Standard Radiation Dose Research Articles

Do Higher Radiation Doses with Concurrent Chemotherapy in the Definitive Treatment of Esophageal Cancer Improve Outcomes? A Meta-Analysis and Systematic Review.

Background: To investigate the effects and safety profile of radiation dose escalation utilizing computerized tomography (CT) based radiotherapy techniques (including 3-Dimensional conformal radiotherapy, intensity-modulated radiotherapy and proton therapy) in the definitive treatment of patients with esophageal carcinoma (EC) with definitive concurrent chemoradiotherapy (dCCRT).Methods: All relevant studies utilizing CT-based radiation planning, comparing high-dose (≥ 60 Gy) versus standard-dose (50.4 Gy) radiation for patients with EC were analyzed for this meta-analysis.Results: Eleven studies including 4946 patients met the inclusion criteria, with 96.5% of patients diagnosed with esophageal squamous cell carcinoma (ESCC). The high-dose group demonstrated a significant improvement in local-regional failure (LRF) (OR 2.199, 95% CI 1.487-3.253; P<0.001), two-year local-regional control (LRC) (OR 0.478, 95% CI 0.309-0.740; P=0.001), two-year overall survival (OS) (HR 0.744, 95% CI 0.657-0.843; P<0.001) and five-year OS (HR 0.683, 95% CI 0.561-0.831; P<0.001) rates relative to the standard-dose group. In addition, there was no difference in grade ≥ 3 radiation-related toxicities and treatment-related deaths between the groups.Conclusion: Under the premise of controlling the rate of toxicities, doses of ≥ 60 Gy in CT-based dCCRT of ESCC patients might improve locoregional control and ultimate survival compared to the standard-dose dCCRT. While our review supports a dose-escalation approach in these patients, multiple ongoing randomized trial initial and final reports are awaited to evaluate the effectiveness of this strategy.

Prevalence of Fractures and Diagnostic Accuracy of Emergency X-ray in Older Adults Sustaining a Low-Energy Fall: A Retrospective Study.

Background: Plain radiography (XR) series are standard of care for detection of fall-related fractures in older patients with low-energy falls (LEF) in the emergency department (ED). We have investigated the prevalence of fractures and diagnostic accuracy of XR imaging in the ED. Methods: 2839 patients with LEF, who were presented to two urban level I trauma centers in 2016 and received XR and computed tomography (CT), were consecutively included in this retrospective cohort study. The primary endpoint was the prevalence of fractures of the vertebral column, rib cage, pelvic ring, and proximal long bones. Secondary endpoints were diagnostic accuracy of XR for fracture detection with CT as reference standard and cumulative radiation doses applied. Results: Median age was 82 years (range 65–105) with 64.1% female patients. Results revealed that 585/2839 (20.6%) patients sustained fractures and 452/2839 (15.9%) patients received subsequent XR and CT examinations of single body regions. Cross-tabulation analysis revealed sensitivity of XR of 49.7%, a positive likelihood ratio of 27.6, and negative likelihood ratio of 0.5. Conclusions: XR is of moderate diagnostic accuracy for ruling-out fractures of the spine, pelvic ring, and rib cage in older patients with LEF. Prospective validations are required to investigate the overall risk–benefit of direct CT imaging strategies, considering the trade-off between diagnostic safety, health care costs, and radiation exposure.

Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer.

RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively (P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.

Therapeutic Efficacy and Dosimetry of Targeted Alpha Therapy using 225Ac-PSMA-617 in a Murine Model of Prostate Cancer

