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regimes in lung cancer, from a literature search carried out between 20/03/2020 and 30/03/2020 as well as published and unpublished audits of hypofractionated regimes from UK centres.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.

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.

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.

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.

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.

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.

Changes in the incidence and mortality of testicular cancer in Scotland with particular reference to the outcome of older patients treated for non-seminomatous germ cell tumours.

This paper describes the temporal pattern of germ cell testicular cancer in Scotland between 1960 and 1990. The effect of age on the prognosis of patients with non-seminomatous germ cell tumours (NSGCT) has been assessed by studying all patients presenting in the West of Scotland between 1975 and 1989. Between 1960 and 1990, the number of testicular germ cell tumours registered has increased more than 2-fold; mortality rates have declined equally dramatically. Univariate and multivariate analysis of the data obtained on 440 patients with NSGCT showed age was not a prognostic factor influencing survival. 52 were patients over 40 years at presentation; their 5 years survival was 71% compared with 79% in the younger patients (n = 388). This small survival difference is probably explained by the higher proportion of older patients treated before 1980. Treatment for this older group should be approached with the same curative intent as for younger patients and the same expectation of success.

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.

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.

A comparison of 'abruptly stopping' with 'tailing off' oral corticosteroids in acute asthma.

Systemic corticosteroids are almost universally used in the treatment of severe acute asthma but the optimum length of treatment with corticosteroids following recovery from an acute attack of asthma is not established. Thirty-five patients admitted with acute asthma and treated with oral prednisolone 40 mg daily in addition to bronchodilator therapy until full recovery, with stable peak expiratory flow recordings (PEF) within 15% of their previous best PEF or predicted PEF were studied. They were all discharged home on regular inhaled corticosteroids and regular or as required use of bronchodilators and randomized to receive either prednisolone 40 mg daily or placebo for the first 14 days. Median PEF values increased from 31% predicted on admission to hospital to 71% predicted on discharge from hospital in the active treatment group (19 patients) and from 32-73% in the placebo group (16 patients). There was no difference between the two groups in the median values of the forced expiratory volume in one second, forced vital capacity, total lung capacity or diurnal variation in PEF either at the time of discharge from hospital or at 14 and 28 days after discharge from hospital. This study suggests that there is no need to reduce prednisolone gradually following recovery from an exacerbation of asthma, provided systemic corticosteroid treatment is continued until a satisfactory and stable PEF is achieved.

Chemotherapy for neuroendocrine tumors: the Beatson Oncology Centre experience.

The role of chemotherapy in malignant neuroendocrine tumours is difficult to assess because of their rarity and variation in biological behaviour. We present a retrospective review of chemotherapy given to 18 patients with metastatic and one with locally advanced neuroendocrine tumours. There were eight poorly differentiated neuroendocrine tumours, six thyroid medullary carcinomas, two phaeochromocytomas, two pancreatic islet cell tumours and one undifferentiated neuroblastoma. Four patients were given 3-weekly dacarbazine, vincristine and cyclophosphamide (DOC) chemotherapy. In eight patients, this regimen was modified by substituting the dacarbazine and cisplatin and etoposide (OPEC). A further six patients were treated with dacarbazine reintroduced into the 3-weekly regimen (DOPEC). The remaining patient received cisplatin and etoposide. There were two complete responses (both with OPEC) and eight partial responses (two with DOC, three with OPEC and three with DOPEC). Five patients had stable disease and four progressed. Four received further chemotherapy on relapse, producing one complete and one partial response. The median response duration to initial chemotherapy was 10 months (range 3-34). The median survival was 12 months (range 1-42). The main toxicity was haematological, with grade 3-4 neutropenia in 12 patients; eight suffered episodes of sepsis. One death was treatment related. Other toxicity was mild although three patients discontinued vincristine with grade 2 neurotoxicity. The response rate and side effects of these three regimens appear comparable. We conclude that, although these patient numbers are small, combination chemotherapy produces an encouraging response rate (53%; 95% CI 30-75) in malignant neuroendocrine tumours, with acceptable toxicity.

