The Use of Palliative Radiotherapy in the Treatment of Lung Cancer.

There have been significant advances in the systemic treatment of stage IV lung cancer, which is now recommended first line in patients with adequate fitness. This includes some patients with brain metastases due to the increased understanding of the central nervous system penetration of targeted therapies. The trials evidence base for palliative radiotherapy pre-dated this routine use of systemic therapy in our practice, which means that the sequence and role of palliative radiotherapy are not currently well defined in the first-line treatment setting. However, due to its efficacy in symptom control, radiotherapy remains a core component in the palliative management of lung cancer, particularly in the second-line setting and those unsuited to primary systemic treatment. This overview focuses on the evidence behind palliative radiotherapy to the thorax and brain for non-small cell and small cell lung cancer and the potential for future studies, including the TOURIST Trial Platform, to guide the future direction of these treatments.

Reduced Fractionation in Lung Cancer Patients Treated with Curative-intent Radiotherapy during the COVID-19 Pandemic.

Patients treated with curative-intent lung radiotherapy are in the group at highest risk of severe complications and death from COVID-19. There is therefore an urgent need to reduce the risks associated with multiple hospital visits and their anti-cancer treatment. One recommendation is to consider alternative dose-fractionation schedules or radiotherapy techniques. This would also increase radiotherapy service capacity for operable patients with stage I-III lung cancer, who might be unable to have surgery during the pandemic. Here we identify reduced-fractionation for curative-intent radiotherapy regimes in lung cancer, from a literature search carried out between 20/03/2020 and 30/03/2020 as well as published and unpublished audits of hypofractionated regimes from UK centres. Evidence, practical considerations and limitations are discussed for early-stage NSCLC, stage III NSCLC, early-stage and locally advanced SCLC. We recommend discussion of this guidance document with other specialist lung MDT members to disseminate the potential changes to radiotherapy practices that could be made to reduce pressure on other departments such as thoracic surgery. It is also a crucial part of the consent process to ensure that the risks and benefits of undergoing cancer treatment during the COVID-19 pandemic and the uncertainties surrounding toxicity from reduced fractionation have been adequately discussed with patients. Furthermore, centres should document all deviations from standard protocols, and we urge all colleagues, where possible, to join national/international data collection initiatives (such as COVID-RT Lung) aimed at recording the impact of the COVID-19 pandemic on lung cancer treatment and outcomes.

Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Non-small Cell Lung Cancer (NSCLC): 7 Years' Experience From Nine UK Centres.

AIM: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009. MATERIALS AND METHODS: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance. RESULTS: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity. CONCLUSION: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules.

Functional Image-guided Radiotherapy Planning for Normal Lung Avoidance.

For patients with lung cancer undergoing curative intent radiotherapy, functional lung imaging can be incorporated into treatment planning to modify the dose distribution within non-target volume lung by differentiation of lung regions that are functionally defective or viable. This concept of functional image-guided lung avoidance treatment planning has been investigated with several imaging modalities, primarily single photon emission computed tomography (SPECT), but also hyperpolarised gas magnetic resonance (MR) imaging, positron emission tomography (PET) and computed tomography (CT)-based measures of lung biomechanics. Here, we review the application of each of these modalities, review practical issues of lung avoidance implementation, including image registration and the role of both ventilation and perfusion imaging, and provide guidelines for reporting of future lung avoidance planning studies.

Quality of life, support and smoking in advanced lung cancer patients: a qualitative study.

BACKGROUND: Lung cancer is the most common cancer and smoking is the principal cause. Due to poor survival rates, symptom palliation and promotion of health-related quality of life (HRQoL) are primary outcomes for lung cancer patients. Given the established relationship between smoking and lung cancer, patients who have smoked may feel stigmatised or guilty after diagnosis, and more pessimistic about their illness and likely outcomes. This may have adverse implications for HRQoL. OBJECTIVES: We explored HRQoL and support experiences among newly diagnosed patients with advanced lung cancer. DESIGN: Semistructured interviews were conducted with nine patients and analysed using interpretative phenomenological analysis. RESULTS: Patients described the physical, emotional and social impact of disease on HRQoL. Fear of compromising their immune system and adjusting to new relationship roles had a wide-ranging effect on patients' HRQoL. Patients acknowledged links between lung cancer and smoking but some continued to smoke. They were sensitive to the opinions of medical staff about smoking especially those who continued to smoke or recently quit. CONCLUSIONS: We conclude that staff should give clearer advice about the adverse implications of continued smoking. We discuss the potential value of diagnosis as a teachable moment for promoting smoking cessation among patients and family members.

