Retrospective analysis of real-world treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer starting first-line systemic therapy in the United Kingdom.

BACKGROUND: The treatment landscape for advanced non-small cell lung cancer (aNSCLC) has evolved rapidly since immuno-oncology (IO) therapies were introduced. This study used recent data to assess real-world treatment patterns and clinical outcomes in aNSCLC in the United Kingdom. METHODS: Electronic prescribing records of treatment-naive patients starting first-line (1 L) treatment for aNSCLC between June 2016 and March 2018 (follow-up until December 2018) in the United Kingdom were assessed retrospectively. Patient characteristics and treatment patterns were analyzed descriptively. Outcomes assessed included overall survival (OS), time to treatment discontinuation, time to next treatment, and real-world tumor response. RESULTS: In all, 1003 patients were evaluated (median age, 68 years [range, 28-93 years]; 53.9% male). Use of 1 L IO monotherapy (0-25.9%) and targeted therapy (11.8-15.9%) increased during the study period, but chemotherapy remained the most common 1 L treatment at all time points (88.2-58.2%). Median OS was 9.5 months (95% CI, 8.8-10.7 months) for all patients, 8.1 months (95% CI, 7.4-8.9 months) with chemotherapy, 14.0 months (95% CI, 10.7-20.6 months) with IO monotherapy, and 20.2 months (95% CI, 16.0-30.5 months) with targeted therapy. In the 28.6% of patients who received second-line treatment, IO monotherapy was the most common drug class (used in 51.6%). CONCLUSIONS: Although use of 1 L IO monotherapy for aNSCLC increased in the United Kingdom during the study period, most patients received 1 L chemotherapy. An OS benefit for first-line IO monotherapy vs chemotherapy was observed but was numerically smaller than that reported in clinical trials. Targeted therapy was associated with the longest OS, highlighting the need for improved treatment options for tumors lacking targetable mutations.

Time-resolved angiography with stochastic trajectories for dynamic contrast-enhanced MRI in head and neck cancer: Are pharmacokinetic parameters affected?

PURPOSE: To investigate the effects of different time-resolved angiography with stochastic trajectories (TWIST) k-space undersampling schemes on calculated pharmacokinetic dynamic contrast-enhanced (DCE) vascular parameters. METHODS: A digital perfusion phantom was employed to simulate effects of TWIST on characteristics of signal changes in DCE. Furthermore, DCE-MRI was acquired without undersampling in a group of patients with head and neck squamous cell carcinoma and used to simulate a range of TWIST schemes. Errors were calculated as differences between reference and TWIST-simulated DCE parameters. Parametrical error maps were used to display the averaged results from all tumors. RESULTS: For a relatively wide range of undersampling schemes, errors in pharmacokinetic parameters due to TWIST were under 10% for the volume transfer constant, Ktrans, and total extracellular extravascular space volume, Ve. TWIST induced errors in the total blood plasma volume, Vp, were the largest observed, and these were inversely dependent on the area of the fully sampled k-space. The magnitudes of errors were not correlated with Ktrans, Vp and weakly correlated with Ve. CONCLUSIONS: The authors demonstrated methods to validate and optimize k-space view-sharing techniques for pharmacokinetic DCE studies using a range of clinically relevant spatial and temporal patient derived data. The authors found a range of undersampling patterns for which the TWIST sequence can be reliably used in pharmacokinetic DCE-MRI. The parameter maps created in the study can help to make a decision between temporal and spatial resolution demands and the quality of enhancement curve characterization.

Characterizing Heterogeneity within Head and Neck Lesions Using Cluster Analysis of Multi-Parametric MRI Data.

