Paul Hatfield

Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity.

BACKGROUND AND PURPOSE Standard treatment for rectal cancer which threatens the expected plane of resection on MRI imaging is long-course, pre-operative chemoradiotherapy (1.8-2Gy, 25-28 fractions). Not all patients are suitable for this because of age, poor performance status or co-morbidities. We describe our experience of short-course (5x5Gy) pre-operative radiotherapy with planned, delayed surgery (SCPRT-delay) in this patient group. MATERIALS AND METHODS Between April 2001 and October 2007, 43 patients were selected for SCPRT-delay. The clinical records were retrospectively evaluated. RESULTS Median age was 82 (range 58-87). Forty-one patients had radiotherapy of which 26 (61%) were subsequently able to have surgery. Of these, R0, R1 and R2 resections were performed in 22, 2 and 2 patients, respectively. Treatment was well tolerated, although two patients required hospital admission for management of diarrhoea and one developed significant late small bowel toxicity, attributable to radiotherapy. In those undergoing R0 or R1 resection there have been no local recurrences (median follow-up 18 months). Median survival for the whole group was 23 months, although this was 44 months in those undergoing surgery. CONCLUSIONS SCPRT-delay appears to be a useful alternative to long-course pre-operative chemoradiotherapy in this high-risk group of patients.

Optimization of Dendritic Cell Loading With Tumor Cell Lysates for Cancer Immunotherapy

The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stress-associated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw “necrotic” lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to well-established maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-α, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-κB pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.

An evaluation of four CT-MRI co-registration techniques for radiotherapy treatment planning of prone rectal cancer patients.

OBJECTIVES MRI is the preferred staging modality for rectal carcinoma patients. This work assesses the CT-MRI co-registration accuracy of four commercial rigid-body techniques for external beam radiotherapy treatment planning for patients treated in the prone position without fiducial markers. METHODS 17 patients with biopsy-proven rectal carcinoma were scanned with CT and MRI in the prone position without the use of fiducial markers. A reference co-registration was performed by consensus of a radiologist and two physicists. This was compared with two automated and two manual techniques on two separate treatment planning systems. Accuracy and reproducibility were analysed using a measure of target registration error (TRE) that was based on the average distance of the mis-registration between vertices of the clinically relevant gross tumour volume as delineated on the CT image. RESULTS An automated technique achieved the greatest accuracy, with a TRE of 2.3 mm. Both automated techniques demonstrated perfect reproducibility and were significantly faster than their manual counterparts. There was a significant difference in TRE between registrations performed on the two planning systems, but there were no significant differences between the manual and automated techniques. CONCLUSION For patients with rectal cancer, MRI acquired in the prone treatment position without fiducial markers can be accurately registered with planning CT. An automated registration technique offered a fast and accurate solution with associated uncertainties within acceptable treatment planning limits.

Allogeneic tumor cells expressing fusogenic membrane glycoproteins as a platform for clinical cancer immunotherapy.

PURPOSE: Fusogenic membrane glycoproteins (FMG), such as the vesicular stomatitis virus G glycoprotein (VSV-G), represent a new class of gene therapy for cancer that cause cytotoxic fusion on expression in tumor cells. In addition, FMG-mediated tumor cell death stimulates antitumor immunity, suggesting potential applications for FMG-expressing cellular vaccines. This study addresses the promise of FMG-expressing allogeneic tumor cells, which are most practical for clinical use, as a novel platform for ex vivo and in situ vaccination. EXPERIMENTAL DESIGN: Murine B16 melanoma-derived cell lines expressing autologous or allogeneic MHC class I, expressing fusogenic or nonfusogenic VSV-G, were used to vaccinate mice in vivo against a live tumor challenge. Exosome-like vesicles released by fusing allogeneic cells (syncitiosomes) and intratumoral injection of fusing vaccines were also tested as novel therapeutic strategies for their antitumor effects. RESULTS: Expression of fusogenic VSV-G enhanced the immunogenicity of an allogeneic cellular vaccine, which was more effective than a fusing autologous vaccine. Allogeneic syncitiosomes were only as effective as cellular vaccines when administered with adjuvant, demonstrating that syncitiosomes cannot account entirely for the mechanism of immune priming. Intratumoral injection of FMG-expressing allogeneic cells led to significant tumor regression using both fusogenic or nonfusogenic VSV-G. However, specific priming against tumor-associated antigenic epitopes and protection against secondary rechallenge only occurred if the initial vaccine was competent for cell fusion. CONCLUSIONS: FMG-expressing allogeneic tumor cells are a potent source of antitumor vaccines. Syncitiosomes given with adjuvant and intratumoral injection of fusing cells represent novel strategies well-suited to clinical translation.