Stereotactic ablative radiotherapy in the UK: current status and developments.

Stereotactic ablative radiotherapy (SABR) has developed from the principles and techniques used in the stereotactic radiosurgery treatment of brain metastases. Advances in computer technology, imaging, planning and treatment delivery and evidence from retrospective analysis of single- and multi-institutional early-phase studies have established SABR in the treatment of medically inoperable early lung cancer. Effective multidisciplinary team working is crucial to safe delivery of SABR. The variation in patient selection, radiotherapy planning and delivery techniques has led to a collective approach to SABR implementation across the UK. Centres developing the technique are represented in the UK SABR Consortium, which is supported by the relevant UK professional bodies and represents a platform to develop extracranial SABR across the UK. The uptake of SABR in the UK has been slowed by workforce issues, but at least 15 centres are currently delivering treatment with over 500 patients treated using UK SABR Consortium guidance. A mentoring program is being piloted helping new centres to develop their programs, and over 30 UK centres are expected to be offering SABR treatment by the end of 2014. The use of consistent guidance for patient selection, treatment planning and delivery in the UK gives the opportunity to collect and audit toxicity and outcome across the centres, contributing to the internationally reported SABR experience. Having established this service in the UK, the development of SABR through clinical research is a priority, and with input from the Radiotherapy Trials Quality Assurance Group, the UK is developing a national study program that includes participation in international trials.

Continuous hyperfractionated accelerated radiotherapy (CHART) and non-conventionally fractionated radiotherapy in the treatment of non-small cell lung cancer: a review and consideration of future directions.

There is a well-established role for radiation treatment in the management of non-small cell lung cancer. As a single modality, it is indicated as a radical treatment option for patients deemed unsuitable for chemotherapy with inoperable locoregional disease or who decline surgery. In this patient group, the evidence shows advantages for accelerated treatment regimes, e.g. continuous hyperfractionated accelerated radiotherapy (CHART). Research efforts should be directed towards dose escalation with the application of the new technologies available. The multi-modality approach of chemoradiotherapy is established in the radical treatment of non-small cell lung cancer in those who are inoperable, radically treatable and fit enough to receive chemotherapy. How best these two modalities are combined remains unclear, and the combination of CHART and other non-conventionally fractionated radiotherapy schedules with chemotherapy and targeted agents is another potentially productive research area.

Review of testing and use of adjuvant trastuzumab across a cancer network--are we treating the right patients?

This review of practice assessed all early breast cancer patients diagnosed over 12 months to determine the frequency of human epidermal growth factor receptor 2 (HER2) positivity and trastuzumab use. The frequency of HER2 positivity in routine practice (185/1319; 14%) was less than expected. A significant proportion of patients (56/185; 30%) did not receive trastuzumab, largely due to concerns about chemotherapy tolerability.

Escalation and intensification of radiotherapy for stage III non-small cell lung cancer: opportunities for treatment improvement.

In this overview we review and model how radiotherapy tumour control and complication rates vary with dose, fractionation, schedule duration, irradiated volume and use of chemotherapy for stage III non-small cell lung cancer (NSCLC), and use the modelling to study the effectiveness of different NSCLC dose-escalation approaches being developed in the UK. Data have been collated for pneumonitis, lung fibrosis, early and late oesophagitis, cord and cardiac complications, and local progression-free survival at 30 months. Dependences of the various end points on treatment-related factors are catalogued and analysed using the linear-quadratic incomplete repair model to account for dose and fractionation effects, making linear corrections for differences in schedule duration, and loosely characterising volume effects using parallel- and series-type concepts. Tolerance limits are calculated for the different end points and distilled into ranges of prescribed dose likely to be tolerable when delivered in 2.5 and 4 week radiation and 6 week chemoirradiation schedules using conformal techniques. Worthwhile ( approximately 20%) gains in 30 month local progression-free survival should be achievable at safely deliverable levels of dose escalation. The analysis suggests that longer schedules may be more beneficial than shorter ones, but this finding is governed by the relative rates of tumour and oesophageal accelerated proliferation, which are quite imprecisely known. Consequently escalated 2.5, 4 and 6 week schedules are being developed; each should lead to useful improvements in local control but it is not yet known which schedule will be most effective.

Accelerated radical radiotherapy for non-small cell lung cancer using two common regimens: a single-centre retrospective study of outcome.