PURPOSE: To describe a methodology, based on cluster analysis, to partition multi-parametric functional imaging data into groups (or clusters) of similar functional characteristics, with the aim of characterizing functional heterogeneity within head and neck tumour volumes. To evaluate the performance of the proposed approach on a set of longitudinal MRI data, analysing the evolution of the obtained sub-sets with treatment. MATERIAL AND METHODS: The cluster analysis workflow was applied to a combination of dynamic contrast-enhanced and diffusion-weighted imaging MRI data from a cohort of squamous cell carcinoma of the head and neck patients. Cumulative distributions of voxels, containing pre and post-treatment data and including both primary tumours and lymph nodes, were partitioned into k clusters (k = 2, 3 or 4). Principal component analysis and cluster validation were employed to investigate data composition and to independently determine the optimal number of clusters. The evolution of the resulting sub-regions with induction chemotherapy treatment was assessed relative to the number of clusters. RESULTS: The clustering algorithm was able to separate clusters which significantly reduced in voxel number following induction chemotherapy from clusters with a non-significant reduction. Partitioning with the optimal number of clusters (k = 4), determined with cluster validation, produced the best separation between reducing and non-reducing clusters. CONCLUSION: The proposed methodology was able to identify tumour sub-regions with distinct functional properties, independently separating clusters which were affected differently by treatment. This work demonstrates that unsupervised cluster analysis, with no prior knowledge of the data, can be employed to provide a multi-parametric characterization of functional heterogeneity within tumour volumes.

Final long-term results of a phase I/II study of dose-escalated intensity-modulated radiotherapy for locally advanced laryngo-hypopharyngeal cancers.

OBJECTIVES: We previously described dose-escalated intensity-modulated radiotherapy (IMRT) in squamous cell cancer of the larynx/hypopharynx (SCCL/H) to offer improved locoregional control with a low incidence of toxicity at 2 years. We now present outcome and safety data at 5 years. MATERIALS AND METHODS: A sequential cohort Phase I/II trial design was used. Patients with SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. RESULTS: Between 09/2002 and 01/2008, 60 patients (29 DL1, 31 DL2) with stage III (41% DL1, 52% DL2) and stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 5.7 (1.0-10.2) years and for DL2 was 6.0 (0.3-8.4) years. Five-year local control rates (95% confidence interval) for DL1 and DL2, respectively, were 68% (50.6-85.4%) and 75% (58.9-91.1%), locoregional progression-free survival rates were 54% (35.6-72.4%) and 62.6% (44.8-80.4%), and overall survival was 61.9% (44.1-79.7) and 67.6 (51.1-84.1%). Five-year laryngeal preservation rates were 66.7% (37.4-87.9%) and 71.4% (44.4-85.8%), respectively. Cumulative toxicities reported were: one patient in DL1 and 2 in DL2 developed benign pharyngeal strictures. No other G3/4 toxicities were reported. CONCLUSIONS: Dose-escalated IMRT at DL2 achieves higher 5-year local control, larynx preservation and survival rates with acceptable late toxicity. Recruitment into a Cancer Research UK Phase III study (ART-DECO), with DL2 as the experimental arm, is ongoing.

Fatigue during chemoradiotherapy for nasopharyngeal cancer and its relationship to radiation dose distribution in the brain.

BACKGROUND AND PURPOSE: Fatigue during head and neck radiotherapy may be related to radiation dose to the central nervous system (CNS). The impact of patient, tumour, and dosimetric variables on acute fatigue was assessed in nasopharyngeal cancer patients undergoing chemoradiotherapy. MATERIAL AND METHODS: Radiation dose to the following retrospectively-delineated CNS structures; brainstem, cerebellum, pituitary gland, pineal gland, hypothalamus, hippocampus and basal ganglia (BG) and clinical variables were related to incidence of ⩾ grade 2 fatigue in 40 patients. RESULTS: Sixty per cent of patients reported fatigue during and following radiotherapy. Dmean and D2 to the BG and Dmean to the pituitary gland were significantly associated with fatigue during radiation (P<0.01). Dmean to the cerebellum was associated with fatigue following radiotherapy and at any time (P < 0.01). After adjusting for clinical factors, an association remained between fatigue during radiotherapy and mean dose and D2 to the pituitary gland and BG (P = 0.012, 0.036, 0.009 and 0.018) and mean dose to the cerebellum following radiation and at any time (P = 0.042 and 0.029). CONCLUSION: Disruption of connections between BG, cerebellum, and higher cortical centres or disruption of pituitary-regulated hormonal balance may be implicated in the pathophysiology of radiation-related fatigue.

