Dorothy M. Gujral

Radiation-induced carotid artery atherosclerosis

PURPOSE Carotid arteries frequently receive significant doses of radiation as collateral structures in the treatment of malignant diseases. Vascular injury following treatment may result in carotid artery stenosis (CAS) and increased risk of stroke and transient ischaemic attack (TIA). This systematic review examines the effect of radiotherapy (RT) on the carotid arteries, looking at the incidence of stroke in patients receiving neck radiotherapy. In addition, we consider possible surrogate endpoints such as CAS and carotid intima-medial thickness (CIMT) and summarise the evidence for radiation-induced carotid atherosclerosis. MATERIALS AND METHODS From 853 references, 34 articles met the criteria for inclusion in this systematic review. These papers described 9 studies investigating the incidence of stroke/TIA in irradiated patients, 11 looking at CAS, and 14 examining CIMT. RESULTS The majority of studies utilised suboptimally-matched controls for each endpoint. The relative risk of stroke in irradiated patients ranged from 1.12 in patients with breast cancer to 5.6 in patients treated for head and neck cancer. The prevalence of CAS was increased by 16-55%, with the more modest increase seen in a study using matched controls. CIMT was increased in irradiated carotid arteries by 18-40%. Only two matched-control studies demonstrated a significant increase in CIMT of 36% and 22% (p=0.003 and <0.001, respectively). Early prospective data demonstrated a significant increase in CIMT in irradiated arteries at 1 and 2 years after RT (p<0.001 and <0.01, respectively). CONCLUSIONS The incidence of stroke was significantly increased in patients receiving RT to the neck. There was a consistent difference in CAS and CIMT between irradiated and unirradiated carotid arteries. Future studies should optimise control groups.

Ipsilateral Breast Tumor Relapse: Local Recurrence Versus New Primary Tumor and the Effect of Whole-Breast Radiotherapy on the Rate of New Primaries

PURPOSE The justification for partial breast radiotherapy after breast conservation surgery assumes that ipsilateral breast tumor relapses (IBTR) outside the index quadrant are mostly new primary (NP) tumors that develop despite radiotherapy. We tested the hypothesis that whole-breast radiotherapy (WBRT) is ineffective in preventing NP by comparing development rates in irradiated and contralateral breasts after tumor excision and WBRT. METHODS AND MATERIALS We retrospectively reviewed 1,410 women with breast cancer who were entered into a prospective randomized trial of radiotherapy fractionation and monitored annually for ipsilateral breast tumor relapses (IBTR) and contralateral breast cancer (CLBC). Cases of IBTR were classified into local recurrence (LR) or NP tumors based on location and histology and were subdivided as definite or likely depending on clinical data. Rates of ipsilateral NP and CLBC were compared over a 15-year period of follow-up. RESULTS At a median follow-up of 10.1 years, there were 150 documented cases of IBTR: 118 (79%) cases were definite or likely LR; 27 (18%) cases were definite or likely NP; and 5 (3%) cases could not be classified. There were 71 cases of CLBC. The crude proportion of definite-plus-likely NP was 1.9% (27/1,410) patients compared with 5% (71/1,410) CLBC patients. Cumulative incidence rates at 5, 10, and 15 years were 0.8%, 2.0%, and 3.5%, respectively, for definite-plus-likely NP and 2.4%, 5.8%, and 7.9%, respectively for CLBC, suggesting a difference in the rates of NP and CLBC. CONCLUSIONS This analysis suggests that WBRT reduces the rate of ipsilateral NP tumors. The late presentation of NP has implications for the reporting of trials that are testing partial breast radiotherapy.

Clinical features of radiation-induced carotid atherosclerosis.

Carotid arteries frequently receive significant incidental doses of radiation during the treatment of malignant diseases, including head and neck cancer, breast cancer and lymphoma. Vascular injury after treatment may result in carotid artery stenosis and increased risk of neurological sequelae, such as stroke and transient ischaemic attack. The long latent interval from treatment to the development of clinical complications makes investigation of this process difficult, particularly in regard to the design of interventional clinical studies. Nevertheless, there is compelling clinical evidence that radiation contributes to carotid atherosclerosis. This overview examines the effect of radiotherapy on the carotid arteries, the underlying pathological processes and their clinical manifestations. The use of serum biomarkers in risk-prediction models and the potential value of new imaging techniques as tools for defining earlier surrogate end points will also be discussed.

