The UK Divide: Does Having a Pembrolizumab-Chemotherapy Option in Head and Neck Cancer Matter? Real-world Experience of First-line Palliative Pembrolizumab Monotherapy and Pembrolizumab-Chemotherapy Combination in Scotland.

AIMS: The Scottish Medical Consortium recently approved first-line pembrolizumab monotherapy or in combination with chemotherapy for head and neck squamous cell carcinoma in the palliative setting, contrasting with the decision made by the National Institute for Health and Care Excellence, who approved monotherapy alone in England and Wales. The aim of this study was to provide real-world performance data for first-line pembrolizumab-containing treatments for head and neck squamous cell carcinoma in the palliative setting in Scotland. MATERIALS AND METHODS: We analysed the electronic records of patients who started pembrolizumab-containing treatment between 1 March 2020 and 30 September 2021. Outcomes included overall survival, progression-free survival (PFS), the duration of response and the disease control rate. Data were compared with the KEYNOTE-048 study and clinical factors were evaluated for association with survival. RESULTS: Our cohort included 91 patients (median follow-up 10.8 months). Patient characteristics were similar to those in the KEYNOTE-048 study, although our cohort had a higher proportion of patients with newly diagnosed, non-metastatic disease. For patients receiving monotherapy (n = 76), 12- and 24-month overall survival were 45% and 27%, respectively. For patients receiving pembrolizumab-chemotherapy (n = 15), 12-month overall survival was 60% (24-month overall survival had not yet been reached). Experiencing one or more immune-related adverse event (irAE; versus no irAEs), of any grade, was associated with favourable overall survival and PFS for patients receiving monotherapy in both univariable Log-rank analysis (median overall survival 17.4 months versus 8.6 months, respectively, P = 0.0033; median PFS 10.9 months versus 3.0 months, respectively, P < 0.0001) and multivariable analysis (Cox proportional hazards regression: overall survival hazard ratio 0.31, P = 0.0009; PFS hazard ratio 0.17, P < 0.0001). CONCLUSION: Our real-world data support the KEYNOTE-048 study findings and the value of combination treatment options. Additionally, our data show that irAEs of any grade, as reported in routine clinical records, are associated with better outcomes in this patient group, adding to the growing body of evidence showing that irAEs are generally a positive marker of programmed death-ligand 1 (PD-L1) inhibitor response.

Defining Biochemical Cure After Low Dose Rate Prostate Brachytherapy: External Validation of 4-year Prostate-specific Antigen Nadir as a Predictor of 10- and 15-year Disease-free Survival.

AIMS: To externally validate a proposed biochemical definition of cure following low dose rate (LDR) brachytherapy for prostate cancer - 4-year post-implant prostate-specific antigen (PSA) ≤0.2 ng/ml - in a UK population, and report the long-term (10- and 15-year) outcomes for patients stratified by National Comprehensive Cancer Network (NCCN) risk groups, through analysis of a large, prospectively collected, single-centre database. MATERIALS AND METHODS: All patients treated with LDR brachytherapy for prostate cancer at a single UK centre between 2001 and November 2020 (n = 1142) were eligible; 632 patients met the inclusion criteria for the analysis. The primary end point was disease-free survival (DFS), defined as freedom from clinical, radiological or PSA progression requiring androgen deprivation therapy. Four-year PSA was categorised as ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml. Kaplan-Meier analysis to 15 years was undertaken for each group, and sensitivity and specificity of 4-year PSA as a surrogate for long-term cure were calculated. Kaplan-Meier analysis to 15 years was repeated, stratifying patients by NCCN risk groups. RESULTS: The median cohort age was 63 years; the median follow-up was 9.1 years (range 3.5-18.7). In total, 248 patients were available for analysis at year 10, 46 at year 15. Sixty-four patients (10.1%) relapsed during the study period. The 10-year DFS for 4-year PSA categories ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml (95% confidence intervals) were 97.5% (95.4-99.6), 89.0% (82.4-96.1), 81.5% (70.5-94.2) and 41.8% (29.7-58.9), respectively. The 10-year DFS results for NCCN low, favourable-intermediate and unfavourable-intermediate risk disease were 93.1% (89.6-96.7), 92.1% (87.6-96.9) and 75.9% (67.8-84.9), respectively. CONCLUSIONS: Patients with 4-year PSA ≤0.2 ng/ml may be considered cured, and could be discharged to general practitioner follow-up. LDR brachytherapy is an excellent treatment option for patients with low and favourable-intermediate risk prostate cancer, but those with unfavourable-intermediate risk disease should be considered for treatment intensification strategies.

