Palliative Lung Radiotherapy: Higher Dose Leads to Improved Survival?

AIMS: Choosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients. MATERIALS AND METHODS: A retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated. RESULTS: Univariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), 'lifelong never' smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively. CONCLUSION: In this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status.

A Sensitivity Analysis of the Impact of Rain on Regional and Global Sea-Air Fluxes of CO2.

The global oceans are considered a major sink of atmospheric carbon dioxide (CO2). Rain is known to alter the physical and chemical conditions at the sea surface, and thus influence the transfer of CO2 between the ocean and atmosphere. It can influence gas exchange through enhanced gas transfer velocity, the direct export of carbon from the atmosphere to the ocean, by altering the sea skin temperature, and through surface layer dilution. However, to date, very few studies quantifying these effects on global net sea-air fluxes exist. Here, we include terms for the enhanced gas transfer velocity and the direct export of carbon in calculations of the global net sea-air fluxes, using a 7-year time series of monthly global climate quality satellite remote sensing observations, model and in-situ data. The use of a non-linear relationship between the effects of rain and wind significantly reduces the estimated impact of rain-induced surface turbulence on the rate of sea-air gas transfer, when compared to a linear relationship. Nevertheless, globally, the rain enhanced gas transfer and rain induced direct export increase the estimated annual oceanic integrated net sink of CO2 by up to 6%. Regionally, the variations can be larger, with rain increasing the estimated annual net sink in the Pacific Ocean by up to 15% and altering monthly net flux by > ± 50%. Based on these analyses, the impacts of rain should be included in the uncertainty analysis of studies that estimate net sea-air fluxes of CO2 as the rain can have a considerable impact, dependent upon the region and timescale.

The Current Role of Radiotherapy in the Treatment of Small Cell Lung Cancer.

Radiotherapy has been shown to play a key role in the management of small cell lung cancer. There are well-established data in the literature for the use of concurrent chemoradiotherapy for stage I-III disease, although key questions remain over the timing of radiation, the optimal dose/fractionation and particularly once versus twice daily treatment, the use of elective nodal irradiation and drug combinations. Data for the use of thoracic radiation in stage IV disease, after chemotherapy, have recently become available and are leading to a change in practice. Prophylactic cranial irradiation has been shown to be of use in both stage I-III and stage IV disease, although uncertainties surround its use in the elderly population and the use of brain imaging before treatment. This overview will address the current available evidence and focus on areas for future research.

Stereotactic body radiotherapy (SBRT) in the management of extracranial oligometastatic (OM) disease.

OBJECTIVE: A review of stereotactic body radiotherapy (SBRT) for oligometastases defined as three or fewer sites of isolated metastatic disease. The aim was to identify local control, overall survival (OS) and progression-free survival (PFS) of patients receiving SBRT for oligometastatic (OM) disease. METHODS: Data were analysed for SBRT delivered between 01 September 2010 and 31 March 2014. End points included local control, PFS, OS and toxicity. RESULTS: 76 patients received SBRT. The median age was 60 years (31-89 years). 44 were male. Median follow-up was 12.3 months (0.2-36.9 months). Major primary tumour sites included colorectal (38%), the breast (18%) and the prostate (12%). The treatment sites included lymph nodes (42%), the bone and spine (29%) and soft tissue (29%). 42% were previously treated with conventional radiotherapy. 45% were disease free after SBRT. 4% had local relapse, 45% had distant relapse, and 6% had local and distant relapse. Local control was 89%. The OS was 84.4% at 1 year and 63.2% at 2 years. PFS was 49.1% at 1 year and 26.2% at 2 years. Toxicities included duodenal ulcer and biliary stricture formation. CONCLUSION: SBRT can achieve durable control of OM lesions and results in minimal radiation-induced morbidity. ADVANCES IN KNOWLEDGE: This cohort is one of the largest reported to date and contributes to the field of SBRT in oligometastases that is emerging as an important research area. It is the only study reported from the UK and uses a uniform technique throughout. The efficacy and low toxicity with durable control of local disease with this approach is shown, setting the foundations for future randomized studies.

Outcomes of primary lymphoma of the ocular adnexa (orbital lymphoma) treated with radiotherapy.