Clinical grade OK432-activated dendritic cells: In vitro characterization and tracking during intralymphatic delivery

Dendritic cells (DC) are under intense preclinical and early clinical evaluation for the immunotherapy of cancer. However, the optimal culture conditions and route of delivery for DC vaccination have not been established. Here we describe the first human application of DC matured with the bacterial agent OK432 (OK-DC), using a short-term serum-free culture protocol, which generates mature DC from CD14+ precursors after 5 days. These cells were prepared within the framework of a National Blood Service facility, demonstrating that DC represent a product which is potentially deliverable alongside current standardized cell therapies within the UK National Health Service. In vitro analysis confirmed that OK-DC were mature, secreted tumor necrosis factor-α, interleukin-6, and interleukin-12, and stimulated both T cell and natural killer cell function. To explore effective delivery of OK-DC to lymph nodes, we performed an initial clinical tracking study of radioactively labeled, unpulsed OK-DC after intralymphatic injection into the dorsum of the foot. We showed that injected DC rapidly localized to ipsilateral pelvic lymph nodes, but did not disseminate to more distant nodes over a 48-hour period. There was no significant toxicity associated with OK-DC delivery. These results show that OK-DC are suitable for clinical use, and that intralymphatic delivery is feasible for localizing cells to sites where optimal priming of innate and adaptive antitumor immunity is likely to occur.

Stereotactic radiosurgery for the treatment of brain metastases: impact of cerebral disease burden on survival

Abstract Stereotactic radiosurgery (SRS) for brain metastases has been carried out at the Leeds Gamma Knife Centre since March 2009. The aim of this study was to examine the outcomes and toxicity in our initial cohort of patients. The medical records of patients with brain metastases referred to the Leeds Gamma Knife Centre between March 2009 and July 2010 were retrospectively reviewed. Data on survival, primary tumour, Karnofsky performance status, time from diagnosis to identification of brain metastases, previous treatment for brain metastases and results of staging prior to SRS were recorded. Patients were followed up with regular magnetic resonance imaging of the brain for a minimum of 6 months and data on toxicity and oral steroid dose were recorded. Statistical analysis was carried out using SPSS v14.0. Survival curves were compared using the Log Rank test. Fifty eight patients (19 male) had a median survival of 50.4 weeks (95% CI, 32.6–68.2 weeks). Lung (36%) and breast (27%) were the most common primary tumours. Patients with a total volume of metastases treated < 5000 mm3 (p = 0.007) or between 5000 mm3 and 10 000 mm3 (p = 0.01) had significantly improved survival compared with patients with a total treated volume > 10 000 mm3. In addition, largest treated lesion < 5000 mm3 was a positive prognostic factor. Patients with a single metastasis did not survive significantly longer than those with multiple metastases. Steroid dose dropped significantly after SRS (p < 0.01) and was the same or less in 91% of patients. There were only three cases of grade 3 toxicity. Our study reports survival comparable with other series on radiosurgery and demonstrates a significant decrease in steroid dose following treatment. It also shows that the size of the largest treated metastasis and total volume of metastatic disease seemed a better predictor of outcome than number of metastases treated.