[Target volume concepts in radiotherapy and their implications for imaging]. / Zielvolumenkonzepte in der Strahlentherapie und ihre Bedeutung für die Bildgebung.

CLINICAL ISSUE: Successful radiotherapy requires precise localization of the tumor and requires high-quality imaging for developing a treatment plan. STANDARD TREATMENT: Irradiation of the tumor region, including a safety margin. TREATMENT INNOVATIONS: The target volume consists of the gross tumor volume (GTV) containing visible parts of the tumor, the clinical target volume (CTV) covering the GTV plus invisible tumor extensions, and the planning target volume (PTV) to account for uncertainties. The non-GTV parts of the CTV are based on historical patient data. The PTV margins are based on a calculation of possible uncertainties during planning, setup, or treatment. Normal tissue deserves the identical care in contouring, since its tolerance may limit the tumor dose, taking into account the contours of organs at risk. Serial risk organs benefit from defining a planning organ of risk volume (PRV) to better limit the dose delivered to them. DIAGNOSTIC WORK-UP: The better the imaging, the more reliable the definition of the GTV and treatment success will be. Multiple imaging sequences are desirable to support the delineation of the tumor. They may result in different CTVs that, depending on their tumor burden, may require different doses. PERFORMANCE: The definition of standardized target volumes according to the ICRU reports 50, 62, and 83 forms the basis for an individualized radiation treatment planning according to unified criteria on a high-quality level. ACHIEVEMENTS: Radio-oncology is by nature interdisciplinary, the diagnostic radiologist being an indispensable team partner. A regular dialogue between the disciplines is pivotal for target volume definition and treatment success. PRACTICAL RECOMMENDATIONS: Imaging for target volume definition requires highest quality imaging, the use of functional imaging methods and close cooperation with a diagnostic radiologist experienced in this field.

Tumour Volume and Dose Influence Outcome after Surgery and High-dose Photon Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine.

AIMS: To evaluate the long-term outcomes of patients with chordoma and low-grade chondrosarcoma after surgery and high-dose radiotherapy. MATERIALS AND METHODS: High-dose photon radiotherapy was delivered to 28 patients at the Neuro-oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2016. Twenty-four patients were treated with curative intent, 17 with chordoma, seven with low-grade chondrosarcoma, with a median dose of 65 Gy (range 65-70 Gy). Local control and survival rates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 83 months (range 7-205 months). The 5 year disease-specific survival for chordoma patients treated with radical intent was 85%; the local control rate was 74%. The 5 year disease-specific survival for chondrosarcoma patients treated with radical intent was 100%; the local control rate was 83%. The mean planning target volume (PTV) was 274.6 ml (median 124.7 ml). A PTV of 110 ml or less was a good predictor of local control, with 100% sensitivity and 63% specificity. For patients treated with radical intent, this threshold of 110 ml or less for the PTV revealed a statistically significant difference when comparing local control with disease recurrence (P = 0.019, Fisher's exact test). Our data also suggest that the probability of disease control may be partly related to both target volume and radiotherapy dose. CONCLUSION: Our results show that refined high-dose photon radiotherapy, following tumour resection by a specialist surgical team, is effective in the long-term control of chordoma and low-grade chondrosarcoma, even in the presence of metal reconstruction. The results presented here will provide a useful source for comparison between high-dose photon therapy and proton beam therapy in a UK setting, in order to establish best practice for the management of chordoma and low-grade chondrosarcoma.

Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy.

To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is [Formula: see text], and the median DBC is ([Formula: see text]) mm. An intra-observer comparison for the same scans gives a median CI of [Formula: see text] and a DBC of ([Formula: see text]) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord.

Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy.

BACKGROUND AND PURPOSE: For the first time, delivered dose to the rectum has been calculated and accumulated throughout the course of prostate radiotherapy using megavoltage computed tomography (MVCT) image guidance scans. Dosimetric parameters were linked with toxicity to test the hypothesis that delivered dose is a stronger predictor of toxicity than planned dose. MATERIAL AND METHODS: Dose-surface maps (DSMs) of the rectal wall were automatically generated from daily MVCT scans for 109 patients within the VoxTox research programme. Accumulated-DSMs, representing total delivered dose, and planned-DSMs, from planning CT data, were parametrised using Equivalent Uniform Dose (EUD) and 'DSM dose-width', the lateral dimension of an ellipse fitted to a discrete isodose cluster. Associations with 6 toxicity endpoints were assessed using receiver operator characteristic curve analysis. RESULTS: For rectal bleeding, the area under the curve (AUC) was greater for accumulated dose than planned dose for DSM dose-widths up to 70Gy. Accumulated 65Gy DSM dose-width produced the strongest spatial correlation (AUC 0.664), while accumulated EUD generated the largest AUC overall (0.682). For proctitis, accumulated EUD was the only reportable predictor (AUC 0.673). Accumulated EUD was systematically lower than planned EUD. CONCLUSIONS: Dosimetric parameters extracted from accumulated DSMs have demonstrated stronger correlations with rectal bleeding and proctitis, than planned DSMs.

