Stereotactic ablative radiotherapy (SABR) as primary, adjuvant, consolidation and re-treatment option in pancreatic cancer: scope for dose escalation and lessons for toxicity.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) offers an alternative treatment for pancreatic cancer, with the potential for improved tumour control and reduced toxicity compared with conventional therapies. However, optimal dose planning and delivery strategies are unelucidated and gastro-intestinal (GI) toxicity remains a key concern. METHODS: Patients with inoperable non-metastatic pancreatic cancer who received CyberKnife® SABR (18-36 Gy) in three fractions as primary, adjuvant, consolidation or re-treatment options were studied. Patient individualised planning and delivery variables were collected and their impact on patient outcome examined. Linear-quadratic (LQ) radiobiology modelling methods were applied to assess SABR parameters against a conventional fractionated radiotherapy schedule. RESULTS: In total 42 patients were included, 37 (88%) of whom had stage T4 disease. SABR was used > 6 months post-primary therapy to re-treat residual disease in 11 (26.2%) patients and relapsed disease in nine (21.4%) patients. SABR was an adjuvant to other primary therapy for 14 (33.3%) patients and was the sole primary therapy for eight (19.0%) patients. The mean (95% CI) planning target volume (PTV), prescription isodose, percentage cover, minimum dose to PTV and biological effective dose (BED) were 76.3(63.8-88.7) cc, 67.3(65.2-69.5)%, 96.6(95.5-97.7)%, 22.3(21.0-23.6) Gy and 50.3(47.7-53.0) Gy, respectively. Only 3/37 (8.1%) patients experienced Grade 3 acute toxicities. Two (4.8%) patients converted to resectable status and median freedom-from-local-progression (FFLP) and overall survival (OS) were 9.8 and 8.4 months, respectively. No late toxicity was experienced in 27/32 (84.4%) patients; however, four (12.5%) patients - of whom two had particularly large PTV, two had sub-optimal number of fiducials and three breached organ-at-risk (OAR) constraints-showed Grade 4 duodenal toxicities. Longer delivery time, extended treatment course and reduced percentage coverage additionally associated with late toxicity, likely reflecting parameters typically applied to riskier patients. Larger PTV size and longer treatment course associated with OS. Comparator regimen LQ modelling analysis indicated 50% of patients received minimum PTV doses less potent than a conventional radiotherapy regimen, indicating scope for dose escalation. CONCLUSION: The results demonstrate the value of SABR for a range of indications in pancreatic cancer. Dose escalation to increase BED may improve FFLP and OS in inoperable, non-metastatic disease: however concomitant enhanced stringency for duodenal protection is critical, particularly for patients where SABR is more challenging.

CyberKnife Radiosurgery of Skull-base Tumors: A UK Center Experience.

The study aim was to evaluate patient individualized Cyberknife® treatment for heterogeneous skull-base tumors. Patients treated between 2009 and 2013 at The Harley Street Clinic were studied. In total, 66 patients received 15-30 Gy in 1-5 fractions to a median planning target volume (PTV) of 6.4 cc, including patients with secondary, multiple, residual and recurrent tumors, and those with tumors of uncertain pathological type. Outcome analysis was pragmatically restricted to 35 patients who had single, primary tumors treated with curative intent, and sufficient diagnostic and outcome information. Sixteen vestibular schwannoma patients with median PTV 3.8 cc (range 0.81-19.6) received 18-25 Gy in 3-5 fractions: 81% showed no acute toxicity, 50% reported no late toxicity, 71% of symptoms were stable/improved and local control was 100% at 11.4 months median follow-up. Twelve meningioma patients with median PTV of 5.5 cc (range 0.68-22.3) received 17-30 Gy in 1-5 fractions: 83% experienced no acute toxicity, 33% reported no late toxicity, 88% of symptoms were stable/improved and local control was 100% at 22.1 months median follow-up. Seven patients with other tumor types with median PTV of 24.3 cc (range 7.6-100.5) received 15-28.5 Gy in 1-5 fractions: 57% experienced no acute toxicity, 57% reported no late toxicities, 66% of symptoms were stable and local control was 43% at 14.9 months median follow-up. When tumor types were considered together, smaller tumors (PTV < 6.4 cc) showed reduced acute toxicity (p = 0.01). Overall, smaller benign tumors showed low acute toxicity, excellent local control, and good symptom management: a focus on enhanced neurological preservation may refine outcomes. For other tumor types outcome was encouraging: a focus on optimal dose and fractionation scheduling may reduce toxicity and improve local control. Individual patient experiences are detailed where valuable lessons were gained for optimizing local control and minimizing toxicity.

