Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer.

BACKGROUND: Identification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use. PATIENTS AND METHODS: We analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). Tumour exome sequencing identified somatic mutations and plasma was analyzed using patient-specific RaDaR™ assays with up to 48 amplicons targeting tumour-specific variants unique to each patient. RESULTS: ctDNA was detected before treatment in 24%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <0.01%. ctDNA detection had clinical specificity >98.5% and preceded clinical detection of recurrence of the primary tumour by a median of 212.5 days. ctDNA was detected after treatment in 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (HR: 5.48, P <0.0003). ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively). CONCLUSIONS: ctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention.

Image-guided Radiotherapy to Manage Respiratory Motion: Lung and Liver.

Organ motion as a result of respiratory and cardiac motion poses significant challenges for the accurate delivery of radiotherapy to both the thorax and the upper abdomen. Modern imaging techniques during radiotherapy simulation and delivery now permit better quantification of organ motion, which in turn reduces tumour and organ at risk position uncertainty. These imaging advances, coupled with respiratory correlated radiotherapy delivery techniques, have led to the development of a range of approaches to manage respiratory motion. This review summarises the key strategies of image-guided respiratory motion management with a focus on lung and liver radiotherapy.

Stage III Non-small Cell Lung Cancer Management in England.

AIMS: We present the first analysis of the management and outcomes of stage III non-small cell lung cancer (NSCLC) conducted in England using National Lung Cancer Audit data. MATERIALS AND METHODS: Patients diagnosed with stage III NSCLC in 2016 were identified. Linked datasets (including Hospital Episode Statistics, the National Radiotherapy Dataset, the Systemic Anti-Cancer Dataset, pathology reports and death certificate data) were used to categorise the treatment received. Kaplan-Meier survival curves were obtained, with survival defined from the date of diagnosis to the date of death. RESULTS: In total, 6276 cases of stage III NSCLC were analysed: 3827 stage IIIA and 2449 stage IIIB; 1047 (17%) patients were treated with radical radiotherapy with 676 (11%) of these also receiving chemotherapy. Twenty per cent of patients with stage IIIA disease underwent surgery, with half of these also receiving chemotherapy, predominantly delivered in the adjuvant setting. Of note, 2148 (34%) patients received palliative-intent treatment and 2265 (36%) received no active anti-cancer treatment. The 1-year survival was 32.9% (37.4% for stage IIIA), with the highest survival seen for those patients receiving chemotherapy and surgery. CONCLUSIONS: We highlight important gaps in the optimal care of patients with stage III NSCLC in England. Multimodality treatment with either surgery or radical radiotherapy combined with chemotherapy was delivered to less than one-fifth of patients, even though these regimens are considered optimal. Timely access to specialist resources and staff, the practice of effective shared decision making and challenging preconceptions have the potential to optimise management.

Evaluating competing and emerging technologies for stereotactic body radiotherapy and other advanced radiotherapy techniques.

Stereotactic body radiotherapy (SBRT) refers to the precise irradiation of an image-defined extracranial lesion, using a high total radiation dose delivered in a small number of fractions. A significant proportion of SBRT treatment has been successfully delivered using conventional gantry-based linear accelerators with appropriate image guidance and motion management techniques, although a number of specialist systems are also available. Evaluating the competing SBRT technologies is difficult due to frequent refinements to all major platforms. Comparison of geometric accuracy or treatment planning performance can be hard to interpret and may not provide much useful information. Nevertheless, a general specification overview can provide information that may help radiotherapy providers decide on an appropriate system for their centre. A number of UK randomised controlled trials (RCTs) have shown that better radiotherapy techniques yield better results. RCTs should play an important part in the future evaluation of SBRT, especially where there is a smaller volume of existing data, and where outcomes from conventional radiotherapy are very good. RCT comparison of SBRT with surgery is more difficult due to the radically different treatment arms, although successful recruitment can be possible if the lessons from previous failed trials are learned. The evaluation of new technology poses a number of challenges to the conventional RCT methodology, and there may be situations where it is genuinely not possible, with careful observational studies or decision modelling being more appropriate. Further development in trial design may have an important role in providing clinical evidence in a more timely manner.

Total body irradiation using a modified standing technique: a single institution 7 year experience.

We describe a simple standing technique for delivering total body irradiation (TBI) using large horizontal fields, made possible by the off-centre installation of a non-dedicated treatment unit in a pre-existing bunker. Patients are treated using anterior and posterior fields with customized lung compensators. This technique enables the dose to the lung to be accurately calculated and modified to avoid overdose and to minimize the risk of pneumonitis. From February 1991 to December 1997, 94 patients with a variety of haematological malignancies were given fractionated TBI using this technique prior to allogenic or autologous bone marrow transplantation. Patients received a total dose of 14.4 Gy given in eight fractions over 4 days, with at least 6 h between fractions. The prescribed dose to the lungs was reduced to 12 Gy in eight fractions. The technique was well tolerated, took less than 10 min to set up and did not disrupt the daily routine use of the machine. Doses to all measured points on the trunk and head were within +/-6% of the prescribed dose. Doses to the lungs were within +/-5% of the prescribed dose. There were no early respiratory deaths in the 37 autologous transplant patients. There were 10 (17%) respiratory deaths in the 57 allogeneic transplant patients, 3 of confirmed infectious aetiology.

Treatment of localized carcinoma of the penis: a survey of current practice in the UK.

Consensus opinion from published reports on the management of localized carcinoma of the penis recommends that patients with small, distal, non-poorly differentiated lesions should be offered penis-conserving treatment, while those with larger or more advanced lesions should be considered for amputative surgery. A questionnaire survey was sent to 289 urologists and 237 oncologists in the UK to assess their practice for the treatment of localized carcinoma of the penis. Consultants were asked to choose between penis-conserving surgery, amputation or radiotherapy as their preferred treatment for four examples of localized disease. Oncologists were also asked to indicate their preferred radiation modality (external beam radiotherapy or brachytherapy). For treating a small lesion situated distally on the glans penis, 56.7% of urologists and 94.5% of oncologists preferred penis-conserving methods; 28.8% of urologists and one oncologist preferred partial or total amputation. In total, 43.2% of urologists would consider amputative surgery for this lesion compared with only 5.5% of oncologists. Only 23.3% of oncologists considered using brachytherapy. For a 4 cm lesion situated distally, the majority of urologists surveyed (82.0%) preferred amputative surgery, while the majority of oncologists (68.5%) preferred conservative treatment. For a 1.5 cm lesion extending on to the penile shaft, 68.5% of urologists preferred amputative surgery while 85.0% of oncologists preferred penis-conserving options. For a 4 cm lesion extending on to the shaft, the vast majority of urologists (86.5%) preferred amputation as treatment compared with only 36.9% of oncologists. The results of the survey suggested that clinicians tended to favour the treatment modality of which they have most experience. As such, urologists tended to prefer surgery while clinical oncologists tended to prefer radiotherapy, irrespective of the size and position of the primary tumour or consensus opinion. These results emphasize the importance of multidisciplinary clinics and site specialization, so that both clinicians and patients can make informed choices about optimal treatment, based on the knowledge of all available treatment options.