AIMS: Low-grade ocular adnexal lymphoma is a rare disease and often treated with local radiotherapy to varying doses. Most previously reported studies have a very heterogeneous patient population and treatments. We report the outcomes from a 10 year cohort of patients at our institution treated with primary radiation therapy. MATERIALS AND METHODS: We analysed a retrospective case series of patients with stage IE low-grade ocular adnexal lymphoma including a review of case notes, histological reports and radiotherapy charts. We assessed local and distant tumour control and relapse rates in addition to toxicity. Disease-free survival was estimated using the Kaplan-Meier method. RESULTS: In total, 81 patients and 85 orbits were treated with primary radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Seventy-nine per cent were treated with standard MV external beam radiotherapy to the whole orbit and 21% with a lens-sparing technique. The median follow-up was 4.4 years (range 0.2-10.4). Local control rates were 100%, with 5% of patients experiencing disease relapse elsewhere. No patients died from lymphoma. Cumulative acute toxicity rates were 51% (mainly erythema and conjunctivitis) and late toxicity rates were 8% (mainly cataract). The lens-sparing technique was associated with a significant reduction in cataract rate (P = 0.013) and an increase in acute toxicity (P < 0.001). CONCLUSIONS: This study has shown excellent local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks.

Assessing response to treatment of bone metastases from breast cancer: what should be the standard of care?

Bone is the most common site for breast cancer metastases, occurring in up to 70% of those with metastatic disease. In order to effectively manage these patients, it is essential to have consistent, reproducible and validated methods of assessing response to therapy. We present current clinical practice of imaging response assessment of bone metastases. We also review the biology of bone metastases and measures of response assessment including clinical assessment, tumour markers and imaging techniques; bone scans (BSs), computed tomography (CT), positron emission tomography, magnetic resonance imaging (MRI) and whole-body diffusion-weighted MRI (WB DW-MRI). The current standard of care of BSs and CT has significant limitations and are not routinely recommended for the purpose of response assessment in the bones. WB DW-MRI has the potential to address this unmet need and should be evaluated in clinical trials.

Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer.

BACKGROUND: [(18)F]fluorothymidine (FLT) has been proposed as a positron emission tomography (PET)-imaging biomarker of proliferation for breast cancer. The aim of this prospective study was to assess the feasibility of FLT-PET-CT as a technique for predicting the response to neoadjuvant chemotherapy (NAC) in primary breast cancer and to compare baseline FLT with Ki-67. METHODS: Twenty women with primary breast cancer had a baseline FLT-PET-CT scan that was repeated before the second cycle of chemotherapy. Expression of Ki-67 in the diagnostic biopsy was quantified. From the FLT-PET-CT scans lesion maximum and mean standardised uptake values (SUVmax, SUVmean) were calculated. RESULTS: Mean baseline SUVmax was 7.3, and 4.62 post one cycle of NAC, representing a drop of 2.68 (36.3%). There was no significant association between baseline, post chemotherapy, or change in SUVmax and pathological response to NAC. There was a significant correlation between pre-chemotherapy Ki-67 and SUVmax of 0.604 (P=0.006). CONCLUSIONS: Baseline SUVmax measurements of FLT-PET-CT were significantly related to Ki-67 suggesting that it is a proliferation biomarker. However, in this series neither the baseline value nor the change in SUVmax after one cycle of NAC were able to predict response as most patients had a sizeable SUVmax reduction.

Fractionated stereotactic radiotherapy for acoustic neuromas: long-term outcomes.

AIMS: Acoustic neuromas are rare, benign intracranial tumours. There are a variety of treatment options, with no clear optimal management strategy and wide variation in treated outcomes. We report the outcomes from a 15 year cohort of patients treated at our centre using fractionated stereotactic radiotherapy (52.5 Gy in 25 fractions). MATERIALS AND METHODS: We analysed a retrospective case series. Patients were identified from patient records and a retrospective review of case notes and imaging reports was undertaken. We assessed tumour response using RECIST criteria and recorded toxicity. Progression-free survival was estimated using the Kaplan-Meier method. The study was conducted according to the STROBE guidelines. RESULTS: In total, 93 patients were identified; 83 patients had follow-up data, with a median follow-up period of 5.7 years. The overall control rate using RECIST criteria was 92%. Data on complications were available for 90 patients, with six (7%) experiencing a reduction in hearing, one (1%) developing trigeminal nerve dysfunction and one (1%) a deterioration in facial nerve function. Other toxicities included four (4%) patients who developed hydrocephalus, requiring the placement of a shunt and one (1%) patient who developed radiation brainstem necrosis. After further evaluation this patient was deemed to have been treated within acceptable dose constraints. CONCLUSION: These data suggest that a good control rate of acoustic neuromas is achievable using fractionated stereotactic radiotherapy to a dose of 52.5 Gy in 25 fractions. Toxicity is considered acceptable but the episode of radiation brainstem necrosis remains of concern and is the subject of further work.