Evaluation of CyberKnife® Fiducial Tracking Limitations to Assist Targeting Accuracy: A Phantom Study with Fiducial Displacement.

Introduction  The underlying assumptions of the CyberKnife® (Accuray, Sunnyvale, CA, US) fiducial tracking system are: i) fiducial positions are accurately detected; ii) inter-fiducial geometry remains consistent (rigid); iii) inter-fiducial geometric array changes are detected and either accommodated with corrections or treatment is interrupted. However: i) soft-tissue targets are deformable & fiducial migration is possible; ii) the accuracy of the tracking system has not previously been examined with fiducial displacement; iii) treatment interruptions may occur due to inter-fiducial geometric changes, but there is little information available to assist subsequent troubleshooting. The purpose of this study was to emulate a clinical target defined with a two, three, or four-fiducial array where one fiducial is displaced to mimic a target deformation or fiducial migration scenario. The objectives: evaluate the fiducial positioning accuracy, array interpretation, & corresponding corrections of the CyberKnife system, with the aim of assisting troubleshooting following fiducial displacement. Methods A novel solid-water phantom was constructed with three fixed fiducials (F1,F2,F3) & one moveable fiducial (F4), arranged as if placed to track an imaginary clinical target. Using either two fiducials (F1,F4), different combinations of three fiducials (F1,F2,F4; F1,F3,F4; F2,F3,F4) or four fiducials (F1,F2,F3,F4), repeat experiments were conducted where F4 was displaced inferiorly at 2-mm intervals from 0-16 mm. Data were acquired at each position of F4, including rigid body errors (RBE), fiducial x, y, & z coordinate displacements, six degrees of freedom (DOF) corrections, & robot center-of-mass (COM) translation corrections. Results Maximum positioning difference (mean±SD) between the reference and live x, y, & z coordinates for the three fixed fiducials was 0.08±0.30 mm, confirming good accuracy for fixed fiducial registration. For two fiducials (F1,F4), F4 registration was accurate to 14-mm displacement and the F4 x-axis coordinate change was 2.0±0.12 mm with each 2 mm inferior displacement validating the phantom for tracking evaluation. RBE was >5 mm (system threshold) at 6-14 mm F4 displacement: however, F1 was misidentified as the RBE main contributor. Further, F1/F4 false-lock occurred at 16 mm F4 displacement with corresponding RBE <3 mm & COM corrections >13 mm. For combinations of three fiducials, F4 registration was accurate to 10-mm displacement. RBE was >5 mm at 6-16 mm F4 displacement: however, F4 false-lock occurred at 12-16 mm with RBE 5-6 mm. For four fiducials, F4 registration was accurate to 4 mm displacement: however, F4 false-lock occurred at 6-16 mm displacement with concerning RBE <2 & <5 at 6 & 8-mm F4 displacement, respectively. False-locks were easily identified in the phantom but frequently uncorrectable. Conclusions Results indicate fiducial positioning accuracy and system output following fiducial displacement depends on the number of fiducials correlated, displacement distance, and clinical thresholds applied. Displacements ≤4 mm were accurately located, but some displacements 6-16 mm were misrepresented, either by erroneous main contributor (two-fiducial array only) or by false-locks and misleading RBE, which underestimated displacement. Operator vigilance and implementation of our practical guidelines based on the study findings may help reduce targeting error and assist troubleshooting in clinical situations.

An effective deep-inspiration breath-hold radiotherapy technique for left-breast cancer: impact of post-mastectomy treatment, nodal coverage, and dose schedule on organs at risk.

BACKGROUND: We developed, applied, and prospectively evaluated a novel deep-inspiration breath-hold (DIBH) screening and delivery technique to optimize cardiac sparing in left-breast radiotherapy (RT) at our clinic. The impact of set-up and dose variables upon organs at risk (OAR) dose in DIBH RT was investigated. METHODS AND MATERIALS: All patients with left-breast cancer referred between 2011 and 2014 - of all disease stages, set-up variations, and dose prescriptions - were included. Radiographers used simple screening criteria at CT simulation, to systematically assess patients for obvious DIBH benefit and capability. Selected patients received forward-planned intensity-modulated RT (IMRT) based on a DIBH CT scan. A 3D-surface monitoring system with visual feedback assured reproducible DIBH positioning during gated radiation delivery. Patient, target set-up, and OAR dose information were collected at treatment. RESULTS: Of 272 patients who were screened, 4 withdrew, 56 showed no obvious advantage, and 56 showed benefit but had suitability issues; 156 patients were selected and successfully completed DIBH treatment. The technique was compatible with complex set-up and optimal target coverage was maintained. Comparison of free-breathing (FB) and DIBH treatment plans in the first five patients enrolled confirmed DIBH reduced heart radiation by ~80% (p = 0.032). Low OAR doses were achieved overall: the mean (95% confidence interval [CI]) heart dose was 1.17 (1.12-1.22) Gy, and the mean ipsilateral lung dose was 5.26 (5.01-5.52) Gy. Patients who underwent a standard radiation schedule (40 Gy/15#) after breast-conserving surgery had the lowest OAR doses: post-mastectomy treatment, simultaneous supraclavicular (SCV) node coverage, and alternative dose schedule (50 Gy/25#) were interrelated variables associated with increased OAR risk and compromised ipsilateral lung dose constraints. CONCLUSION: The DIBH technique was successfully implemented and resulted in optimally low heart radiation. All patients who demonstrate sufficient DIBH technique at planning CT are now offered DIBH RT at our clinic. Patients with more advanced disease, particularly those with additional pulmonary risk factors, warrant additional focus to improve lung sparing.

Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.

CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.

Dose-Volume Histogram Analysis of Stereotactic Body Radiotherapy Treatment of Pancreatic Cancer: A Focus on Duodenal Dose Constraints.

Pancreatic carcinoma is an aggressive disease and radiotherapy treatment delivery to the primary tumor is constrained by the anatomical close location of the duodenum, stomach, and small bowel. Duodenal dose tolerance for radiosurgery in 2-5 fractions has been largely unknown. The literature was surveyed for quantitative models of risk in 1-5 fractions and we analyzed our own patient population of 44 patients with unresectable pancreatic tumors who received 3 or 5 fractions of stereotactic body radiotherapy (SBRT) between March 2009 and March 2013. A logistic model was constructed in the dose-volume histogram (DVH) Evaluator software for the duodenal D50%, D30cc, D5cc, D1cc, and maximum point dose D0.035cc. Dose tolerance limits from the literature were overlaid onto the clinical duodenal data in the form of a DVH Risk Map, with risk levels of the published limits estimated from the model of clinical data. In 3 fractions, Kopek 2010 found a statistically significant difference in D1cc of patients with no common terminology criteria for adverse events (CTCAE) v3 grade 2 or higher duodenal complications (mean D1cc = 25.3Gy) as compared with patients with grade 2 or higher toxicity (mean D1cc = 37.4Gy). From the logistic model of our duodenal data in 3 fractions, D1cc = 25.3Gy had 4.7% risk of grade 3-4 hemorrhage or stricture and D1cc = 37.4Gy had 20% risk. The 10% risk level was D1cc = 31.4Gy and we were able to keep duodenum dose for all our patients later this level.

Stereotactic ablative body radiotherapy (SABR) for primary and secondary lung tumours.

Stereotactic ablative body radiotherapy (SABR) represents a technological breakthrough in radiotherapy technique, with proven benefits to patients in terms of improved tumour control and overall survival. The key components of SABR are described. The current evidence base for SABR for the treatment of primary and secondary lung tumours is appraised, and key ongoing trials are identified.

Large breast size as a risk factor for late adverse effects of breast radiotherapy: is residual dose inhomogeneity, despite 3D treatment planning and delivery, the main explanation?

BACKGROUND AND PURPOSE: Large breast size is associated with an increased risk of late adverse effects after breast conservation surgery and radiotherapy, even when 3D dosimetry is used. The purpose of this study is to test the hypothesis that residual dose inhomogeneity is sufficient to explain the association. METHODS: Patients previously treated after breast conservation surgery with whole breast radiotherapy using 3D dosimetry and followed up in the UK FAST hypofractionation trial were selected for this analysis. The residual level of dose inhomogeneity across the whole breast treatment volume was used to test for association between residual dosimetry and post-treatment change in breast appearance at 2 years post-radiotherapy. RESULTS: At 2 years, 201/279 (72%) of women had no change in photographic breast appearance, 61 (22%) had mild change and 17 (6%) had marked change. Breast size and dosimetry were both significantly associated with late effects in univariate analyses, but only breast size remained an independent significant risk factor for change in breast appearance when included in a multiple regression model together with other prognostic factors (p=0.006 for trend). CONCLUSION: Large-breasted women are more likely to suffer change in breast size and shape after whole breast radiotherapy delivered using 3D dosimetry, but residual dose inhomogeneity is insufficient to explain the association.

Neuroendocrine tumour of the cystic duct: a case report and literature review.

This is a case report of a neuroendocrine tumour of the cystic duct which is extremely rare and was an incidental finding during laparoscopic surgery. A literature review of similar cases is also provided.