Evaluation of therapeutic radiographer contouring for magnetic resonance image guided online adaptive prostate radiotherapy.

BACKGROUND AND PURPOSE: The implementation of MRI-guided online adaptive radiotherapy has facilitated the extension of therapeutic radiographers' roles to include contouring, thus releasing the clinician from attending daily treatment. Following undergoing a specifically designed training programme, an online interobserver variability study was performed. MATERIALS AND METHODS: 117 images from six patients treated on a MR Linac were contoured online by either radiographer or clinician and the same images contoured offline by the alternate profession. Dice similarity coefficient (DSC), mean distance to agreement (MDA), Hausdorff distance (HD) and volume metrics were used to analyse contours. Additionally, the online radiographer contours and optimised plans (n = 59) were analysed using the offline clinician defined contours. After clinical implementation of radiographer contouring, target volume comparison and dose analysis was performed on 20 contours from five patients. RESULTS: Comparison of the radiographers' and clinicians' contours resulted in a median (range) DSC of 0.92 (0.86 - 0.99), median (range) MDA of 0.98 mm (0.2-1.7) and median (range) HD of 6.3 mm (2.5-11.5) for all 117 fractions. There was no significant difference in volume size between the two groups. Of the 59 plans created with radiographer online contours and overlaid with clinicians' offline contours, 39 met mandatory dose constraints and 12 were acceptable because 95 % of the high dose PTV was covered by 95 % dose, or the high dose PTV was within 3 % of online plan. A clinician blindly reviewed the eight remaining fractions and, using trial quality assurance metrics, deemed all to be acceptable. Following clinical implementation of radiographer contouring, the median (range) DSC of CTV was 0.93 (0.88-1.0), median (range) MDA was 0.8 mm (0.04-1.18) and HD was 5.15 mm (2.09-8.54) respectively. Of the 20 plans created using radiographer online contours overlaid with clinicians' offline contours, 18 met the dosimetric success criteria, the remaining 2 were deemed acceptable by a clinician. CONCLUSION: Radiographer and clinician prostate and seminal vesicle contours on MRI for an online adaptive workflow are comparable and produce clinically acceptable plans. Radiographer contouring for prostate treatment on a MR-linac can be effectively introduced with appropriate training and evaluation. A DSC threshold for target structures could be implemented to streamline future training.

Interobserver variation of clinical oncologists compared to therapeutic radiographers (RTT) prostate contours on T2 weighted MRI.

The implementation of MRI-guided online adaptive radiotherapy has enabled extension of therapeutic radiographers' roles to include contouring. An offline interobserver variability study compared five radiographers' and five clinicians' contours on 10 MRIs acquired on a MR-Linac from 10 patients. All contours were compared to a "gold standard" created from an average of clinicians' contours. The median (range) DSC of radiographers' and clinicians' contours compared to the "gold standard" was 0.91 (0.86-0.96), and 0.93 (0.88-0.97) respectively illustrating non-inferiority of the radiographers' contours to the clinicians. There was no significant difference in HD, MDA or volume size between the groups.

A pilot of Blood-First diagnostic cell free DNA (cfDNA) next generation sequencing (NGS) in patients with suspected advanced lung cancer.

INTRODUCTION: The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic. METHODS: A pilot study assessing Guardant360™ cfDNA-NGS in patients with radiological-suspected advanced-stage lung cancer was performed at an academic cancer centre during COVID-19. Variants were tiered using AMP/ASCO/CAP guidelines and discussed at a tumour molecular board. The primary endpoint was the proportion of patients who commenced targeted treatment based on cfDNA-NGS results without tissue molecular results, predicted to be ≥ 10%. RESULTS: Between April 2020-May 2021, 51 patients were enrolled; 49 were evaluable. The median age was 71 years, 43% were never-smokers, 86% had stage IV disease. 80% of evaluable cfDNA-NGS were informative (tumour-derived cfDNA detected). cfDNA-NGS detected 30 (61%) AMP/ASCO/CAP tier 1 variants, including 20 additional tier 1 variants compared to tissue testing. Three patients with non-informative cfDNA-NGS had tier 1 variants identified on tissue testing. Eleven (22%; 95%CI 12%-27%) patients commenced targeted therapy based on cfDNA-NGS results without tissue molecular results, meeting the primary endpoint. Median time to results was shorter for cfDNA-NGS compared to standard-of-care tissue tests (9 versus 25 days, P < 0.0001). CONCLUSION: Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making.

