. These findings will extend an already strong foundation of evidence for preparatory information in radiation therapy. Furthermore, these findings will strengthen current evidence that computerized assessment of patient self-report information is feasible and an important adjunct to clinical practice.