Quantifying and improving the efficiency of Gamma Knife treatment plans for brain metastases: results of a 1-year audit

OBJECT A method for quantifying the efficiency of Gamma Knife treatment plans for metastases was previously implemented by the authors to retrospectively identify the least efficient plans and has provided insights into improved planning strategies. The aim of the current work was to ascertain whether those insights led to improved treatment plans. METHODS Following completion of the initial study, a 1-year audit of metastasis plans created at St. Jamess Institute of Oncology was carried out. Audited recent plans were compared with the earlier plans of the initial study, in terms of their efficiency and dosimetric quality. The statistical significance of any differences between relevant plan parameters was quantified by Mann-Whitney U-tests. Comparisons were made between all plans and repeated for a reduced set of plans from which the smallest lesions treated with a single 4-mm shot were excluded. The plan parameters compared were a plan efficiency index (PEI), the number of shots, Paddick conformity index (PCI), gradient index (GI), and percent coverage (of the lesion by the prescription isodose). RESULTS A total of 157 metastatic lesions were included in the audit and were compared with 241 in the initial study. In a comparison of all cases, the audited plans achieved a higher median PEI score than did the earlier plans from the initial study (1.08 vs 1.02), indicating improved efficiency of the audited plans. When the smallest lesions (for which there was little scope for varying plan strategy) were discounted, the improvement in median PEI score was greater (1.23 vs 1.03, p < 0.001). This improvement in efficiency corresponds to an estimated mean (maximum) time saving of 15% (66%) per lesion (11 minutes [64 minutes] on the day of treatment). The modified planning strategy yielding these efficiency improvements did not rely on the use of significantly fewer shots (median 11 vs 11 shots, p = 0.924), nor did it result in significant detriment to dosimetric quality (median coverage 99% vs 99%, median PCI 0.84 vs 0.83, p = 0.449, and median GI 2.72 vs 2.67, p = 0.701, audited plans vs initial plans, respectively). CONCLUSIONS Choice of planning strategy can substantially affect plan efficiency and thus strongly influence treatment time. Through increased emphasis on efficiency, resulting from the introduction of PEI combined with a modified planning strategy informed by previous work, it has been possible to reduce times for metastatic plans without compromising their dosimetric quality. Although the average time savings achieved per lesion are moderate, the potential benefits per patient are greater for those with multiple metastases. Reducing treatment times has clear benefits with regard to patient comfort and throughput. In addition, optimization of plan efficiency may potentially affect the biologically effective dose from Gamma Knife treatments and offers opportunity for further work.

A method for scoring treatment time efficiency of Gamma Knife radiosurgical treatment plans for brain metastases.

PURPOSE In Gamma Knife radiosurgery, an efficient plan is one that achieves dosimetric quality while minimizing treatment time. Although minimization of treatment time to improve throughput and benefit patient comfort is a common and important goal of radiosurgery planning, to date no studies have attempted to specifically quantify efficiency. The aim of this study was to define simple index to score efficiency, and by quantifying time savings achieved by replanning those cases identified as least efficient, so demonstrate the efficacy of the index. METHODS To quantify efficiency, it is necessary to determine treatment times expected for specified lesions. However, because of numerous case-specifics, efficiency cannot be quantified in terms of treatment times alone. This study defines a new quantity, the attenuation-corrected normalized treatment time-dose rate product, nTRP(corr), to account for differing dose rates, prescriptions, and attenuation. A plan efficiency index (PEI) is then defined for lesions of similar volume and shape in terms of expected and planned nTRP(corr). nTRP(corr) was retrospectively calculated for metastatic lesions of comparable shape. A curve fitted to data describing how nTRP(corr) typically varied with volume for these lesions was then used to determine expected nTRP(corr). For each lesion, PEI was calculated as the ratio of expected-to-planned nTRP(corr). Plans with the lowest PEI were replanned, with the aim of maintaining dosimetric quality while minimizing treatment time. Dosimetric quality was defined in terms of coverage, conformity, and gradient index. Statistical significance of differences between original and replans was quantified via paired t-tests. RESULTS The mean(standard deviation) PEI of all reviewed lesions was 1.08(0.28). The 14 least efficient plans across the range of investigated volumes (45-19 800 mm(3)) had a mean PEI of 0.64, versus 1.18 when replanned (p < 0.0001). This corresponded to a mean(range) time saving of 42%(19%-62%), [29(8-52) min at date of treatment] with no statistically significant (p > 0.05) change in dosimetric quality. CONCLUSIONS The PEI is a viable metric for identifying those plans that benefit from a more efficient planning strategy.