AIMS: A variety of radical radiotherapy regimens are in use for non-small cell lung cancer. Continuous hyperfractionated accelerated radiotherapy (CHART: 54 Gy in 36 fractions over 12 days) and accelerated hypofractionated radiotherapy using 55 Gy in 20 fractions over 4 weeks are standard fractionations in our centre. The primary aim of this retrospective study was to evaluate survival outcome seen in routine clinical practice. MATERIALS AND METHODS: All case notes and radiotherapy records of radically treated patients between 1999 and 2004 were retrospectively reviewed. Basic patient demographics, tumours, characteristics, radiotherapy and survival data were collected. RESULTS: In total, 277 patients received radical radiotherapy: 137 and 140 patients received CHART and hypofractionated radiotherapy, respectively. There were differences noted in the demographics between the two treatment schedules: median age 65 years (range 41-83) vs 73 years (range 33-87); histological confirmation rates 90% vs 76%; prior chemotherapy 34% vs 19% for CHART and hypofractionated treatment, respectively. For CHART patients, stages I, II, III and unclassified were 12, 8, 68 and 12% and the staging for the hypofractionated regimen was 54, 11, 34 and 2%, respectively. The median overall survival from the time of diagnosis was 20.4 months with a 40% 2-year survival rate. For the two fractionations the median survival was 16.6 months vs 21.4 months and 34% vs 45% of patients were alive at 2 years in the CHART and hypofractionated groups, respectively. On multivariate analysis, stage was the only factor affecting overall survival - no difference was seen according to radiotherapy regimen. CONCLUSION: This single-centre study reflects the outcome of unselected consecutively treated non-small cell lung cancer patients. Adjusting for stage, there was no significant difference in survival seen according to regimen. Encouragingly, CHART outcome shows reproducibility with the original CHART paper. Our hypofractionated outcome is similar to that previously reported, but despite this being the UK's most common regimen, 55 Gy in 20 daily fractions remains unvalidated by phase III trial data.

Epirubicin/vinorelbine adjuvant chemotherapy in young women with breast cancer is associated with preservation of menstrual function.

AIMS: To determine whether the epirubicin and vinorelbine regimen in the adjuvant (neoadjuvant) treatment of breast cancer has minimum adverse effects on menstrual function. PATIENTS AND METHODS: Thirty-six premenopausal women with a median age of 32 (25-47) years received epirubicin and vinorelbine. Twenty-eight received only epirubicin and vinorelbine without any other neo/adjuvant chemotherapy agents. Amenorrhoea was defined as absence of periods 6 months after the completion of chemotherapy. The medical records of all patients were reviewed retrospectively. RESULTS: Twenty-six patients were assessable for effects of epirubicin and vinorelbine on menstruation. All the 26 patients resumed menstruation within 6 months of completing epirubicin and vinorelbine treatment. Epirubicin and vinorelbine was well tolerated. After a median follow-up of 38.5 (11-78) months, six (21%) patients had developed disease relapse and three (11%) had died. The 6.5-year disease-free survival and overall survival probabilities were 77 and 86%, respectively. CONCLUSION: Adjuvant (neoadjuvant) epirubicin and vinorelbine is an effective and well-tolerated regimen that is associated with the retention of menstrual function.

The use of lung dose-volume histograms in predicting post-radiation pneumonitis after non-conventionally fractionated radiotherapy for thoracic carcinoma.

AIMS: To assess the use of lung dose-volume histogram (DVH) parameters (specifically V20Gy) in the prediction of radiation pneumonitis for non-conventional fraction sizes used in the treatment of lung cancer. MATERIALS AND METHODS: Patients requiring computed tomography planning for thoracic radiotherapy between January 1999 and January 2002 were identified. The patients receiving radical or high-dose palliative radiotherapy had DVH produced routinely during planning. These were retrospectively reviewed and the case notes accessed for additional pre-treatment parameters, demographics and evidence of radiation pneumonitis. The severity of the pneumonitis was then scored using Radiation Therapy Oncology Group criteria. Data were analysed using the SPSS computer program. RESULTS: One hundred and sixty consecutive patients were reviewed. Ninety patients received hypofractionated treatment (fraction size > 2.5 Gy) and 57 continuous hyperfractionated accelerated radiation therapy (CHART) (fraction size 1.5 Gy). Lung V20Gy values ranged from 3% to 53%, with a median value of 24%. Only six patients reported grade 2, and 16 patients grade 3 pneumonitis. Two patients developed fatal, grade 5 pneumonitis. No correlation between pneumonitis score and V20Gy or other possible predictive factors was found. CONCLUSION: The 15% grade 2-5 pneumonitis rate we document is at the lower end of the spectrum reported in other studies. This suggests that using published data on limiting V20Gy values to reduce the risk of radiation pneumonitis can be extrapolated to planning treatment with non-conventionally fractionated radiotherapy.