Highly Conformal Craniospinal Radiotherapy Techniques Can Underdose the Cranial Clinical Target Volume if Leptomeningeal Extension through Skull Base Exit Foramina is not Contoured.

AIMS: Craniospinal irradiation (CSI) remains a crucial treatment for patients with medulloblastoma. There is uncertainty about how to manage meningeal surfaces and cerebrospinal fluid (CSF) that follows cranial nerves exiting skull base foramina. The purpose of this study was to assess plan quality and dose coverage of posterior cranial fossa foramina with both photon and proton therapy. MATERIALS AND METHODS: We analysed the radiotherapy plans of seven patients treated with CSI for medulloblastoma and primitive neuro-ectodermal tumours and three with ependymoma (total n = 10). Four had been treated with a field-based technique and six with TomoTherapy™. The internal acoustic meatus (IAM), jugular foramen (JF) and hypoglossal canal (HC) were contoured and added to the original treatment clinical target volume (Plan_CTV) to create a Test_CTV. This was grown to a test planning target volume (Test_PTV) for comparison with a Plan_PTV. Using Plan_CTV and Plan_PTV, proton plans were generated for all 10 cases. The following dosimetry data were recorded: conformity (dice similarity coefficient) and homogeneity index (D2 - D98/D50) as well as median and maximum dose (D2%) to Plan_PTV, V95% and minimum dose (D99.9%) to Plan_CTV and Test_CTV and Plan_PTV and Test_PTV, V95% and minimum dose (D98%) to foramina PTVs. RESULTS: Proton and TomoTherapy™ plans were more conformal (0.87, 0.86) and homogeneous (0.07, 0.04) than field-photon plans (0.79, 0.17). However, field-photon plans covered the IAM, JF and HC PTVs better than proton plans (P = 0.002, 0.004, 0.003, respectively). TomoTherapy™ plans covered the IAM and JF better than proton plans (P = 0.000, 0.002, respectively) but the result for the HC was not significant. Adding foramen CTVs/PTVs made no difference for field plans. The mean Dmin dropped 3.4% from Plan_PTV to Test_PTV for TomoTherapy™ (not significant) and 14.8% for protons (P = 0.001). CONCLUSIONS: Highly conformal CSI techniques may underdose meninges and CSF in the dural reflections of posterior fossa cranial nerves unless these structures are specifically included in the CTV.

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity.

There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.

Exploiting biological and physical determinants of radiotherapy toxicity to individualize treatment.

The recent advances in radiation delivery can improve tumour control probability (TCP) and reduce treatment-related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally, IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day to day. Daily image guidance scans can be used to identify the position of normal tissue structures and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues that limits radiotherapy (RT) dose and therefore tumour control. However, the dose-response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of RT. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be owing to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In patients with prostate cancer receiving curative RT, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses was -2.7 Gy (5%), and a dose reduction was seen in 7 of the 10 cases. If dose escalation was performed to take rectal dose back to the planned level, this should increase the mean TCP (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical RT who might benefit from either dose escalation, suggesting improved tumour cure or reduced toxicity or both.

Revival of an old problem: an increase in Salmonella enterica serovar Typhimurium definitive phage type 8 infections in 2010 in England and Northern Ireland linked to duck eggs.

Salmonella enterica serovar Typhimurium definitive phage type (DT) 8 is uncommon in humans in the UK. In July 2010, the Health Protection Agency reported an excess isolation rate of pan-susceptible S. Typhimurium DT8 in England and Northern Ireland. By the end of October, this amounted to 81 laboratory-confirmed human cases for all regions of England and Northern Ireland in 2010, an increase of 26% and 41% on 2009 and 2008, respectively. Descriptive epidemiological investigation found a strong association with infection and consumption of duck eggs. Duck eggs contaminated with S. Typhimurium DT8 were collected from a patient's home and also at farms in the duck-egg supply chain. Although duck eggs form a small part of total UK eggs sales, there has been significant growth in sales in recent years. This is the first known outbreak of salmonellosis linked to duck eggs in the UK since 1949 and highlighted the impact of a changing food source and market on the re-emergence of salmonellosis linked to duck eggs. Control measures by the duck-egg industry should be improved along with a continued need to remind the public and commercial caterers of the potential high risks of contracting salmonellosis from duck eggs.