Targeted alpha therapy shows promise as a treatment in metastatic castration-resistant prostate cancer (mCRPC), owing to the high dose deposition and short range characteristics of alpha particle radiation. Ac-225 decays via multiple alpha particles – each capable of inducing irreparable DNA double-strand breaks in cell nuclei. PSMA-617 is a targeting ligand with specific affinity for prostate-specific membrane antigen (PSMA), a protein that is overexpressed in mCRPC but has low expression in normal tissues. Coupled with the lethal effects of alpha radiation, 225Ac-PSMA-617 is potentially highly cytotoxic to mCRPC while sparing normal tissues. The objective of this study was to evaluate the efficacy of alpha-particle radioligand therapy in a mouse model of mCRPC. Radiation dosimetry analysis was carried out to determine tumor dose as well as dose-limiting organs. NSG mice bearing subcutaneous PSMA-expressing C4-2 tumors were injected with escalating activities of 225Ac-PSMA-617: 20, 40, and 100 kBq/mouse (n=8/group). The tumor volumes were assessed over time by weekly low-dose microCT and compared with an untreated control group. In parallel, twenty-five NSG mice were used in a biodistribution study at five time points – 1, 4, 24, 48, and 168 hours post-administration of 40 kBq of the radiopharmaceutical. After sacrifice, percent tumor and organ radioactivity uptake was measured using gamma spectroscopy. Biexponential curve-fitting was used to fit the time-activity curves for the tumor and each organ, and integrated according to standard medical internal radiation dose methods to estimate the tumor and organ doses. Significant tumor growth retardation was observed in all treatment groups compared with the untreated group. Mice treated with 100 kBq exhibited some weight loss, while the mice treated with lower activities experienced only transient weight loss. There was a significant survival benefit conferred on tumor-bearing mice treated with 225Ac-PSMA617. The biodistribution over five time points showed high uptake and slow tumor activity clearance, and low uptake with fast clearance in non-target organs. The salivary glands, a dose-limiting organ in humans, did not show high uptake in mice, possibly due to lower PSMA expression. Estimates of the absorbed dose to the tumor and organs are reported. An administered activity of 40 kBq per mouse of the peptidomimetic 225AcPSMA-617 is well-tolerated and results in significant tumor growth retardation and improved survival. This work provides a preclinical foundation for further studies towards a more effective treatment option for advanced castration-resistant prostate cancer.

P1.18-27 Chemoradiotherapy of Inoperable Non-Small Cell Lung Cancer (NSCLC) with IGRT Technique Using TomoTherapy HD

Concurrent chemoradiotherapy (CCRT) of locally advanced NSCLC is considered a standard of care last two decades without important improvement except of adjuvant check-point inhibitor therapy. We present one-institutional results of chemoradiotherapy of inoperable NSCLC using daily 3D IGRT with TomoTherapy HD unit. A total of 39 patients with inoperable NSCLC staged by UICC7 and treated since April 2015 till September 2018 were included. Clinical data and radiation plans were retrospectively reviewed. Survival was analysed using Kaplan-Meier method, univariate analysis was done using Cox regression model. Our preferential chemotherapy regimen was cisplatin/vinorelbine three-weekly, carboplatin doublet with vinorelbine or paclitaxel was acceptable as well. Standard radiation dose was 66Gy/33fractions/6.5 weeks, daily MVCT was done. Minimal and median follow-up was 7/30 months, respectively. Patient characteristics were as follows: mean age 66 years, male 46%, stage II+IIIA/IIIB/locoregional recurrences 44%/33%/23%, respectively. PET/CT was done in 77% of patients. Histology: adenocarcinoma 41%, squamous 38.5%, NOS 20.5%. All patients had chemotherapy, 59% cisplatin-based, 41% carboplatin-based, full radiation dose of 66Gy was delivered to 69% of patients, mean size of PTV was 366ml. CCRT had 69% patients. Subsequently, only one patient passed radical surgery, check-point inhibitors were used in 5 patients as second line palliative therapy. We observed low treatment toxicity, radiation esophagitis grade 1-2 in 64%, grade 3 in one patient. Radiation pneumonitis of grade 1-2 started in 13% of patients. Median survival and median time to progression (TTP) was 35.3 and 22.3 months, 2-year survival and TTP 63% and 44%, respectively. The reason of progression was mainly distant metastases alone (26%) or with locoregional failure (15%). Only locoregional progression occurred in 8% of patients. Univariate analysis did not find any difference in survival or TTP by age, gender, tumour location, regimen and length of chemotherapy, or concurrent treatment delivery. Non-significant trend of better outcome of stage II+IIIA, squamous cancer, higher dose of radiation and shorter interval between chemotherapy and radiotherapy start was observed. Only significant variable was size of PTV. With cut-off 440ml the patients having greater size of PTV had significantly worse survival in compare with those with smaller one (HR 4.209, 95%CI: 1.519;11.665). Chemoradiation of inoperable NSCLC with IGRT technique using TomoTherapy HD has excellent results with 77% of durable local control, 63% of 2-year survival and nearly 3-year median survival. Only negative prognostic factor was higher size of PTV.