Long-term outcomes following low-dose radioiodide ablation for differentiated thyroid cancer.

CONTEXT: Randomized trials show that low-dose (1.1 GBq [30 mCi]) radioiodide (RAI) has efficacy equivalent to high-dose RAI (3.7 GBq [100 mCi]) in thyroid remnant ablation (TRA) for differentiated thyroid cancer. Long-term follow-up is required to ensure detection of late recurrences and to confirm equivalence in terms of survival end points. However, median follow-up duration within randomized trials is currently limited. PATIENTS AND SETTING: We studied 53 patients undergoing TRA for differentiated thyroid cancer with long-term follow-up in the Thyroid Unit of The Royal Marsden Hospital (Sutton, United Kingdom). INTERVENTION: Patients were treated with TRA using low-dose (1.1 GBq) RAI. MAIN OUTCOME MEASURES: Disease-free survival, overall survival, and the incidence of second malignancies were measured. Multivariable analysis was used to determine clinical risk factors for failure to achieve TRA after low-dose RAI. RESULTS: Median follow-up was 24 (range, 4-34) years. Low-dose RAI TRA was successful in 26 (49%) patients (successful ablation [SA] group), whereas 27 (51%) patients required further treatment (unsuccessful ablation [UA] group). Thirty-year disease-free survival was 92% in the SA group vs 87% in the UA group (P = .601). Thirty-year overall survival was 81% in the SA group vs 62% in the UA group (P = .154). Nine (17%) patients developed second malignancies (4 in the SA group and 5 in the UA group). Predictors of failure to achieve TRA with low-dose RAI were male sex and stage pT4 disease. CONCLUSIONS: There is no evidence from long-term follow-up of our cohort that treatment outcomes are compromised for patients that fail TRA with low-dose RAI and subsequently receive high-dose RAI.

Changes in functional imaging parameters following induction chemotherapy have important implications for individualised patient-based treatment regimens for advanced head and neck cancer.

BACKGROUND: When induction chemotherapy (IC) is used prior to chemoradiotherapy (CRT) in head and neck cancer (HNC), functional imaging (FI) may inform adaptation of treatment plans with the aim of optimising outcomes. Understanding the impact of IC on FI parameters is, therefore, essential. PURPOSE: To prospectively evaluate the feasibility of acquiring serial FI ((18)F-FDG-PET, diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI) and its role in defining individualised treatment regimens following IC in HNC. METHODS AND MATERIALS: Ten patients with stage III and IV HNC underwent conventional (CT and MRI) and functional (DW, DCE-MRI and (18)F-FDG-PET/CT) imaging at baseline and following two cycles of IC prior to definitive CRT. RESULTS: One patient withdrew due to claustrophobia. Seven out of nine patients had a complete metabolic response to IC on (18)F-FDG-PET imaging. DCE-MRI showed a significant fall in transfer constant (K(trans)) (0.209 vs 0.129 min(-1)P<0.01) and integrated area under gadolinium curve at 60s (IAUGC6O) (18.4 vs 11.9 mmol/min, P<0.01) and DW-MRI a rise in ADC (0.89 vs 1.06 × 10(-3) mm(2)/s, P<0.01) following IC. CONCLUSIONS: Acquiring FI sequences is feasible in HNC. There are marked changes in FI parameters following IC which may guide adaptation of individualised treatment regimens.

PET/CT in Radiotherapy Planning for Head and Neck Cancer.