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.

Zalutumumab in head and neck cancer

Introduction: Over 90% of head and neck cancers overexpress EGFR. This correlates with advanced disease stage and worse prognosis. Strategies to inhibit the EGFR pathway have been developed over the last decade. Zalutumumab is a recent high-affinity completely human IgG1k antibody targeting EGFR. Areas covered: The mechanism of action and data on efficacy and safety of zalutumumab in head and neck cancer. Expert opinion: Zalutumumab has demonstrated acceptable toxicity in head and neck cancer patients, with rash being the most common adverse event. The toxicity profile makes zalutumumab an attractive option for patients who are heavily pretreated and/or have poor performance status due to concurrent co-morbidities. As the molecule is fully human, the likelihood of hypersensitivity to the drug is low. Zalutumumab may be effective at low concentrations through antibody-dependant cellular cytotoxicity. Current data from Phase I and II trials identify zalutumumab as a promising drug for the treatment of locally advanced head and neck cancer and recent data from a Phase III randomized trial showed encouraging survival results compared with best supportive care. Results from other ongoing Phase III trials will provide clarification on zalutumumab as a treatment option. The clinical development of this compound has been suspended from June 2011 until a development and commercialization partner is found.

Arterial Stiffness as a Biomarker of Radiation-Induced Carotid Atherosclerosis

Arterial stiffness is thought to be a precursor to atherosclerosis. Conventional arterial stiffness parameters as potential biomarkers of radiation-induced damage were investigated. Patients with head and neck cancer treated with radiotherapy ≥2 years previously to one side of the neck were included. The unirradiated side was the internal control. Beta stiffness index (B) and elastic modulus (Ep) were used to assess arterial stiffness and were measured in proximal, mid, and distal common carotid artery (CCA) and compared with the corresponding unirradiated segments. Fifty patients (68% male; median age 58 years; interquartile range 50-62) were included. Mean ± standard deviation maximum doses to irradiated and unirradiated arteries were 53 ± 13 and 1.9 ± 3.7 Gy, respectively. Differences in B were not significant. Significant differences in Ep were demonstrated—proximal CCA: 1301 ± 1223 versus 801 ± 492 (P < .0001), mid CCA: 1064 ± 818 versus 935.5 ± 793 (P < .0001), and distal CCA: 1267 ± 1084 versus 775.3 ± 551.9 (P < .0001). Surgery had no impact on arterial stiffness. Arterial stiffness is increased in irradiated arteries, in keeping with radiation-induced damage. Prospective data may show an association between arterial stiffness and atherosclerosis in this setting.

Attenuation correction and normalisation for quantification of contrast enhancement in ultrasound Images of carotid arteries

An automated attenuation correction and normalisation algorithm was developed to improve the quantification of contrast enhancement in ultrasound images of carotid arteries. The algorithm first corrects attenuation artefact and normalises intensity within the contrast agent-filled lumen and then extends the correction and normalisation to regions beyond the lumen. The algorithm was first validated on phantoms consisting of contrast agent-filled vessels embedded in tissue-mimicking materials of known attenuation. It was subsequently applied to in vivo contrast-enhanced ultrasound (CEUS) images of human carotid arteries. Both in vitro and in vivo results indicated significant reduction in the shadowing artefact and improved homogeneity within the carotid lumens after the correction. The error in quantification of microbubble contrast enhancement caused by attenuation on phantoms was reduced from 55% to 5% on average. In conclusion, the proposed method exhibited great potential in reducing attenuation artefact and improving quantification in contrast-enhanced ultrasound of carotid arteries.

Cardiac tumors: the role of cardiovascular imaging

Evaluation of cardiac tumors with cardiovascular imaging aims to establish aetiology, identify complications of tumor and help define management strategy. 2D echocardiography remains the primary diagnostic modality. Additional use of newer echocardiographic techniques such as 3D, strain and contrast echocardiography better characterise tumor morphology, tissue characteristics and vascularity respectively. Cardiac MRI and computed tomography provide complementary information and are able to identify extra-cardiac infiltration and also provide further tissue characterisation. This review explores the non-invasive diagnostic approach to evaluation of cardiac tumors.