The management and survival of patients with advanced germ-cell tumours: improving outcome in intermediate and poor prognosis patients.

AIMS: The survival of germ-cell tumours (GCT) was transformed after the introduction of cisplatin-based therapy. Previous trials have indicated BEP (bleomycin, etoposide and cisplatin) as the optimum treatment, although some centres including our own advocate the use of the alternating regimen POMB-ACE (cisplatin, vincristine, methotrexate, bleomycin and dactinomycin, cyclophosphamide and etoposide) for men with intermediate or poor prognosis disease. We analysed the survival and management of GCT patients treated at a specialist cancer centre in relation to internationally recognised prognostic groupings. MATERIALS AND METHODS: We retrieved patient information using the Trent Testicular Tumour Registry and supplemented it with information from patient notes. This included all patients with Royal Marsden Hospital Stage II, III and IV disease and patients with stage I disease at diagnosis with raised markers or subsequent relapse. We compared the efficacy and toxicity of the BEP and POMB-ACE chemotherapy regimens, and assessed relapse-free and overall survival. RESULTS: We identified 178 non-seminomatous germ cell tumours (NSGCT) and 71 seminoma patients. Overall survival was similar to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification for the good (95% vs 92%) and intermediate groups (82% vs 80%). The outcome for the poor prognosis group was better than expected in our series (57% vs 48%). There was a higher proportion of both immediate and late side-effects with POMB-ACE. CONCLUSION: Survival and disease progression rates at this single institution were at least as good as reported by the IGCCCG and somewhat better for the poor-prognosis group. This may reflect use of the POMB-ACE chemotherapy regimen as opposed to standard BEP regimen. However, a randomised comparison of BEP and POMB-ACE would be required to validate this.

The impact of virtual simulation in palliative radiotherapy for non-small-cell lung cancer.

BACKGROUND AND PURPOSE: Radiotherapy is widely used to palliate local symptoms in non-small-cell lung cancer. Using conventional X-ray simulation, it is often difficult to accurately localize the extent of the tumour. We report a randomized, double blind trial comparing target localization with conventional and virtual simulation. METHODS: Eighty-six patients underwent both conventional and virtual simulation. The conventional simulator films were compared with digitally reconstructed radiographs (DRRs) produced from the computed tomography (CT) data. The treatment fields defined by the clinicians using each modality were compared in terms of field area, position and the implications for target coverage. RESULTS: Comparing fields defined by each study arm, there was a major mis-match in coverage between fields in 66.2% of cases, and a complete match in only 5.2% of cases. In 82.4% of cases, conventional simulator fields were larger (mean 24.5+/-5.1% (95% confidence interval)) than CT-localized fields, potentially contributing to a mean target under-coverage of 16.4+/-3.5% and normal tissue over-coverage of 25.4+/-4.2%. CONCLUSIONS: CT localization and virtual simulation allow more accurate definition of the target volume. This could enable a reduction in geographical misses, while also reducing treatment-related toxicity.

Acute changes in peak expiratory flow rate following palliative radiotherapy for bronchial carcinoma.

PURPOSE: Changes in respiratory function occurring in the months and years following radiotherapy have been well documented. The changes that occur in the hours after treatment are less clear, we report a study that recorded peak expiratory flow rate (PEFR) in the 72 h following radiotherapy to the mediastinum and large airways. METHODS: Fifty-six patients with carcinoma affecting the major bronchii were recruited; 39 were male, with a median age of 66 years; 49 had histologically confirmed lung cancer. The median baseline PEFR was 300 1/s (range: 120-600). Patients were asked to record home PEFR readings in the 72 h that followed the first fraction of radiotherapy. Doses ranges from an 8-Gy single fraction to 60 Gy in 30 fractions. RESULTS: Forty-nine patients recorded a fall in PEFR (3%-60% of the baseline value) in the 24 h after radiotherapy, the mean for all 56 patients was a fall of 20.3% (95% confidence interval -15.8% to -24.8%). These lowest values occurred a median time of 6 h after treatment (range: 2-24 h). By 72 h the mean PEFR had returned to the baseline. Tumour site (central or lobar bronchus) and fraction size (<3 GY or >3 Gy) had no significant effect on the fall in PEFR (Mann-Whitney U-test P = 0.15 and P = 0.06, respectively). CONCLUSION: We conclude that a fall in PEFR can occur after radiotherapy treatment to the mediastinum. This is of concern in patients being treated for bronchial carcinoma whose respiratory function may already be compromised.