The use of PET/CT as an adjunct in radiotherapy planning is an attractive option in head and neck cancer (HNC) for several reasons. First, with potentially better identification of the disease extent, i.e., staging, the risk of geographical miss of radiation delivery to the gross tumor volume is reduced. Second, in characterizing the biological behavior of the disease for example, areas of hypoxia, rich or poor vascularity, or high cell proliferation, PET/CT can identify biological target volumes either for escalation of radiation dose or to predict the requirement for the addition of a radiosensitizer or alternative treatment strategies. (18)F-FDG is the most common tracer used in oncology studies, but many other tracers have been investigated with several entering clinical practice, although these remain predominantly in the research domain in HNC.

Fractionated stereotactic radiotherapy in the treatment of vestibular schwannoma (acoustic neuroma): predicting the risk of hydrocephalus.

PURPOSE: To determine the incidence and predictive factors for the development of hydrocephalus in patients with acoustic neuromas (AN) treated with fractionated stereotactic radiotherapy. PATIENTS AND METHODS: Seventy-two patients with AN were treated with fractionated stereotactic radiotherapy between 1998 and 2007 (45-50 Gy in 25-30 fractions over 5 to 6 weeks). The pretreatment MRI scan was assessed for tumor characteristics and anatomic distortion independently of subsequent outcome and correlated with the risk of hydrocephalus. RESULTS: At a median follow-up of 49 months (range, 1-120 months), 5-year event-free survival was 95%. Eight patients (11%) developed hydrocephalus within 19 months of radiotherapy, which was successfully treated. On univariate analysis, pretreatment factors predictive of hydrocephalus were maximum diameter (p = 0.005), proximity to midline (p = 0.009), displacement of the fourth ventricle (p = 0.02), partial effacement of the fourth ventricle (p < 0.001), contact with the medulla (p = 0.005), and more brainstem structures (p = 0.004). On multivariate analysis, after adjusting for fourth ventricular effacement, no other variables remained independently associated with hydrocephalus formation. CONCLUSIONS: Fractionated stereotactic radiotherapy results in excellent tumor control of AN, albeit with a risk of developing hydrocephalus. Patients at high risk, identified as those with larger tumors with partial effacement of the fourth ventricle before treatment, should be monitored more closely during follow-up. It would also be preferable to offer treatment to patients with progressive AN while the risk of hydrocephalus is low, before the development of marked distortion of fourth ventricle before tumor diameter significantly exceeds 2 cm.

Anemia during sequential induction chemotherapy and chemoradiation for head and neck cancer: the impact of blood transfusion on treatment outcome.

PURPOSE: Sequential treatment (chemotherapy followed by concomitant chemoradiation; CCRT) is increasingly being used for radical treatment of squamous cell cancer of the head and neck (SCCHN), which results in increased myelosuppression. In this study, we review the incidence of anemia and the effect of a policy of hemoglobin (Hb) maintenance by blood transfusion on disease outcomes in these patients. METHODS AND MATERIALS: Retrospective review of the records of patients with SCCHN treated with sequential CCRT formed the basis of this study. The incidence of anemia and statistics on blood transfusion were documented. For the purpose of outcome analyses, patients were divided into four categories by (1) transfusion status, (2) nadir Hb concentration, (3) number of transfusion episodes, and (4) number of units of blood transfused (NOUT). Data on 3-year locoregional control (LRC), relapse-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were analyzed. RESULTS: One hundred and sixty-nine patients were identified. The median follow-up was 23.6 months. The RFS (52% vs. 41%, p = 0.03), DSS (71% vs. 66%, p = 0.02), and OS (58% vs. 42% p = 0.005) were significantly better for patients who did not have a transfusion vs. those who did. The LRC, RFS, DSS, and OS were also significantly better for patients with nadir Hb level >12 vs. <12 g/dL and NOUT 1-4 vs. >4. CONCLUSION: Our study seems to suggest that blood transfusion during radical treatment for SCCHN might be detrimental. Further research should be undertaken into the complex interactions among tumor hypoxia, anemia, and the treatment of anemia before making treatment recommendations.

Systemic therapy for advanced renal cell carcinoma.

Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy - immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors - sorafenib sunitinib, temsirolimus and everolimus - are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease.