Gillian R Watkins

Inter-fraction motion and dosimetric consequences during breast intensity-modulated radiotherapy (IMRT)

BACKGROUND AND PURPOSE Intensity-modulated radiotherapy (IMRT) can improve dose homogeneity within the breast planned target volume (PTV), but may be more susceptible to patient/organ motion than standard tangential radiotherapy (RT). We used daily cone-beam CT (CBCT) imaging to assess inter-fraction motion during breast IMRT and its subsequent impact on IMRT and standard RT dose homogeneity. MATERIALS AND METHODS Ten breast cancer patients selected for IMRT were studied. CBCT images were acquired immediately after daily treatment. Automatic image co-registration was used to determine patient positioning variations. Daily PTV contours were used to calculate PTV variations and daily delivered IMRT and theoretically planned tangential RT dose. RESULTS Group systematic (and random) setup errors detected by CBCT were 5.7 (3.9)mm laterally, 2.8 (3.5)mm vertically and 2.3 (3.2)mm longitudinally. Rotations >2 degrees in any axis occurred on 53/106 (50%) occasions. Daily PTV volume varied up to 23%. IMRT dose homogeneity was superior at planning and throughout the treatment compared with standard RT (1.8% vs. 15.8% PTV received >105% planned mean dose), despite increased motion sensitivity. CONCLUSIONS CBCT revealed inadequacies of current patient positioning and verification procedures during breast RT and confirmed improved dose homogeneity using IMRT for the patients studied.

Quantifying motion for pancreatic radiotherapy margin calculation.

BACKGROUND AND PURPOSE Pancreatic radiotherapy (RT) is limited by uncertain target motion. We quantified 3D patient/organ motion during pancreatic RT and calculated required treatment margins. MATERIALS AND METHODS Cone-beam computed tomography (CBCT) and orthogonal fluoroscopy images were acquired post-RT delivery from 13 patients with locally advanced pancreatic cancer. Bony setup errors were calculated from CBCT. Inter- and intra-fraction fiducial (clip/seed/stent) motion was determined from CBCT projections and orthogonal fluoroscopy. RESULTS Using an off-line CBCT correction protocol, systematic (random) setup errors were 2.4 (3.2), 2.0 (1.7) and 3.2 (3.6)mm laterally (left-right), vertically (anterior-posterior) and longitudinally (cranio-caudal), respectively. Fiducial motion varied substantially. Random inter-fractional changes in mean fiducial position were 2.0, 1.6 and 2.6mm; 95% of intra-fractional peak-to-peak fiducial motion was up to 6.7, 10.1 and 20.6mm, respectively. Calculated clinical to planning target volume (CTV-PTV) margins were 1.4 cm laterally, 1.4 cm vertically and 3.0 cm longitudinally for 3D conformal RT, reduced to 0.9, 1.0 and 1.8 cm, respectively, if using 4D planning and online setup correction. CONCLUSIONS Commonly used CTV-PTV margins may inadequately account for target motion during pancreatic RT. Our results indicate better immobilisation, individualised allowance for respiratory motion, online setup error correction and 4D planning would improve targeting.

The degree of circumferential tumour involvement as a prognostic factor in oesophageal cancer.

OBJECTIVE Tumour length is an adverse prognostic factor in oesophageal cancer. However, the prognostic role of the degree of oesophageal circumference (DOC) involved by tumour with or without resection margin invasion is not clear. This work assessed the relationship between DOC involved by tumour, clinico-pathological variables and prognosis. METHODS The clinico-pathological details of 320 patients who underwent potentially curative oesophagogastrectomy for cancer between 1994 and 2007 were analysed. The DOC involved with tumour measured macroscopically on the resected specimen was classified as small (<2.5 cm, n = 115), large (> or = 2.5 cm, n = 144) or circumferential (i.e. involving the whole circumference, n = 61). Univariate and multivariate survival analyses were carried out. RESULTS The DOC with tumour was higher in ulcerating tumours than stenosing or polypoidal types (p = 0.017). Tumour length, T-stage, neoadjuvant chemotherapy and vascular invasion were independently associated with DOC with tumour on multivariate analysis (p < 0.05 for all). DOC > or = 2.5 cm was an adverse prognostic factor in univariate analysis (p = 0.002) with a hazard ratio of 1.52 [95% CI 1.13-2.04] compared with those <2.5 cm. Circumferential tumours had a similar prognosis to tumours > or = 2.5 cm (p = 0.60). The prognostic significance of DOC with tumour was lost in multivariate analysis where the factors retaining independence were patient age, T-stage, lymph node metastasis, vascular invasion and positive resection margins. However, when patients were stratified by use of neoadjuvant chemotherapy (n = 121), the DOC with tumour retained prognostic significance on multivariate analysis in the 199 patients who did not undergo neoadjuvant chemotherapy (p = 0.04). CONCLUSION The DOC with tumour appears to provide prognostic information in oesophageal cancer surgery, especially in patients who do not undergo preoperative chemotherapy.