Primary lymphoma of the ocular adnexa (orbital lymphoma) and primary intraocular lymphoma.

Lymphomas of the orbit and eye are rare conditions that should be treated as separate entities due to the differences in presumed aetiology, investigations, management and outcomes. Orbital lymphoma is most often of low-grade histology; thyroid eye disease may predispose and chlamydial infection has been suggested as a trigger. Commonly, stage IE, in most cases, can be managed with radiotherapy alone using either a kilovoltage portal for conjunctival disease or a wedged pair of megavoltage beams for more infiltrative disease to a dose of 30 Gy in 15 fractions over 3 weeks. However, medical therapy is being investigated, including a rituximab-only approach for conjunctival-only presentations. The cure rate for stage IE disease is very high. In contrast, primary ocular lymphoma is often of high-grade histology, in particular diffuse large B-cell lymphoma, and can be regarded as one end of primary central nervous system lymphoma - both eyes and brain being at risk. Immunosuppression predisposes to the disease. Management consists of an initial high-dose chemotherapy regimen with methotrexate. In most cases, this should be followed by radiotherapy to the whole brain and globes to a dose of 30-36 Gy with a boost to bulk/presenting disease. Cure rates are rarely above 50%.

The influence of the North Atlantic Oscillation on the sea-level around the northern European coasts reconsidered: the thermosteric effects.

The thermosteric contribution of the North Atlantic Oscillation (NAO) to the North Sea sea-level for the winter period is investigated. Satellite sea surface temperature as well as in situ measurements are used to define the sensitivity of winter water temperature to the NAO as well as to determine the trends in temperature. The sea surface temperature sensitivity to the NAO is about 0.85 degrees C per unit NAO, which results in thermosteric sea-level changes of about 1-2 cm per unit NAO. The sensitivity of sea surface temperatures to the NAO is strongly time-dependent. Model data from a two-dimensional hydrodynamic tide+surge model are used in combination with the estimated thermosteric anomalies to explain the observed sea-level changes and, in particular, the sensitivity of the datasets to the NAO variability. The agreement between the model and the observed data is improved by the inclusion of the thermosteric effect.

Towards a vulnerability assessment of the UK and northern European coasts: the role of regional climate variability.

Within the framework of a Tyndall Centre research project, sea level and wave changes around the UK and in the North Sea have been analysed. This paper integrates the results of this project. Many aspects of the contribution of the North Atlantic Oscillation (NAO) to sea level and wave height have been resolved. The NAO is a major forcing parameter for sea-level variability. Strong positive response to increasing NAO was observed in the shallow parts of the North Sea, while slightly negative response was found in the southwest part of the UK. The cause of the strong positive response is mainly the increased westerly winds. The NAO increase during the last decades has affected both the mean sea level and the extreme sea levels in the North Sea. The derived spatial distribution of the NAO-related variability of sea level allows the development of scenarios for future sea level and wave height in the region. Because the response of sea level to the NAO is found to be variable in time across all frequency bands, there is some inherent uncertainty in the use of the empirical relationships to develop scenarios of future sea level. Nevertheless, as it remains uncertain whether the multi-decadal NAO variability is related to climate change, the use of the empirical relationships in developing scenarios is justified. The resulting scenarios demonstrate: (i) that the use of regional estimates of sea level increase the projected range of sea-level change by 50% and (ii) that the contribution of the NAO to winter sea-level variability increases the range of uncertainty by a further 10-20cm. On the assumption that the general circulation models have some skill in simulating the future NAO change, then the NAO contribution to sea-level change around the UK is expected to be very small (<4cm) by 2080. Wave heights are also sensitive to the NAO changes, especially in the western coasts of the UK. Under the same scenarios for future NAO changes, the projected significant wave-height changes in the northeast Atlantic will exceed 0.4m. In addition, wave-direction changes of around 20 degrees per unit NAO index have been documented for one location. Such changes raise the possibility of consequential alteration of coastal erosion.