Standard and Hypofractionated Dose Escalation to Intraprostatic Tumor Nodules in Localized Prostate Cancer: Efficacy and Toxicity in the DELINEATE Trial.

PURPOSE: To report a planned analysis of the efficacy and toxicity of dose escalation to the intraprostatic dominant nodule identified on multiparametric magnetic resonance imaging using standard and hypofractionated external beam radiation therapy. METHODS AND MATERIALS: DELINEATE is a single centre prospective phase 2 multicohort study including standard (cohort A: 74 Gy in 37 fractions) and moderately hypofractionated (cohort B: 60 Gy in 20 fractions) prostate image guided intensity modulated radiation therapy in patients with National Comprehensive Cancer Network intermediate- and high-risk disease. Patients received an integrated boost of 82 Gy (cohort A) and 67 Gy (cohort B) to lesions visible on multiparametric magnetic resonance imaging. Fifty-five patients were treated in cohort A, and 158 patients were treated in cohort B; the first 50 sequentially treated patients in cohort B were included in this planned analysis. The primary endpoint was late Radiation Therapy Oncology Group rectal toxicity at 1 year. Secondary endpoints included acute and late toxicity measured with clinician- and patient-reported outcomes at other time points and biochemical relapse-free survival for cohort A. Median follow-up was 74.5 months for cohort A and 52.0 months for cohort B. RESULTS: In cohorts A and B, 27% and 40% of patients, respectively, were classified as having National Comprehensive Cancer Network high-risk disease. The cumulative 1-year incidence of Radiation Therapy Oncology Group grade 2 or worse rectal and urinary toxicity was 3.6% and 0% in cohort A and 8% and 10% in cohort B, respectively. There was no reported late grade 3 rectal toxicity in either cohort. Within cohort A, 4 of 55 (7%) patients had biochemical relapse. CONCLUSIONS: Delivery of a simultaneous integrated boost to intraprostatic dominant nodules is feasible in prostate radiation therapy using standard and moderately hypofractionated regimens, with rectal and genitourinary toxicity comparable to contemporary series without an intraprostatic boost.

A prospective observational study of on-treatment plasma homocysteine levels as a biomarker of toxicity, depression and vitamin supplementation lead-in time pre pemetrexed, in patients with non-small cell lung cancer and malignant mesothelioma.

OBJECTIVES: Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity. MATERIAL AND METHODS: Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities. RESULTS: Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities. CONCLUSION: On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short.

Spect perfusion imaging versus CT for predicting radiation injury to normal lung in lung cancer patients.

OBJECTIVES: In non-small cell lung cancer (NSCLC) patients, to establish whether the fractional volumes of irradiated anatomic or perfused lung differed between those with and without deteriorating lung function or radiation associated lung injury (RALI). METHODS: 48 patients undergoing radical radiotherapy for NSCLC had a radiotherapy-planning CT scan and single photon emission CT lung perfusion imaging (99mTc-labelled macroaggregate albumin). CT defined the anatomic and the single photon emission CT scan (co-registered with CT) identified the perfused (threshold 20 % of maximum) lung volumes. Fractional volumes of anatomic and perfused lung receiving more than 5, 10, 13, 20, 30, 40, 50 Gy were compared between patients with deteriorating (>median decline) vs stable (30, 40, 50 Gy). Fractional volumes of anatomic and perfused lung receiving > 10 Gy best predicted decline in FEV1 (Area under receiver operating characteristic curve (Az = 0.77 and 0.76 respectively); sensitivity/specificity 75%/81 and 80%/71%) for a 32.7% anatomic and 33.5% perfused volume cut-off. Irradiating an anatomic fractional volume of 4.7% to > 50 Gy had a sensitivity/specificity of 83%/89 % for indicating RALI (Az = 0.83). CONCLUSION: A 10-20 Gy radiation dose to anatomic or perfused lung results in decline in FEV1. A fractional anatomic volume of >5% receiving >50 Gy influences development of RALI. ADVANCES IN KNOWLEDGE: Extent of low-dose radiation to normal lung influences functional respiratory decline.

Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls.

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.

A phase 1b trial of the combination of an all-oral regimen of capecitabine and erlotinib in advanced non-small cell lung cancer in Caucasian patients.

PURPOSE: Erlotinib is active in advanced non-small cell lung cancer (aNSCLC) particularly in patients with EGFR-sensitizing mutations. The thymidylate synthase inhibitors are active in NSCLC, but capecitabine is not well studied. This study explored the safety and activity of this oral combination. METHODS: This phase Ib trial used a 3 + 3 escalation design with a combination of erlotinib (100 mg daily) with increasing doses of capecitabine (500, 750 and 1000 mg/m(2) BD, 14/21 days), in first- and second-line aNSCLC of adenocarcinoma histology. The DLT was any drug-induced toxicity ≥grade (G)2 causing dose interruption or dose delay during the first 2 cycles. RESULTS: Forty patients were recruited, and 1 patient had an EGFR mutation. Dose escalation stopped at capecitabine 1000 mg/m(2) with expansion to 6 patients due to unpredicted DLTs in 2/6 patients: G2 creatinine rise, G2 anaemia, G3 atrial fibrillation and G3 pneumonia. MTD was capecitabine 750 mg/m(2). First-line dose escalation at the MTD led to unpredicted DLTs in 3/4 patients (G3 troponin rise, G2 rash and G2 hyperbilirubinaemia). MTD expansion in the second-line setting was well tolerated. The most common drug toxicities were gastrointestinal (35 %), followed by skin disorders (28 %). The response rate was 3 % with a disease control rate of 34 %. Median progressive-free survival was 1.6 months (95 % CI 1.4-3.5), and median overall survival was 6.1 months (95 % CI 5.1-10.1). CONCLUSION: The MTD for the combination of capecitabine and erlotinib is 750 mg/m(2) BD, 14/21 days, and 100 mg daily, respectively, which is lower than predicted. Capecitabine did not improve the efficacy of erlotinib in aNSCLC unselected for EGFR mutation.

Resolution of severe hyponatraemia is associated with improved survival in patients with cancer.

BACKGROUND: Hyponatraemia is a common finding in patients with cancer, and has been shown to be associated with poor prognosis in different settings. We have analysed the impact of severe hyponatraemia in patients with cancer. METHODS: A retrospective review of all patients admitted to a specialist cancer hospital with a plasma sodium of less than 115 mmol/l and a diagnosis of malignancy was undertaken. Patient and tumour characteristics were analysed as well as impact of hyponatraemia management on overall survival and number of lines of cancer treatment received. RESULTS: 57 patients were identified. 84% had advanced Stage 3 or 4 cancer and approximately 85% with data available had symptoms attributable to hyponatraemia. Mean length of hospital stay was 12 days, and overall survival (OS) was 5.1 months. Plasma sodium level corrected in 56% of patients and here OS was 13.6 months compared to 16 days in those whose sodium did not correct (p < 0.001). Those whose sodium corrected were more likely to receive further lines of anti-cancer treatment. CONCLUSIONS: Severe hyponatraemia in cancer is associated with very poor survival, but correction of the sodium level leads to additional treatment and significantly greater overall survival (although it is not possible to determine if this is due to specific therapy of the hyponatraemia or the resolving hyponatraemia reflects an improvement in the clinical condition). Aggressive treatment of hyponatraemia may allow more anti-cancer treatment and improve survival.

A serum mesothelin level is a prognostic indicator for patients with malignant mesothelioma in routine clinical practice.