Computed tomography overestimation of esophageal tumor length: Implications for radiotherapy planning

AIM To assess the relationship between preoperative computed tomography (CT) and postoperative pathological measurements of esophageal tumor length and the prognostic significance of CT tumor length data. METHODS A retrospective study was carried out in 56 patients who underwent curative esophagogastrectomy. Tumor lengths were measured on the immediate preoperative CT and on the post-operative resection specimens. Inter- and intra-observer variations in CT measurements were assessed. Survival data were collected. RESULTS There was a weak correlation between CT and pathological tumor length (r = 0.30, P = 0.025). CT lengths were longer than pathological lengths in 68% (38/56) of patients with a mean difference of 1.67 cm (95% CI: 1.18-2.97). The mean difference in measurements by two radiologists was 0.39 cm (95% CI: -0.59-1.44). The mean difference between repeat CT measured tumor length (intra-observer variation) were 0.04 cm (95% CI: -0.59-0.66) and 0.47 cm (95% CI: -0.53-1.47). When stratified, patients not receiving neoadjuvant chemotherapy showed a strong correlation between CT and pathological tumor length (r = 0.69, P = 0.0014, n = 37) than patients that did (r = 0.13, P = 0.43, n = 19). Median survival with CT tumor length > 5.6 cm was poorer than with smaller tumors, but the difference was not statistically significant. CONCLUSION Esophageal tumor length assessed using CT does not reflect pathological tumor extent and should not be the only modality used for management decisions, particularly for planning radiotherapy.

Pesticide exposure and screen-positive neuropsychiatric disease in British sheep farmers

BACKGROUND Epidemiological evidence linking low dose pesticide exposure and chronic ill-health in UK sheep farmers is limited. Our aim was to examine whether neuropsychiatric disorders were associated with low dose chronic and/or more acute pesticide exposure in sheep farmers. METHODS A cohort of British farmers working in the 1970s was sent a screening questionnaire which asked about their health and work history. The prevalence of screen-positive depression, dementia, Parkinsonism and neuropathy was determined using a priori algorithms. Self-reported pesticide exposure was assessed by whether the participant had ever handled the pesticide concentrate (for low dose chronic exposure) or sought advice for pesticide poisoning (acute exposure) and participants categorised into those with only acute or chronic exposure, those with both acute and chronic exposure and those with neither acute nor chronic exposure. Associations between acute and chronic pesticide exposure, and screen-positive ill-health were determined after adjustment for demographic, lifestyle, occupation and somatic severity scores and other variables. RESULTS In those participants, who had never sought advice for pesticide poisoning, handling the pesticide concentrate for treating sheep was associated with elevated ORs for screen-positive neuropathy (ORadi 1.57 95%CI 0.97-2.54) and Parkinsonism (ORadj 1.56 95%CI 0.95-2.56) but not depression or dementia. In those participants who had handled the pesticide concentrate, seeking advice for pesticide poisoning was associated with screen-positive depression (Odds ratio, ORadj=9.97 95%CI 4.76-20.8 ), dementia (OR=6.94 95%CI 3.44-14.0), Parkinsonism (ORadj=4.77 95% 2.39-9.52), and neuropathy (ORadj=4.77 95%CI 2.39-9.52). Adjustment for somatic severity score modified little the associations with pesticide handling in those not acutely exposed but reduced the ORs for seeking advice for pesticide poisoning in those exposed chronically. Furthermore, stratification of results based upon somatic severity score indicated that the highest ORs for handling the pesticide concentrate associated with neuropathy and Parkinsonism were found in those participants whose somatic score was minimal. CONCLUSIONS Results are consistent with low-dose exposure to pesticides being associated with screen-positive neuropathy and Parkinsonism but the stronger associations between seeking advice for pesticide poisoning and screen-positive ill-health suggest that acute pesticide exposure remains an important determinant of ill-health. Further work is required to better delineate to what extent low dose exposures may contribute to ill-health in populations without acute exposures. Somatising tendency does not appear to play an important role in this population.

Efficacy and Tolerability of Limited Field Radiotherapy with Concurrent Capecitabine in Locally Advanced Pancreatic Cancer

AIMS Patients with locally advanced pancreatic cancer (LAPC) are most commonly managed with chemotherapy or concurrent chemoradiotherapy (CRT), which may or may not include non-involved regional lymph nodes in the clinical target volume. We present our results of CRT for LAPC using capecitabine and delivering radiotherapy to a limited radiation field that excluded non-involved regional lymph nodes from the clinical target volume. MATERIALS AND METHODS Thirty patients were studied. Patients received 50.4 Gy external beam radiotherapy in 28 fractions, delivered to a planning target volume expanded from the primary tumour and involved nodes only. Capecitabine (500-600 mg/m2) was given twice daily continuously during radiotherapy. Toxicity and efficacy data were prospectively collected. RESULTS Nausea, vomiting and tumour pain were the most common grade 2 toxicities. One patient developed grade 3 nausea. The median time to progression was 8.8 months, with 20% remaining progression free at 1 year. The median overall survival was 9.7 months with a 1 year survival of 30%. Of 21 patients with imaged progression, 13 (62%) progressed systemically, three (14%) had local progression, two (10%) had locoregional progression and three (14%) progressed with both local/locoregional and systemic disease. CONCLUSION CRT using capecitabine and limited field radiotherapy is a well-tolerated, relatively efficacious treatment for LAPC. The low toxicity and low regional progression rates support the use of limited field radiotherapy, allowing evaluation of this regimen with other anti-cancer agents.

Abstract 4123: Monocarboxylate transporter 4 expression is a prognostic factor for radiotherapy outcome in squamous cell carcinoma of the head and neck

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Hypoxia contributes significantly to tumor progression and resistance to radiotherapy, decreasing local tumor control and lowering the rates of disease-free and overall survival. Hypoxic tumor cells utilize the glycolytic pathway for survival, producing vast quantities of lactate. Monocarboxylate Transporters (MCTs) 1 and 4 are key transporters of lactate, enabling sustained high glycolytic rates and maintenance of intra-cellular pH. Aim: To carry out the first study evaluating tumor MCT1 and 4 expression as potential biomarkers of prognosis in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy, and to determine the impact of MCT expression on radiation resistance. Methods: 125 histologically confirmed SCC pre-treatment diagnostic oropharyngeal cancer biopsies (tonsil or posterior third of the tongue) were collected retrospectively from diagnostic archives. The biopsies were analyzed immunohistochemically to evaluate MCT1 and 4 membrane expression. MCT expression was assessed in a double blind manner using a semi-quantitative scoring system. Scores were analyzed for possible correlations with clinicopathological data relating to outcome 5 years post diagnosis, where all patients had received radiotherapy to the primary site. FaDu HNSCC cells expressing doxycycline inducible shRNA targeting MCT4 were used to evaluate radiosensitivity of wild-type and MCT4-knockdown cells. Results: A univariate analysis comparing high (top 25% of scores) vs low MCT expression (lower 75%) showed that MCT4, but not MCT1, is a significant adverse prognostic factor for radiotherapy outcome. High MCT4 expression correlates with poor loco-regional control (p = 0.017), reduced cancer-specific survival (p = 0.02) and reduced overall survival (p = 0.055). In a multivariate analysis high MCT4 expression retained prognostic significance for poor loco-regional control (p = 0.007). Confirmation of MCT4 as a novel target for increasing hypoxic radiosensitivity was carried out by clonogenic assay in FaDu wild-type and shMCT4 cell lines, MCT4-knockdown cells showed a marked increase in hypoxic radiosensitivity compared to wild-type cells. Conclusions: The increase in significance from overall survival to loco-regional control is consistent with a hypoxia-regulated marker of radiotherapy resistance. The functional role of MCT4 as a lactate transporter in hypoxia may be of key underlying biological importance to this finding, maintaining intracellular pH in a hypoxic microenvironment. These findings suggest that inhibition of MCT4 may modify hypoxic tumor regions and sensitize tumor cells to radiation treatment. Therefore, MCT4 should be explored further as a novel target and biomarker for prognosis and prediction of benefit from hypoxia-modifying therapy in patients undergoing radiotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4123. doi:10.1158/1538-7445.AM2011-4123

Efficacy and toxicity of limited field concurrent chemoradiotherapy (CRT) with capecitabine for locally advanced pancreatic cancer (LAPC)

15586 Background: Treatment outcome in LAPC remains poor. As treatment-related toxicity limits CRT dose-intensification, we evaluated the efficacy/toxicity of capecitabine based CRT in LAPC patients using limited field irradiation, excluding elective nodal areas. Methods: 25 consecutive LAPC patients eligible for CRT were treated at a single institute. Capecitabine was administered at 500–600 mg/m2/b.i.d continuously (including weekends) from day one to completion of radiotherapy (RT). RT was delivered conformally to a dose of 50.4Gy in 28 fractions over 5.5 weeks. The gross tumour volume consisting of the pancreatic tumour and any involved peri-pancreatic nodes was isometrically expanded by 0.5 cm to generate the clinical target volume (CTV). The planning target volume (PTV) comprised the CTV plus a 1cm margin AP/LR and a 1.5 - 2 cm margin SI. Patients were reviewed weekly to monitor weight and collect toxicity data. Time to disease progression and survival were calculated from diagnosis. Results: Median...