The prevalence of menopausal symptoms in patients treated for breast cancer.

A survey has been performed to discover the prevalence of menopausal symptoms in 108 patients successfully treated for breast cancer. Patients were assessed by them answering a custom designed questionnaire, and the use of the Hospital Anxiety and Depression (HAD) scale and the Greene Climacteric Scale. During the first year after treatment 70% of women suffered such symptoms; overall 60% of women surveyed were affected. Adjuvant hormonal treatment was the largest contributing factor in the development of symptoms. There was a relationship with borderline cases of anxiety, but not with definite cases of anxiety, as measured by the HAD scale. The high proportion of women shown to be affected means that treatment of menopausal symptoms should be incorporated into randomized trials of adjuvant therapy.

Immediate side effects of large fraction radiotherapy.

The use of hypofractionated radiotherapy regimens is becoming more widely recognized in the palliation of non-small cell lung carcinoma (NSCLC). Anecdotal reports of chest pain, rigors and fevers in the hours that follow radiotherapy led us to perform a survey estimating the frequency and severity of these symptoms following treatment to the thorax. One hundred and eighteen patients completed questionnaires 24 hours after palliative radiotherapy treatment; 84 were male. The median age was 67 years. One hundred and seven had histologically confirmed NSCLC. A parallel opposed technique was used in 113 patients. Doses ranged from 8 Gy in a single fraction to 60 Gy in 30 fractions. Chest pain was reported by 54 (45.8%) patients after the first radiotherapy fraction; in 42 it commenced within 12 hours of treatment. The pain varied in site, nature and duration; on 23 occasions, it lasted under 2 hours. Systemic symptoms (rigors, sweating, fevers) were documented on 43 questionnaires, starting within 12 hours of treatment in 33 patients and on 30 occasions lasting less than 2 hours. Chest pain and systemic symptoms occurred together in 28 patients. Only 49 (41.5%) patients reported no immediate side effects. We conclude that patients receiving palliative radiotherapy for bronchial carcinoma often develop significant symptoms in the hours following treatment. The timing and duration suggest a relationship with the radiotherapy, and we feel that patients should be warned of the possible occurrence of these symptoms.

Ulcerative skin reaction from subcutaneous infusion of isotonic methotrimeprazine and diamorphine.

We report an ulcerative skin reaction resulting from a subcutaneous infusion of isotonic methotrimeprazine and diamorphine. Skin reactions are a recognized side effect of this treatment, although they are reduced by the use of the isotonic formulation of methotrimeprazine. Frank ulceration has not been previously reported. It occurred in our patient despite low doses of diamorphine and methotrimeprazine, an isotonic formulation, and a short infusion time.

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.

Carboplatin, 5-fluorouracil and folinic acid: a 48-hour chemotherapy regimen in advanced and recurrent squamous carcinoma of the head and neck.

Eighty patients with advanced squamous carcinoma of the head and neck were entered into a study using a 2-day, inpatient, intravenous regimen. Folinic acid 200 mg/m2, 5-fluorouracil (5-FU) 500 mg/ m2 bolus followed by 5-FU 500 mg/m2 in a 22-hour infusion were given on days 1 and 2, with carboplatin 300 mg/m2 on day 2. The whole was repeated every 21 days. Forty-three patients had advanced disease with no prior treatment; 37 had recurred following radical treatment. Fifty-eight patients were male and the median age was 60 years. In total, 275 cycles of chemotherapy were given. The major toxicity was haematological, which delayed 65 cycles of chemotherapy and contributed to the death of two patients. Non-haematological toxicity was mild, with less than 8% of patients experiencing any toxicity greater than WHO grade 2. The patients who had had no previous treatment had a 65% response rate (95% confidence interval (95% CI) 48-80). Those who had been previously treated had a 37% response rate (95% CI 21-55). The overall response rate was 52% (95% CI 40-64), of whom 5% were complete responders. The median survival time was 36 weeks (95% CI 29-45), with the majority of patients dying with progressive disease. We conclude that this chemotherapy regimen was well tolerated and produced minimal toxicity, while maintaining an acceptable response rate of 52%.