B. Van Triest

Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors

Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331, LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331. Although TS has been considered as a target for chemotherapy, the precise mechanism by which TS inhibition leads to cell death is still not completely resolved. TS inhibition results in depletion of dTTP, an essential precursor for DNA, and an increase in dUTP. This results in the so-called thymine-less death due to misincorporation of dUTP into DNA; its excision, catalysed by uracil-DNA glycosylase, results in DNA damage. Both this imbalance in dTTP/dUTP and DNA damage can result in induction of downstream events, leading to apoptosis. On the other hand a specific interaction exists between oncogenes and TS, by binding of TS protein to the p53 and c-myc RNA, while wt p53 can also inhibit TS promotor activity. TS inhibition by either 5-FU or antifolates can also result in a depression of TS protein mediated inhibition of TS mRNA translation leading to induction of more TS protein synthesis, and p53 protein may further deregulate this process. These complex indirect and direct interactions between oncogenes and TS may have as yet unclear clinical implications, since most data are based on in vitro or in vivo studies and some results are contradictive. In some preliminary clinical studies evidence was postulated for a combined prognostic role for TS and p53. This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease.

Selecting indicators for international benchmarking of radiotherapy centres.

Introduction: Benchmarking can be used to improve hospital performance. It is however not easy to develop a concise and meaningful set of indicators on aspects related to operations management. We developed an indicator set for managers and evaluated its use in an international benchmark of radiotherapy centres. The indicator set assessed the efficiency, patient-centeredness and timeliness of the services delivered. Methods: We identified possible indicators from literature and professionals. Stakeholders’ feedback helped to produce a shortlist of indicators. For this indicator set, data were obtained in a pilot that included four European radiotherapy centres. With these data, the indicators were evaluated on definition clarity, data availability, reliability and discriminative value. Results: Literature produced a gross list of 81 indicators. Based on stakeholder feedback, 33 indicators were selected and evaluated in the benchmark. Six negatively evaluated indicators were adapted, together with eight positively evaluated indicators 14 indicators seemed feasible. Examples of indicators concerned utilisation, waiting times, patient satisfaction and risk analysis. Conclusions: This study provides a pragmatic indicator development process for international benchmarks on operations management. The presented indicators showed to be feasible for use in international benchmarking of radiotherapy centres. The pilot identified attainable performance levels and provided leads for improvements

Evaluation of clinical and endoscopic toxicity after external beam radiotherapy and endorectal brachytherapy in elderly patients with rectal cancer treated in the HERBERT study

INTRODUCTION The HERBERT study evaluated a high-dose-rate endorectal brachytherapy boost (HDREBT) after EBRT in medically inoperable/elderly patients with rectal cancer. The response-rates are promising but not without risk of toxicity. The current analysis provides a comprehensive overview of patient reported, physician reported and endoscopically observed toxicity. MATERIAL AND METHODS A brachytherapy dose finding study was performed in 38 inoperable/elderly patients with T2-T4N0-1 rectal cancer. Patients received EBRT (13 × 3 Gy) followed by three weekly HDREBT applications (5-8 Gy). Toxicity was assessed via three methods: patient and physician (CTCAEv3) reported rectal symptoms and endoscopically. Wilcoxons signed rank test, paired t-test and Spearmans correlation were used. RESULTS Patient reported bowel symptoms showed a marked increase at the end of EBRT and two weeks after HDREBT. Acute grade 2 and 3 proctitis occurred in 68.4% and 13.2% respectively while late grade 2 and ≥3 proctitis occurred in 48% and 40%. Endoscopic evaluation mainly showed erythema and telangiectasia. In three patients frank haemorrhage or ulceration occurred. Most severe toxicity was observed 12-18 months after treatment. CONCLUSION For elderly patients with rectal cancer, definitive radiotherapy can provide good tumour response but has a substantial risk of toxicity. The potential benefit and risks of a HDREBT boost above EBRT alone must be further evaluated.

Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy

BackgroundPORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis.Methods427 women with HIR endometrial cancer were randomised between 2002–2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis.ResultsMedian follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors.ConclusionLong-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

OC-0470: Library of plans in radiotherapy of rectal cancer: feasible and inter-observer consistent?

S223 ______________________________________________________________________________________________________ nearest whole number. The median DVH value of new genitalia contours denotes the optimal constraint and the 75th centile denotes the mandatory constraint. Horizontal lines represent current genitalia dose constraints. It can be observed that new recommended dose constraints contrast the current dose constraints highlighting the need for gender and tumour stage specific genitalia dose constraints.

OC-0617: The PARP inhibitor olaparib is effective as radiosensitizer at 10-fold lower doses than as single agent

classes of CBVTUMOR were reported to the total CBVTUMOR to show volume variations in percentage. Results: Variations of median rCBV between M0 and M2 were different for two groups of patients: rCBV increased when initial rCBV was <1.0 (Group_rCBV_M0<1) and rCBV decreased when initial rCBV was >=1.0 (Group_rCBV_M0>1), this was statistically significant (p<0.013). Mapping of color-coded voxels between M0 and M2 provided additional spatial and quantitative information about tumor perfusion: Group_rCBV_M0>1 presented a significant decrease of High_CBVTUMOR volume (p=0.015) simultaneously with a significant increase of the Normal_CBVTUMOR volume (p=0.012) after treatment. Group_rCBV_M0<1 presented a significant decrease of Low_CBVTUMOR volume (p=0.035) after treatment and an increase of the Normal_ and High_CBVTUMOR volumes. Two examples of these CBVTUMOR volumes variations between M0 and M2 are illustrated for a patient of each group over their anatomical MRI, respectively Fig1A for a patient of Group_rCBV_M0>1 and Fig1B for a patient of Group_rCBV_M0<1.