BACKGROUND: Malignant mesothelioma (MM) carries a poor prognosis and response rates to palliative chemotherapy remain low. Identifying patients with MM that are unlikely to respond to chemotherapy could prevent futile treatments and improve patient quality of life. Studies have suggested that soluble mesothelin is a potential biomarker for early diagnosis and prognosis of MM. We set out to explore the utility of serum mesothelin in routine clinical practice. METHODS: We conducted a prospective exploratory study of serum mesothelin levels in 53 consecutive patients with MM at our institution between April 2009 and February 2011. Survival was assessed and analysed by mesothelin level as both continuous and categorical variables using Cox regression models. Differences in response rate between treatment groups were assessed by the Kruskal-Wallis Test. RESULTS: All 53 patients, who had been given study information agreed to participate. The patients' median age was 69 (range 24-90). Median mesothelin level was 2.7 nM and this value was used to dichotomize categories: ≤2.7 nM (low) and >2.7 nM (high). The progression free survival (PFS) for low vs high mesothelin was 8.0 vs 5.1 months (HR 1.8, p-0.058). When mesothelin was accessed as a continuous variable for PFS the HR was 1.03 (95% CI: 1.01-1.06; p=0.013). The overall survival (OS) for low vs high mesothelin was 17.2 vs 11.3 months (HR 1.9, p=0.088). When mesothelin was assessed as a continuous variable for OS the HR was 1.02 (95% CI: 0.99 - 1.04; p=0.073). Thirty patients received chemotherapy of which 18 had a pre-chemotherapy serum mesothelin level. In these 18 patients, the pre-chemotherapy mesothelin level did not correlate with response. CONCLUSIONS: A single random sample provides information about patient prognosis but does not predict treatment response. We suggest further prospective validation of mesothelin testing as a prognostic biomarker.

A pilot study of a novel home telemonitoring system for oncology patients receiving chemotherapy.

We examined the accuracy and acceptability of a home telemonitoring system for patients receiving chemotherapy. Patients undergoing two cycles of chemotherapy (over six weeks) used the telemonitoring system to analyse their own blood (capillary) and to enter symptom and temperature data. The blood results obtained from self-testing were compared with those from a venous blood sample analysed in the hospital laboratory analyser (the gold standard). We also documented the number and type of alerts generated by the telemonitoring system. Acceptability (ease of use and patient satisfaction) was assessed using questionnaires. Ten patients (mean age 61 years, 60% female) provided 48-paired samples. None of the patients succeeded in obtaining all blood results within pre-defined limits of agreement (i.e. within 15% for haemoglobin, haematocrit, white cell count; and 20% for neutrophil count) during the study. However, the level of clinical agreement between the system and the laboratory standard was good; only three out of the 48 samples and two out of the 10 patients had differences in blood results that might have had clinical implications. The telemonitoring system correctly generated 42 alerts. The patients found the telemonitoring system easy to use. With further refinement this should become an acceptable component of routine clinical practice for monitoring patients receiving chemotherapy.

Diethylstilbestrol in castration-resistant prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Diethylstilbestrol (DES) was the first hormone treatment used for prostate cancer and has also shown effectiveness in castration-resistant disease in small studies; however, concerns over thromboembolic toxicity have restricted its use in the past. Over 200 elderly men with castration-resistant prostate cancer were treated with 1-3 mg of DES, given with 75 mg aspirin and breast bud irradiation. Almost 30% of men showed a significant PSA response and the median time to PSA progression was 4.6 months. Almost 20% of patients with pain had a significant analgesic benefit. The most important toxicity was thromboembolism in 10% of men. Overall the drug has an acceptable toxicity profile and offers a palliative benefit in frail elderly men who may not be fit for chemotherapy. OBJECTIVE: • To assess the efficacy and toxicity of diethylstilbestrol (DES) in the management of castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: • A total of 231 patients with CRPC received treatment with DES at the Royal Marsden Hospital between August 1992 and August 2000. • The median pre-treatment prostate-specific antigen (PSA) level was 221 ng/mL. • DES was used at a dose of 1-3 mg daily, with aspirin 75 mg. • The primary endpoint was PSA response rate. RESULTS: • The PSA response rate (using PSA Working Group criteria) was 28.9%. • The median time to PSA progression was 4.6 months. • Of patients with bone pain, 18% had an improvement in their European Organisation for the Research and Treatment of Cancer pain score. • Thromboembolic complications were seen in 9.9% of all patients. CONCLUSIONS: • DES has significant activity in CRPC and can be of palliative benefit. • DES has an acceptable toxicity profile in the management of patients with symptomatic CRPC when used at a dose of 1-3 mg, combined with aspirin and prophylactic breast bud radiotherapy.