Hypofractionated Concomitant Chemoradiation in Inoperable Locally Advanced Non-small Cell Lung Cancer: A Report on 100 Patients and a Systematic Review.

AIMS: Concomitant chemoradiation is the standard of care in patients with inoperable non-small cell lung cancer. The purpose of this study was to analyse the survival outcome and toxicity data of using hypofractionated chemoradiation. MATERIALS AND METHODS: One hundred patients were treated from June 2011 to November 2016. Treatment consisted of 55 Gy in 20 daily fractions concurrently with split-dose cisplatin vinorelbine chemotherapy over 4 weeks followed by two cycles of cisplatin vinorelbine only. Survival was estimated using Kaplan-Meier and Cox regression was carried out for known prognostic factors. A systematic search of literature was conducted using Medline, Embase and Cochrane databases and relevant references included. RESULTS: In total, 97% of patients completed radiotherapy and 73% of patients completed all four cycles of chemotherapy. One patient died of a cardiac event during consolidative chemotherapy. There were two cases of grade 4 toxicities (one sepsis, one renal impairment). Grade 3 toxicities included nausea/vomiting (17%), oesophagitis (15%), infection with neutropenia (12%) and pneumonitis (4%). Clinical benefit was seen in 86%. Two-year progression-free survival and overall survival rates were 49% and 58%, respectively. The median progression-free survival and overall survival were 23.4 and 43.4 months, respectively. The only significant prognostic factor was the number of chemotherapy cycles received (P = 0.02). The systematic review identified 13 relevant studies; a variety of regimens were assessed with variable reporting of outcomes and toxicity but with overall an improvement in survival over time. CONCLUSION: Our experience compared with the original phase II trial showed improved treatment completion rates and survival with acceptable morbidity. With appropriate patient selection this regimen is an effective treatment option for locally advanced non-small cell lung cancer. This study helps to benchmark efficacy and toxicity rates while considering the addition of new agents to hypofractionated concurrent chemoradiotherapy. The agreement of a standard regimen for assessment in future trials would be beneficial.

Interim results in clinical trials: do we need to keep all interim randomised clinical trial results confidential?

OBJECTIVES: Guidelines for the conduct of clinical trials emphasize the importance of keeping the interim results from the main endpoints confidential, in order to maintain the integrity of the trial and to safeguard patients' interests. However, is this essential in every situation? MATERIALS AND METHODS: We review the evidence for these guidelines and consider recent randomised trials that have released interim results, to assess their impact on the success of the trial. However, because the strength of opinion to keep interim results confidential is so strong, there are limited examples of such trials. RESULTS: In the QUARTZ trial (which is assessing the value of whole brain radiotherapy in patients with brain metastases from non-small cell lung cancer) the decision to release interim results was taken in response to threatened closure due to poor accrual, whereas in the GRIT trial (which compared two obstetric strategies for the delivery of growth retarded pre-term fetuses) the regular release of interim results was pre-planned. Nevertheless there are a number of common factors between these two trials. In particular, the trial treatments were already in wide use, with no reliable randomised evidence on which treatment should be used for which patients, and there was diverse clinical opinion, which meant that accrual was likely to be challenging. In a situation where a quarter to a third of trials do not accrue their required number of patients, the QUARTZ trial continues to accrue patients, and the GRIT trial successfully accrued its target of nearly 600 babies. CONCLUSIONS: This article therefore argues that there is a need to re-consider whether it is always essential to keep the interim results of randomized clinical trials confidential, and suggests some criteria that may help groups planning or running challenging trials decide whether releasing interim results would be a useful strategy.

Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme.

INTRODUCTION: Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. PATIENTS AND METHODS: Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. RESULTS: Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. CONCLUSIONS: Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial.

Interim data from the Medical Research Council QUARTZ Trial: does whole brain radiotherapy affect the survival and quality of life of patients with brain metastases from non-small cell lung cancer?