Current attitudes of head and neck oncologists in the United Kingdom to induction chemotherapy for locally advanced head and neck cancer: A survey of centres participating in a national randomised controlled trial

OBJECTIVES Induction chemotherapy (IC) followed by chemoradiation (CRT) for locally advanced squamous cell head and neck cancer (SCCHN) remains controversial in the absence of clear evidence to define its role. As part of a prospective, randomised, multicentre study of CRT for stage III/IV laryngeal/hypopharyngeal cancers (ART DECO, CRUK/10/018), we have examined the attitudes of oncologists in the United Kingdom (UK) to IC. MATERIALS AND METHODS Head and neck oncologists across the UK who expressed an interest in participating in the ART DECO trial were asked to complete a short written questionnaire designed to identify current UK practice of IC for stage III-IVb SCCHN. Completed questionnaires were returned to the clinical trials office prior to patient recruitment. RESULTS Clinicians from twenty-five/48 centres (52.1%) responded. Twenty centres (80%) elected to use IC in the trial. For stage III disease, 80% of centres did not prescribe IC for T1N1 disease and 60% did not offer IC for T3N0 disease. Patients with bulky primary tumours or extensive nodal disease were more likely to receive IC. Thirteen prescribing centres (65%) use 3 drugs (docetaxel, cisplatin, and 5-fluorouracil) compared to 7 (35%) using 2 drugs (cisplatin and 5-fluorouracil). Fifteen centres (75%) prescribed 2 cycles of IC, and 5 (25%) prescribed 3 cycles. There was variation in the dosage for both the 2- and 3-drug regimens. CONCLUSION Results suggest that clinical practice in the UK is currently divided between a 2- versus 3-drug regimen for IC for specific subgroups of patients. A consensus regarding the optimal combinations and dosages is required before further optimization of systemic therapy with other cytotoxics and biological agents is attempted.

Carotid intima-medial thickness as a marker of radiation-induced carotid atherosclerosis

PURPOSE Arterial thickening is a precursor to atherosclerosis. Carotid intima-medial thickness (CIMT), a measure of arterial thickening, is a validated surrogate for prediction of cerebrovascular events. This study investigates CIMT as an early marker of radiation-induced carotid artery damage. MATERIALS/METHODS Head and neck cancer patients treated with radiotherapy (RT) (minimum dose of 50 Gy) to one side of the neck (unirradiated side as control) at least 2 years previously were included. CIMT was measured in 4 arterial segments: proximal, mid, distal common carotid artery (CCA), and bifurcation and were compared to corresponding unirradiated segments. CIMT measurements >75th percentile of a reference population were considered abnormal and at increased cerebrovascular risk. RESULTS 50 patients (34 males) with a median age of 58 years (interquartile range (IQR) 50-62) were included. The mean maximum dose to the irradiated and unirradiated artery was 53 Gy (standard deviation (SD) 13 Gy) and 1.9 Gy (SD 3.7 Gy), respectively. Mean CIMT was significantly greater in irradiated versus unirradiated arteries: proximal CCA (0.76 mm ± 0.15 vs 0.68 mm ± 0.14 (p<0.0001), mid CCA (0.74 mm ± 0.2 vs 0.68 mm ± 0.16 (p=0.01), distal CCA (0.77 mm ± 0.2 vs 0.68 mm ± 0.15 (p=0.004), and bifurcation (0.85 mm ± 0.25 vs 0.72 mm ± 0.17 (p=0.001). For all arterial segments, a significantly greater number of CIMT measurements were abnormal on the irradiated side (proximal: p=0.004, mid: p=0.05, distal: p=0.005, bifurcation: p=0.03). There was no effect of time from RT, age, smoking status, surgery and chemotherapy on CIMT difference (irradiated-unirradiated) in all segments. CONCLUSIONS CIMT is increased after RT and may be a useful marker of radiation-induced carotid atherosclerosis. There appears to be no additional effect of other atherosclerotic risk factors on CIMT following RT.