P14.06 Phase II randomized trial of short course hypofractionated radiotherapy with or without temozolomide in elderly patients with Glioblastoma

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary brain tumor. Although treatment advances and introduction of temozolomide has improved the outcome in young patients, it is still a concern in elderly patients. Elderly population is often excluded from the trials, thus established treatment guidelines are not available. Trials have shown that short course hypofractionated radiotherapy (HRT) is equally effective in terms of overall survival (OS) and progression free survival (PFS) as compared to standard RT in elderly population. While the benefit of adding Temozolomide (TMZ) to standard dose radiotherapy is well established, there is lack of evidence that addition of TMZ to HRT improves survival in elderly patients.We conducted this study to see if addition of temozolomide to HRT improves OS, PFS and quality of life (QOL) in elderly GBM patients. MATERIAL AND METHODS The study was conducted over a period of 21 months from January 2017 to September 2018. Histologically proven 70 newly diagnosed Glioblastoma patients (age&gt;60 years) were enrolled and randomized into two arms (Arm I- HRT alone, Arm II- HRT and TMZ) using computer generated randomization table (1:1 ratio). The radiotherapy dose in both arms was same and consisted of a dose of 25Gy in 5 daily fractions over 1 week. In addition, arm II patients received daily concurrent TMZ 75mg/m2 1 hour prior to RT followed by adjuvant TMZ 175mg/m2 from Day1-5 for 6 cycles (q 4weeks), started after a month of RT completion. Quality of life score and global health status was assessed in both arms at baseline, 1, 3, 6 and 9 months after the treatment using QOL questionnaire EORTC QLQ-C 30 and QLQ-BN20. Data entry was done in Microsoft Excel 2016 and analysis was done in SPSS version 18. Kaplan Meier survival analysis was done for OS and PFS. To see the trend of time related observations at different point of time repeated ANOVA was used. A p value of &lt;0.05 was taken significant. RESULTS The median OS in arm I and II was 121 (range 40–360 days) and 146 (range 40–450 days) days respectively (P=0.146). The median PFS in arm 1 and arm 2 were 77 (range 30–300 days) and 109.50 (range 30–300) days respectively (p-0.028). On further analysis, the prognostic factors were type of surgery (Median PFS 159 days in gross total excision and 129 days in subtotal excision or biopsy, p-0.03) and KPS (0.04). QOL score for symptom and functional domain was comparable in both arms. However score of nausea and vomiting was higher during concurrent chemoradiotherapy. A non significant improvement in QLQ BN 20 score was observed at 9 months in arm I. CONCLUSION Addition of Temozolomide to HRT is a compelling option in elderly Glioblastoma patients as it significantly improves the PFS and a non significant improvement in OS without compromising quality of life.

Radiomic Biomarkers Evaluation of the High Dose Arm of RTOG 0617

The multi-institutional RTOG 0617 study compares the efficacy of high-dose (74 Gy) and standard-dose (60 Gy) radiotherapy for non-small cell lung cancer. The reported, unexpected outcome in the high-dose cohort not displaying a survival advantage differed from that observed in a previous multi-center study RTOG 0117. Patient heterogeneity may be attributed to the variation in radiotherapy effectiveness and might have explained why the high dose arm was not as effective as anticipated. This study aims to evaluate radiomic biomarkers with the potential to predict who would benefit from a high dose with predictive models built with radiomic characteristics. We analyzed 184 baseline planning CTs from DICOM images of patients in the high-dose cohort. The Radiomic features were extracted from the target structures within the GTV or ITV. Overall, 1130 radiomic characteristics were extracted from each patient using an open source software package. Furthermore, image pre-processing was performed with open source software. We used feature-selection methods, such as LASSO, Recursive Feature Elimination, forward selection, backward selection, Boruta, and Multivariate Adaptive Regression Spline (MARS), and evaluated their reduction efficiency and consistencies in feature selection. The MARS method provided the best results by identifying nine consistent features, which were used to build survival models. The accuracy of all models was estimated using 50-fold cross-validation. The Cox regression model was predictive with a C-index of 0.6552. The decision tree method exhibited the following: accuracy, 65.8%; AUC, 0.67; specificity, 70%; and sensitivity, 61%. The Ensemble Boosted Tree adopted an AdaBoost ensemble method with following characteristics: overall accuracy, 63%; AUC, 0.69; specificity, 73%; and sensitivity, 49%. The Ensemble Bagged Tree adopted the normal bootstrap aggregating method with the following characteristics: accuracy, 66.3%; AUC, 0.72; sensitivity, 77%; and specificity, 52%. Finally, the RUSBoosted tree method exhibited an accuracy of 65.8%, an AUC of 0.69, a sensitivity of 73%, and a specificity of 49%. Using the MARS method, we identified nine significant radiomic features. Using these features, 2-year survival predictive models were generated with reasonable performance. These nine features can also be used to calculate the prognostic index for patients to classify them into a high risk or low risk cohort. Hence determining who may benefit from a high dose prescription. Nevertheless, further investigation using more data and validation of the methodology is warranted.

Chemoradiation with ENI versus IFI, High-Dose Versus Standard-Dose Radiation Therapy for Locally Advanced Esophageal Squamous Cell Carcinoma: Preliminary Results of Multicenter, Phase Ⅲ Clinical Trial (NROG 001-Northern Radiation Oncology Group of China)

Chemoradiation with ENI versus IFI, High-Dose Versus Standard-Dose Radiation Therapy for Locally Advanced Esophageal Squamous Cell Carcinoma: Preliminary Results of Multicenter, Phase Ⅲ Clinical Trial (NROG 001-Northern Radiation Oncology Group of China)

Feasibility of Dose Escalation in Patients With Intracranial Pediatric Ependymoma.

Background and purpose: Pediatric ependymoma carries a dismal prognosis, mainly owing to local relapse within RT fields. The current prospective European approach is to increase the radiation dose with a sequential hypofractionated stereotactic boost. In this study, we assessed the possibility of using a simultaneous integrated boost (SIB), comparing VMAT vs. IMPT dose delivery.Material and methods: The cohort included 101 patients. The dose to planning target volume (PTV59.4) was 59.4/1.8 Gy, and the dose to SIB volume (PTV67.6) was 67.6/2.05 Gy. Gross tumor volume (GTV) was defined as the tumor bed plus residual tumor, clinical target volume (CTV59.4) was GTV + 5 mm, and PTV59.4 was CTV59.4 + 3 mm. PTV67.6 was GTV+ 3 mm. After treatment plan optimization, quality indices and doses to target volume and organs at risk (OARs) were extracted and compared with the standard radiation doses that were actually delivered (median = 59.4 Gy [50.4 59.4]).Results: In most cases, the proton treatment resulted in higher quality indices (p < 0.001). Compared with the doses that were initially delivered, mean, and maximum doses to some OARs were no higher with SIB VMAT, and significantly lower with protons (p < 0.001). In the case of posterior fossa tumor, there was a lower dose to the brainstem with protons, in terms of V59 Gy, mean, and near-maximum (D2%) doses.Conclusion: Dose escalation with intensity-modulated proton or photon SIB is feasible in some patients. This approach could be considered for children with unresectable residue or post-operative FLAIR abnormalities, particularly if they have supratentorial tumors. It should not be considered for infratentorial tumors encasing the brainstem or extending to the medulla.

MDM2 inhibitor AMG-232 and radiation therapy in treating patients with soft tissue sarcoma with wild-type TP53: A phase IB study (NRG-DT001).

TPS11076 Background: Over-expression of mdm2 is a major block to p53 activation in soft tissue sarcoma (STS). AMG-232 specifically inhibits human MDM2-p53 interactions in vitro and in vivo, thereby activating p53. Resistance mechanisms to MDM2 inhibition by AMG-232 is through accumulation of MDM2 and MDMX. However, DNA damaging agents, such as radiotherapy (RT), promote MDMX degradation and lead to sustained p53 activation, which is critically important for radiation-induced tumor cell killing in STS. Indeed, preclinical studies reveal that AMG-232 synergizes with RT in vitro and in vivo when treating STS with wild type (WT) P53 gene . Since a majority of STS harbor WT TP53 gene and RT is part of the standard of care in treating STS; it is the next rational step to test the safety and efficacy of combination of AMG-232 and RT followed by surgery. In this clinical trial, we hypothesize that preoperative AMG-232 plus RT is safe and well tolerated in 2 separate cohorts: (A) extremity and body wall; (B) abdomen/pelvis/retroperitoneum. Methods: A key feature of this trial is to incorporate TP53 NGS sequencing result as one of the eligibility criteria. Adult patients with pathologically proven grade 2-3 STS with size ≥ 5 cm are eligible to enroll if there is a planned definitive surgical resection of the primary tumor. There must be sufficient tissue to submit to central laboratory for NGS sequencing of the TP53 gene, which is an integral biomarker. Only those with tumors harboring WT p53 gene will be allowed to continue protocol treatment. The primary objective is to evaluate the safety and tolerability of AMG-232 in combination with standard-dose RT in STS in two separate cohort; as well as to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of AMG-232 in combination with RT. We define DLT as grade 4-5 toxicities attributable to AMG-232 for up to 4 weeks after the completion of combination treatment (prior to surgery) as well as any AMG-232 related grade 3 toxicity that should lead to &gt; 2 weeks treatment delay or ≥ two dose reductions. There are 3 dose levels for AMG-232: dose level 1 is 120 mg daily for 3 days per week; dose level 2 is 120 mg daily 4 days per week and dose level 5 is 120 mg daily 5 days a week. If patients did not tolerate dose level 1, AMG-232 will be de-escalated to a lower level, which is 120 mg daily 2 days a week. The trial was open since 11/2017; 3 patients have been enrolled to cohort A and 2 patients in cohort B at dose level 1. The first patient has a tumor with WT p53 gene and has completed protocol treatment safely. Clinical trial information: NCT03217266.

OA02 - Dose De-Escalated Radiation Therapy versus Standard Dose Radiation Therapy in Definitive Treatment of HPV-Positive Oropharyngeal Squamous Cell Carcinoma

OA02 - Dose De-Escalated Radiation Therapy versus Standard Dose Radiation Therapy in Definitive Treatment of HPV-Positive Oropharyngeal Squamous Cell Carcinoma

Therapeutic Efficacy and Dosimetry of Targeted Alpha Therapy using 225Ac-PSMA-617 in a Murine Model of Prostate Cancer

Targeted alpha therapy shows promise as a treatment in metastatic castration-resistant prostate cancer (mCRPC), owing to the high dose deposition and short range characteristics of alpha particle radiation. Ac-225 decays via multiple alpha particles – each capable of inducing irreparable DNA double-strand breaks in cell nuclei. PSMA-617 is a targeting ligand with specific affinity for prostate-specific membrane antigen (PSMA), a protein that is overexpressed in mCRPC but has low expression in normal tissues. Coupled with the lethal effects of alpha radiation, 225Ac-PSMA-617 is potentially highly cytotoxic to mCRPC while sparing normal tissues. The objective of this study was to evaluate the efficacy of alpha-particle radioligand therapy in a mouse model of mCRPC. Radiation dosimetry analysis was carried out to determine tumor dose as well as dose-limiting organs. NSG mice bearing subcutaneous PSMA-expressing C4-2 tumors were injected with escalating activities of 225Ac-PSMA-617: 20, 40, and 100 kBq/mouse (n=8/group). The tumor volumes were assessed over time by weekly low-dose microCT and compared with an untreated control group. In parallel, twenty-five NSG mice were used in a biodistribution study at five time points – 1, 4, 24, 48, and 168 hours post-administration of 40 kBq of the radiopharmaceutical. After sacrifice, percent tumor and organ radioactivity uptake was measured using gamma spectroscopy. Biexponential curve-fitting was used to fit the time-activity curves for the tumor and each organ, and integrated according to standard medical internal radiation dose methods to estimate the tumor and organ doses. Significant tumor growth retardation was observed in all treatment groups compared with the untreated group. Mice treated with 100 kBq exhibited some weight loss, while the mice treated with lower activities experienced only transient weight loss. There was a significant survival benefit conferred on tumor-bearing mice treated with 225Ac-PSMA617. The biodistribution over five time points showed high uptake and slow tumor activity clearance, and low uptake with fast clearance in non-target organs. The salivary glands, a dose-limiting organ in humans, did not show high uptake in mice, possibly due to lower PSMA expression. Estimates of the absorbed dose to the tumor and organs are reported. An administered activity of 40 kBq per mouse of the peptidomimetic 225AcPSMA-617 is well-tolerated and results in significant tumor growth retardation and improved survival. This work provides a preclinical foundation for further studies towards a more effective treatment option for advanced castration-resistant prostate cancer.

The efficacy and safety of high dose versus standard dose radiotherapy in concurrent chemoradiotherapy for patients with esophageal squamous cell carcinoma

Objective: To compare the efficacy and treatment-related toxicity of high dose versus standard dose radiotherapy in concurrent chemoradiotherapy (CCRT) for patients with esophageal squamous cell carcinoma (ESCC). Methods: From 2005 to 2012, 183 pairs of patients with esophageal squamous cell carcinoma in the Fourth Hospital of Hebei Medical University were enrolled, all had undergone CCRT based on three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). A propensity score was constructed to match the cohort. The overall survival (OS), local control (LC) probability, as well as the acute and late toxicities between standard-dose and high-dose groups were compared. Results: Patients in the high-dose group had significantly better OS and LC probability compared with those in the standard-dose group: the 3-, 5- and 10-year LC rate were 60.9%, 57.6%, 52.3% versus 50.8%, 46.4%, 30.8%, respectively (P=0.032). The 3-, 5- and 10-year OS were 44.3%, 36.9% and 24.5% for high-dose group, and 31.7%, 20.6% and 14.1% for the standard-dose group, respectively(P=0.002). The incidence of acute radiation esophagitis (especially in grade 2 and 3) was 63.9% in high-dose group, which was significantly higher than that in the standard-dose group (59.6%). Severe (≥ grade 3) late-onset esophagitis was observed in neither group. The grade 4 acute esophagitis was rare. There was no significant difference in the incidence of radiation pneumonitis, gastrointestinal reactions or hematological toxicities between the two groups. Six patients in high-dose group and two patients in standard-dose group experienced ≥ grade 4 leukocytopenia, while no one experienced > grade 3 thrombocytopenia and anemia in both group. Conclusions: 60 Gy was the preferred dosage of CCRT in patients with ESCC. Compared with standard-dose, the high-dose CCRT yielded slightly increased mild to moderate acute radiation esophagitis, while life-threatening toxicities were not increased.

Examining adjuvant radiation dose in head and neck squamous cell carcinoma.

Compare adjuvant radiation dose trends and outcomes in head and neck squamous cell carcinoma (HNSCC). Nonmetastatic HNSCCs treated between 2004 and 2014 with primary site surgery, lymph node dissection, and adjuvant radiation were identified in the National Cancer Database. Standard dose radiation (SD-RT) was defined as an equivalent dose in 2 Gy (EQD2) ≥56.64 and ≤60 Gy and high-dose radiation (HD-RT) as an EQD2 >60 and <70 Gy. HD-RT was given to 46% of the 15 836 HNSCC patients managed with adjuvant radiation. When adjusted for poor prognostic factors, HD-RT was associated with increased mortality (HR1.09; 95%CI 1.02-1.16). In nonoropharynx or human papillomavirus-negative oropharynx primary that had positive margins, ≥5 positive lymph nodes, and/or extranodal extension, HD-RT was still not associated with improved survival (HR 1.01, 95% CI 0.91-1.12). There was no survival benefit from postoperative dose escalation above EQD2 60 Gy even in a high-risk cohort.

Radiation therapy dose de-escalation compared to standard dose radiation therapy in definitive treatment of HPV-positive oropharyngeal squamous cell carcinoma

BackgroundDespite existing evidence that human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has a favorable prognosis compared to HPV-negative OPSCC, randomized studies have yet to report the effect of de-escalating radiation therapy (RT) dose for definitive treatment. The aim of this study was to assess the effectiveness of dose de-escalated RT (DDRT) vs. standard dose RT (SDRT) in patients with HPV-positive OPSCC. MethodsThis was an observational study using the National Cancer Database (Year 2010–2014) to identify patients who had HPV-positive OPSCC and were treated with definitive RT or chemo-RT. Patients undergoing surgery were excluded. Patients receiving ≥50 Gy, but <66 Gy were categorized as receiving DDRT. Patients receiving ≥66 Gy were categorized as receiving SDRT. Inverse probability of treatment weighting (IPTW) using propensity scores was used to balance the two groups. Kaplan–Meier analysis was used to estimate overall survival (OS). Subset analyses in patients receiving RT alone and concurrent chemo-RT were also performed. Multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS. Results759 patients with HPV-positive OPSCC were identified: 104 received DDRT and 655 received SDRT. The median follow-up was 30.5 (2.4–81.4) months. After IPTW-adjusted analysis, there was no difference in the 3-yr OS between the two groups (82.2% vs. 79.3%; P = 0.85). In the subset of patients receiving concurrent chemoradiotherapy, IPTW-adjusted analysis also did not show a difference in the 3-yr OS between the two groups (83.1% vs. 79.6%; P = 0.83). On multivariable analysis, DDRT was not associated with an inferior OS (HR 0.88; 95% CI, 0.53–1.47; P = 0.63). ConclusionsIn this study, DDRT was not associated with an inferior OS compared to SDRT in patients with HPV-positive OPSCC. Randomized clinical trials to address DDRT in this patient population are currently ongoing.

Study protocol: a multi-centre randomised study of induction chemotherapy followed by capecitabine \xb1 nelfinavir with high- or standard-dose radiotherapy for locally advanced pancreatic cancer (SCALOP-2)

BackgroundInduction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2).MethodsPatients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19–9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme.DiscussionSCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen.Trial registrationEudract No: 2013–004968-56; ClinicalTrials.gov: NCT02024009.

Improved repeatability of subsolid nodule measurement in low-dose lung screening with monoenergetic images: a phantom study.

To investigate whether monoenergetic images captured with dual-layer spectral computed tomography (CT) can improve the repeatability of subsolid nodule measurement, and whether this approach can further reduce the radiation dose of CT while maintaining its measurement repeatability. An anthropomorphic phantom with simulated subsolid nodules at three different levels was repeatedly scanned with both conventional single-energy CT and dual-layer spectral CT. A proxy for the measurement repeatability in the National Lung Screening Trial (proxy for NLST) was calculated with the typical CT protocol used in NLST. Using the dual-layer spectral CT, monoenergetic images of 40 to 110 keV, with an interval of 10 keV, were generated. The average diameter and volume of a total of 15,120 nodules in 840 CT images were measured by using a commercially-available computer-aided detection (CAD) system. The repeatability coefficient (RC), %RC, and 95% confidence intervals (CIs) of each image set were calculated and compared. At the same tube voltage and tube current-time product, monoenergetic images resulted in significantly lower RC than the proxy for NLST, indicating that measurement repeatability was enhanced. When the radiation dose was lowered by 30% or 55%, monoenergetic images showed significantly lower RC at high-energy keV than the proxy for NLST. The estimated measurement repeatability from monoenergetic images with 30% or 55% lower radiation dose was comparable to the repeatability from conventional single-energy CT images with standard radiation dose and iterative reconstruction. Monoenergetic images captured by using dual-layer spectral CT can improve the repeatability of subsolid nodule measurement. The use of monoenergetic images would allow lung cancer screening with a lower radiation dose, while maintaining comparable measurement repeatability.

Cognitive effects of second-generation antipsychotic polypharmacy in stabilized patients with schizophrenia

To assess the utility of circulating serum microRNAs (c-miRNAs) to predict response to high-dose radiation therapy for locally advanced non-small cell lung cancer (NSCLC).Data from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiation therapy for stages II-III NSCLC as part of 4 prospective institutional clinical trials were evaluated. Pretreatment serum levels of 62 miRNAs were measured by quantitative reverse transcription–polymerase chain reaction array. We combined miRNA data and clinical factors to generate a dose–response score (DRS) for predicting overall survival (OS) after high-dose versus standard-dose radiation therapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross-validation. The DRS was also correlated with local progression, distant metastasis, and grade 3 or higher cardiac toxicity using Cox regression, and grade 2 or higher esophageal and pulmonary toxicity using logistic regression.Eleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiation therapy was associated with significantly improved OS compared to treatment with standard-dose radiation therapy (hazard ratio 0.22). In these patients, high-dose radiation also conferred lower risk of distant metastasis and local progression, although the latter association was not statistically significant. Patients with high DRS exhibited similar rates of OS regardless of dose (hazard ratio 0.78). The DRS did not correlate with treatment-related toxicity.Using c-miRNA signature and clinical factors, we developed a DRS that identified a subset of patients with locally advanced NSCLC who derive an OS benefit from high-dose radiation therapy. This DRS may guide dose escalation in a patient-specific manner.

