Ceri Powell

Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers

Approximately two million fractions of radiotherapy are administered in the UK every year, as part of adjuvant, radical or palliative cancer treatment. For many tumour types, radiotherapy is routinely combined with concomitant chemotherapy as part of adjuvant or radical treatment. In addition, new agents have been developed in recent years and tested in phase 1, 2 and 3 trials concomitantly with radiotherapy or chemoradiotherapy. One such class of drugs, the poly(ADP-ribose) polymerase (PARP) inhibitors, has shown activity in conjunction with radiotherapy in several cancer cell lines. Pre-clinical data suggest that PARP inhibitors may potentiate the effects of radiotherapy in several tumour types, namely lung, colorectal, head and neck, glioma, cervix and prostate cancers. In vitro, PARP inhibitors are radiosensitisers in various cell lines with enhancement ratios of up to 1.7. In vivo, non-toxic doses of PARP inhibitors have been shown to increase radiation-induced growth delay of xenograft tumours in mice. Clinical trials to assess the toxicity and potential benefit of combining radiotherapy with PARP inhibition are now needed.

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.

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.

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.

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.

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.

External Beam Radiotherapy for Differentiated Thyroid Cancer

The management of differentiated thyroid cancer involves a combination of surgery, thyroid stimulating hormone suppression and radioactive iodine for most patients. In a small subset of patients, external beam radiotherapy is also used. However, its role remains controversial and there are no randomised controlled trials to guide practice. In this overview we review the evidence from the published literature for the use of external beam radiotherapy in the management of differentiated thyroid cancer and discuss the indications for which it is most commonly used. The technique of external beam radiotherapy, including the emerging role for intensity-modulated radiotherapy, will also be discussed.

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. 18F-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.

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.

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.