AIMS: Over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases. If inoperable, optimal supportive care (OSC), including steroids, and whole brain radiotherapy (WBRT) are generally considered to be standard care, although there is no randomised evidence demonstrating that the addition of WBRT to OSC improves survival or quality of life. MATERIALS AND METHODS: QUARTZ is a randomised, non-inferiority, phase III trial comparing OSC + WBRT versus OSC in patients with inoperable brain metastases from NSCLC. The primary outcome measure is quality-adjusted life years (QALYs). QUARTZ was threatened with both loss of funding and early closure due to poor accrual. A lack of preliminary randomised data supporting the trial's hypotheses was thought to underlie the poor accrual, so, with no knowledge of the data, the independent trial steering committee agreed to the unusual step of releasing interim data. RESULTS: Between March 2007 and April 2010, 151 (of the planned 534) patients were randomised (75 OSC + WBRT, 76 OSC). Participants' baseline demographics included median age 67 years (interquartile range 62-73), 60% male, 50% with a Karnofsky performance status <70; steroid usage was similar in the two groups; 64/75 (85%) received WBRT (20 Gy in five fractions). Median survival was: OSC + WBRT 49 days (95% confidence interval 39-61), OSC 51 days (95% confidence interval 27-57) - hazard ratio 1.11 (95% confidence interval 0.80-1.53) in favour of WBRT. Quality of life assessed using EQ-5D showed no evidence of a difference. The estimated mean QALYs was: OSC + WBRT 31 days and OSC 30 days, difference -1 day (95% confidence interval -12.0 to +13.2 days). CONCLUSION: These interim data indicate no early evidence of detriment to quality of life, overall survival or QALYs for patients allocated to OSC alone. They provide key information for discussing the trial with patients and strengthen the argument for continuing QUARTZ to definitively answer this important clinical question.

The management of brain metastases in patients with non-small cell lung cancer-is it time to go back to the drawing board?

Unless confirmation of a solitary brain metastasis is made in the context of absent extracranial disease and good performance status, patients with metastatic brain disease from non-small cell lung cancer fare badly. There are no level I recommendations for the management of those with multiple brain metastases. The role of whole brain radiotherapy is not certain in those of poorer performance status. This overview assesses what we know and what we are uncertain of in the context of a changing paradigm for some subsets of patients who may obtain superior palliation with treatments targeted at the histological or molecular level. Once the standard treatment is established (steroids plus or minus whole brain radiotherapy), those who are of better performance status may be considered for comparison of this standard with or without systemic management.

The implementation of an advanced treatment planning algorithm in the treatment of lung cancer with conventional radiotherapy.

AIMS: Recent improvements in planning systems have made use of sophisticated dose calculation algorithms such as collapsed cone, a realistic possibility for routine lung radiotherapy treatment planning. However, it is more difficult to achieve ICRU 50/62 compliant plans (i.e. a minimum of 95% of the prescribed dose to the planning target volume) with the collapsed cone algorithm, due to the more accurate modelling of dose in heterogeneous media. The aim of this study was to determine planning guidance for the implementation of the collapsed cone algorithm for conventional radiotherapy treatment planning. MATERIALS AND METHODS: Ten pencil beam lung plans were recalculated using the collapsed cone algorithm. Then, beam weights were optimised on the recalculated collapsed cone plan, without altering field sizes. Finally, both field sizes and beam weights were optimised on the same plan in an attempt to deliver a minimum of either 90 or 95% of the prescribed dose to the planning target volume. Thus, four sets of plans were available for comparison. RESULTS: Compared with pencil beam plans recalculated with the collapsed cone algorithm, all collapsed cone plans had improved dose coverage of the planning target volume. For two of the beam weight optimised plans, less than 80% of the planning target volume received 90% of the prescribed dose. For the field size, beam weight optimised plans, nearly 100% of the planning target volume attained 90% of the prescribed dose, with the clinical target volume generally reaching 95%. Compared with the original pencil beam plans, the volume of lung receiving greater than 20 Gy (V(20)) increased by 3.1 and 6.8%, respectively, for those plans optimised to deliver a minimum of 90 or 95% of the prescribed dose to the planning target volume. CONCLUSIONS: We suggest that the collapsed cone algorithm might reasonably be implemented for conventional radiotherapy treatment planning with the aim of delivering a minimum of 90% of the prescribed dose to the planning target volume and 95% of the prescribed dose to the clinical target volume. This guidance offers consistent prescription of dose to target volumes.

Clinical trials assessing the optimal management of brain metastases--the state of play.

These three clinical trials offer the opportunity to answer the controversies and uncertainties that exist in managing patients with brain metastases: for patients with solitary brain metastasis there is the EORTC trial, for patients with NSCLC, where there is a certainty that the patient should receive radiotherapy, there is TACTIC, and where there is uncertainty of the benefit of radiotherapy there is QUARTZ. We would encourage all clinical oncologists seeing patients with brain metastases to consider patients for entry into any one of these trials.

Life-threatening tamoxifen-induced hypercalcaemia.

This case report serves to emphasize two important features of metastatic breast carcinoma. First, that tamoxifen-induced flare, although a rare and self-limiting phenomenon, may be fatal and must thus be recognized and treated promptly. Secondly, those patients presenting with hypercalcaemia, as part of tamoxifen-induced tumour flare, invariably have metastatic disease but they may enjoy a durable prognosis if this is confined to the skeleton.