Simultaneous bilateral total knee replacement: a persistent controversy.

The benefits and risks of Simultaneous Bilateral Total Knee Replacement (SBTKR) remain controversial. A review of the English speaking literature was undertaken and found that many papers took staunch positions either for or against the procedure. It was also noted that earlier papers supporting SBTKR suggested cost benefits. There was a huge disparity in the incidence of mortality and morbidity and it was not possible to compare many papers, because in some medically frail patients were excluded from the SBTKR cohorts. In large published series the proportion of patients having a SBTKR varied between 3% and 70%. Many, but not all, series highlighted age and co-morbidity as risk factors. Overall there was no clear case for or against SBTKR. The evidence suggested that careful preoperative assessment and patient selection on a strict protocol were essential. The procedure should be confined to hospitals where high dependency nursing is readily available and the literature indicated that the risk is less in high through-put units. By refining preoperative assessment and preparation it can be a safe and effective procedure in an appropriate clinical setting for postoperative care.

Ultrasonographic analysis of bladder tumors.

To analyze the ultrasonographic features of bladder tumors during transabdominal ultrasonography. Ultrasonograms of consecutive patients diagnosed to have bladder tumors from August 1992 to May 1999 were reviewed retrospectively and correlated with the final histological diagnoses. Various features, including the location, size, multiplicity, shape, surface and presence of calcification, of the bladder tumors were analyzed. Of 109 patients reviewed, 104 had transitional cell carcinoma, 3 adenocarcinoma, 1 carcinosarcoma and 1 prostatic carcinoma. A total of 130 tumors (including 13 multifocal tumors) were detected with 30 (27.5%) patients having more than one tumor in the bladder. Tumor size ranged from 0.5 to 9.7 cm (mean 2.7 cm). The tumor involved the trigone (63, 48.5%), lateral wall (32, 24.6%), posterior wall (17, 13.1%), anterior wall (5, 3.8%) or was multifocal (13, 10%). Sixty-seven (51.5%) tumors were polypoidal, 47 (36.2%) were sessile and 16 (12.3%) plaque-like. The surface was regular in 50 (38.5%) tumors and irregular in 80 (61.5%) tumors. Calcified foci were noted in 54 (41.5%) tumors. There was no statistically significant correlation between ultrasonographic features. The most common appearance is a polypoid lesion arising from the trigone, but there was much variation in the ultrasonographic features of bladder tumors.

Comparison of supraspinatus tendon and glenohumeral joint axes in MR imaging of the shoulder.

OBJECTIVE: In magnetic resonance (MR) imaging of the shoulder, oblique coronal images are used for evaluating the supraspinatus tendon (SST) of patients with suspected rotator cuff tear or impingement. This study aimed to compare orientation of the SST long axis with planes perpendicular to the glenohumeral joint (GHJ). DESIGN AND PATIENTS: The axial scans of 100 consecutive patients referred for MR imaging or MR arthrography of the shoulder were reviewed. Using the electronic cursors of a computer workstation, the angle of the SST long axis was measured and compared with the angle obtained through the GHJ utilizing three different landmarks: perpendicular to the joint (GHJ-90), joint-humeral head center axis (GHJ-H) and joint-scapular body axis (GHJ-S). RESULTS: Differences in angulation between axes of the SST and the three GHJ axes averaged only about 5 degree [range of means 4.5-5.3 degrees, range of standard deviation (SD) 3.8-4.6 degrees]. In the majority of shoulders, angular differences measured 4 or less for all SST/GHJ comparisons. Similarly, small angular differences in the three GHJ axes were found: 4.5 degrees (SD 3.3 degrees) for GHJ-90/GHJ-S, 5.0 degree (SD 4.0 degrees) for GHJ-S/GHJ-H and 2.9 degrees (SD 3.0 degrees) for GHJ-90/GHJ-H. Correlation between the GHJ-90 and GHJ-H axes was particularly good, with differences of 4 degree or less in 84% of shoulders. The orientations of the GHJ axes and that of the SST long axis are comparable. CONCLUSION: The GHJ may potentially be used as a landmark for obtaining oblique coronal images of the SST.