De-intensified adjuvant (chemo)radiotherapy versus standard adjuvant chemoradiotherapy post transoral minimally invasive surgery for resectable HPV-positive oropharyngeal carcinoma.

More than 400,000 cases of oropharyngeal squamous cell cancer (OPSCC) are diagnosed every year worldwide and this is rising. Much of the increase has been attributed to human papillomavirus (HPV). HPV-positive OPSCC patients are often younger and have significantly improved survival relative to HPV-negative patients. Traditional management of OPSCC has been with radiotherapy with or without chemotherapy, as this was shown to have similar survival to open surgery but with significantly lower morbidity. Techniques have evolved, however, with the development of computerised planning and intensity-modulated radiotherapy, and of minimally invasive surgical techniques. Acute and late toxicities associated with chemoradiotherapy are a significant burden for OPSCC patients and with an ever-younger cohort, any strategies that could decrease treatment-associated morbidity should be investigated. To assess the effects of de-intensified adjuvant (chemo)radiotherapy in comparison to standard adjuvant (chemo)radiotherapy in patients treated with minimally invasive transoral surgery (transoral robotic surgery or transoral laser microsurgery) for resectable HPV-positive oropharyngeal squamous cell carcinoma. The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 26 April 2018. Randomised controlled trials (RCTs) in patients with carcinoma of the oropharynx (as defined by the World Health Organization classification C09, C10). Cancers included were primary HPV-positive squamous cell tumours originating from the oropharyngeal mucosa. Tumours were classified as T1-4a with or without nodal spread and with no evidence of distant metastatic spread. The intervention was minimally invasive transoral surgery followed by de-intensified adjuvant therapy (either omission of chemotherapy or reduced-dose radiotherapy). The comparator was minimally invasive transoral surgery followed by standard concurrent chemoradiotherapy or standard-dose radiotherapy. The treatments received were of curative intent and patients had not undergone any prior intervention, other than diagnostic biopsy. We used the standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival (disease-related survival was to be studied where possible) and disease-free survival, measured at one, two, three and five years. Our secondary outcomes included assessment of swallowing ability and voice, measured at one, six, 12 and 24 months. We planned to use GRADE to assess the quality of evidence for each outcome. We did not identify any completed RCTs that met our inclusion criteria. However, three eligible studies are in progress:ADEPT is a phase III trial comparing postoperative radiotherapy with or without cisplatin in HPV-positive T1-4a OPSCC patients. Included patients must have received minimally invasive surgery and demonstrated extra-capsular spread from disease in the neck.ECOG-E3311 is a phase II trial of treatment for HPV-positive locally advanced OPSCC (stages III-IVa + IVb without distant metastasis). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy.PATHOS is a phase III trial of treatment for HPV-positive OPSCC (T1-3, N0-2b). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy. High-risk patients are randomised to radiotherapy with or without concurrent cisplatin. This review highlights the current lack of high-quality randomised controlled trials studying treatment de-escalation after minimally invasive surgery in patients with HPV-positive OPSCC. However, trials that will meet the inclusion criteria for this review are in progress with results expected between 2021 and 2023.

High-dose versus standard-dose radiation therapy for cervical esophageal cancer: Retrospective single-institution study.

To evaluate the role of definitive radiotherapy using higher-than-standard-dose radiation of 50 Gy for carcinoma of the cervical esophagus (CCE). We reviewed 79 patients with stage I-III CCE, treated between 2000 and 2012. Patients received 5-fluorouracil/cisplatin-based chemotherapy concurrently and were divided into high-dose (≥59.4 Gy, n = 44) and standard-dose (<59.4 Gy, n = 35) groups. The median follow-up was 35 months for surviving patients. The high-dose group had significantly better 3-year local (90.0% vs 60.4%, P = .001) and locoregional (70.4% vs 45.3%, P = .04) control. Progression-free (45.4% vs 37.5%, P = .32) and overall (58.4% vs 49.1%, P = .69) survival rates were not different. High-dose radiation was an independent prognostic factor for locoregional control (P = .04). No differences in late toxicities (esophageal stenosis or tracheoesophageal fistula) were observed. High-dose radiation for CCE improves local and locoregional control, without increasing severe toxicities.