Lymphangiosarcomata--experience in a lymphoedema clinic.

Two cases of patients attending a lymphoedema clinic and developing lymphangiosarcomata are described. The epidemiology, natural history and management of this uncommon malignancy are discussed and the pertinent features that should be sought by professionals involved in routine follow-up of patients prone to lymphoedema outlined.

Alveolar macrophage populations are distorted in immunocompromised patients with pneumonitis.

Alveolar macrophages (AM) were obtained by bronchoalveolar lavage (BAL) from patients presenting with pneumonitis: 30 human immunodeficiency virus (HIV)-infected individuals and 12 transplant recipients. Nine normal volunteers acted as controls. The cells were washed and cytospins prepared. Monoclonal antibodies (MoAbs) and immunoperoxidase methods were used to analyse the expression of HLA-DR molecules as well as phenotypic macrophage markers. P values apply to the differences between medians using the Mann-Whitney test. Median percentages of macrophages, lymphocytes and neutrophils were similar in all three groups. No differences were found in the median percentages of macrophages expressing the monocyte phenotype (MoAb UCHM1, CD14). However, in HIV-infected patients and transplant recipients a median of only 45% of macrophages expressed the pan-macrophage phenotype identified by MoAb EBM11 (CD68) in contrast with 98% in the normal volunteers. The AM population expressing the dendritic cell marker (MoAb RFD1) was also markedly reduced in both groups of immunocompromised patients (2 vs 28% in normal volunteers). Transplant recipients had significantly more phagocytic cells identified by MoAb RFD7 than the HIV-infected patients (25 vs 2%), but the numbers were still low when compared with the volunteers (48%). HLA-DR expression on BAL cells was reduced by 90% in both immunocompromised groups. For the transplant recipients, severity of pneumonitis was correlated with expression of dendritic cell marker RFD1, (Spearman's rank correlation r = 0.538, p less than 0.05) and pan-macrophage marker EBM11 (r = 0.581, p less than 0.05), while no such correlation was found in HIV-infected patients. These results suggest that a defective macrophage population is probably a serious factor contributing to immunosuppression.

Severe cytomegalovirus pneumonitis in HIV infected patients with higher than average CD4 counts.

BACKGROUND: Cytomegalovirus may replicate within the lungs both of recipients of transplants and of patients infected with the human immunodeficiency virus (HIV). A hypothesis formulated by this group was that a host damaging immune response might be provoked by cytomegalovirus infection and cause a severe pneumonitis in recipients of allogeneic transplants, whereas the progressive impairment of cellular immunity in patients with HIV disease would preclude a damaging immune response in the lungs, and thus protect these patients from severe cytomegalovirus pneumonitis. This study set out to discover whether severe cytomegalovirus pneumonitis arises in HIV infected patients. METHODS: Data were prospectively collected on severity of pneumonitis and infectious agents identified in consecutive respiratory episodes in HIV infected patients undergoing diagnostic bronchoalveolar lavage during 20 months. RESULTS: Eighty five episodes of pneumonitis occurred in 68 patients. Cytomegalovirus was identified as the only infectious agent in nine episodes (nine patients). Seven of the episodes were mild; all these patients had CD4 counts below 0.1 x 10(9)/1. The remaining two episodes were severe and ventilatory support was required. In both cases the CD4 counts were above 0.2 x 10(9)/1 and HIV infection appeared to have been acquired shortly before presentation. CONCLUSION: Although rare, severe cytomegalovirus pneumonitis may occur in HIV infected patients. Both patients with severe pneumonitis in this series had relatively well preserved immune function. These findings support the hypothesis that severe cytomegalovirus pneumonitis is an immunopathological condition.

Varicella-zoster infection in adults with cystic fibrosis: role of acyclovir.

Of 159 adult patients with cystic fibrosis, 5 were documented to have varicella-zoster infection that resulted in an infective pulmonary exacerbation that required intravenous acyclovir and additional antibiotic treatment. Stable serial pulmonary function values were observed over a 1-year period in 4 patients and no complications resulted from treatment. Early treatment with acyclovir in combination with appropriate antibiotics may prevent pulmonary deterioration in adult patients with cystic fibrosis who develop varicella-zoster infection.

Life threatening haemoptysis in cystic fibrosis: an alternative therapeutic approach.

Desmopressin and vasopressin were used to control massive haemoptysis in a patient with cystic fibrosis. After bolus doses a continuous infusion of vasopressin was maintained for 36 hours and haemoptysis stopped.