R.P. Symonds

Concomitant (without Adjuvant) Temozolomide and Radiation to Treat Glioblastoma: a Retrospective Study

Between November 2004 and August 2006 we treated 35 patients with concomitant temozolomide (TMZ) and radiotherapy. Twelve patients had very large or multicentric glioblastoma multiforme with a poor performance status and received TMZ plus radiation doses of 45-50.4 Gy. The median survival of these patients was only 3.8 months. Twenty-three patients would have been eligible for randomisation in the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) trial comparing combined and adjuvant TMZ plus radiation against radiotherapy alone. This group of patients received 60 Gy in 30 fractions plus concomitant TMZ (75 mg/m(2)) but no adjuvant chemotherapy. At a median follow-up of 26 months, five of 23 patients are alive. The median survival time was 17 months (1.43 years; 95% confidence interval 0.96-1.55). Eighteen per cent were alive at 2 years. Toxicity from TMZ was infrequent. This series adds to indirect evidence that the concomitant rather than the adjuvant is the more efficacious part of the EORTC/NCIC schedule for this type of patient. Further trials should include a concomitant chemoradiotherapy regimen as well as concomitant plus adjuvant chemotherapy.

SCOTCERV: a phase II trial of docetaxel and gemcitabine as second line chemotherapy in cervical cancer.

OBJECTIVE The aim of the study was to determine the response rate and response duration of cervical cancer previously treated by cisplatin (with or without radiation) to a combination of docetaxel and gemcitabine. Secondary endpoints were assessment of toxicity and quality of life (QoL) of patients receiving the treatment. METHODS This was a multicentre phase II trial of 3 weekly docetaxel 75 mg/m(2) day 1 (reduced to 60 mg/m(2) after 32 cycles had been administered) and gemcitabine 1000 mg/m(2) (days 1 and 8). A two stage Gehan design was used initially. Twenty-nine patients recruited had disease outside the irradiated pelvis (Group 1), and 21 had disease confined to the irradiated pelvis (Group 2). The target response for the Gehan 2 design was 25% (Group 1) and 10% (Group 2). RESULTS The overall response rate for Group 1 was 21.4% (95% CI 8.3-41.0%). Amongst those who had at least 3 cycles of chemotherapy the response rate was 27.3% (95% CI 10.7-50.2%). The median survival was 7.3 months (95% CI 5.4 to 9.2 months) with 39.3% (95% CI 21.7-56.5%) alive at 1 year. In Group 2 the overall response rate was 9.5% (95% CI 1.2%-30.4%). The response rate for those who had at least 3 cycles of chemotherapy was 12.5% (95% CI 1.6-38.4%). The median survival was 7.9 months (95% CI 2.2-13.6 months). Toxicity was mainly haematological with 51% developing grade 3 or 4 neutropenia after at least 1 cycle of chemotherapy. QoL showed a significant deterioration from baseline for physical and role function but there was an improvement in emotional function during treatment. CONCLUSION Response rates and survival duration were similar to those reported following treatment with platinum based doublets. In view of the relatively poor response rates (no more than 36%) to conventional chemotherapy future developments should be a combination of chemotherapy and biological agents such as VEGFR inhibitors.

Potential Clinical Exploitation of the Radiation-induced DNA Damage Response

The major theme of this second special edition dealing with radiobiology is radiation DNA damage and the complex processes (response and repair) that follow damage both in normal and malignant tissue. Dillon and colleagues [1] point out that targeting the molecular response to radiotherapy-induced DNA damage holds great promise for selective tumour radiosensitisation. Shibata and Jeggo [2] summarise very succinctly the state of knowledge of repair of DNA double-strand breaks. The roles of non-homologous end-joining and homologous recombination repair are very well explained. The importance of the signalling pathways are emphasised and DNA repair signalling is a theme that is repeated in many of the other papers in this special issue. DNA damage kinases, particularly ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and RAD3-related (ATR), are promising important targets for new therapeutic agents. ATM is particularly important as it can lead to cell cycle arrest, allowing for accurate repair. The role of new therapeutic agents is explored further by Ruth Plummer [3] who charts the clinical development to date of poly(ADP-ribose) polymerase (PARP) inhibitors. This novel class of anticancer agents targets DNA damage response pathways. PARP inhibitors were first developed as chemo-potentiating agents. Phase III studies are ongoing combining these drugs with radiation but, owing to the fact that these agents may potentiate late radiation effects, such studies tend to be protracted and less attractive to the pharmaceutical industry. Dillon, Good and Harrington [1] expand further the theme of selective targeting. As a result of p53 pathway mutation or inactivation, the G1/S checkpoint is often absent in cancer cells, leading them to become reliant on a

The Patient Perspective on Radiogenomics Testing for Breast Radiation Toxicity

Aims In the field of radiogenomics, several potential predictive genetic markers have been identified that are associated with individual susceptibility to radiation toxicity. Predictive models of radiation toxicity incorporating radiogenomics and other biomarkers are being developed as part of the ongoing multicentre REQUITE trial. The purpose of this study was to explore patient attitudes towards future predictive radiogenomics testing for breast radiation toxicity. Patients and methods Twenty-one semi-structured interviews were conducted with breast cancer patients taking part in the REQUITE study at one centre. We used inductive thematic analysis to generate common themes. Results We identified three emerging themes describing attitudes and feelings towards a predictive radiogenomics test for breast radiation toxicity: theme 1 – willingness to undergo a test (subthemes – information, trusted expert); theme 2 – implications of a test (subthemes – preparation and planning, anxiety without recourse); theme 3 – impact on treatment decision-making (subthemes – prioritising cancer cure, preserving breast integrity, patient preferences). Conclusions Results from the present study indicate that patients support and have confidence in the validity of a radiogenomics test for breast radiation toxicity, but they would prefer the result be provided to healthcare professionals. Except in cases of significant chronic symptoms and pain or significant end-organ damage, participants in this study rarely felt that advance knowledge of their personal risk of breast radiation toxicity would influence their treatment decision-making. These findings provide a number of insights that will allow us to anticipate how patients are likely to engage with predictive radiogenomics testing in the future.

Abstract P6-09-51: the REQUITE-AB study: validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients

Clinically significant side-effects from radiotherapy affect around a quarter of breast cancer patients and may impact considerably on outcomes from treatment. An increasing number of replicated genetic associations for radiotherapy toxicity are being reported[1],[2]. The international REQUITE consortium aims to validate genetic markers and clinical factors implicated in radiotoxicity. The purpose of the REQUITE-AB project is to develop an integrated set of predictors for acute radiotherapy side-effects in breast cancer patients to be used as a clinical decision-making tool. As part of the REQUITE prospective cohort study, 2,000 patients eligible for adjuvant breast radiotherapy will be recruited in nine centres across Europe and North America between April 2014 and August 2016, with centralised data management, biobanking and two years9 follow-up using a standardised data collection protocol. Patient characteristics and treatment details being captured also include dose-volume histograms and DICOM files. Genotyping will take place in fall 2016. Primary endpoints are acute skin toxicity (CTC-AE v4.0) and quality-of-life (QoL) on completion of radiotherapy and at 3 months from start of radiotherapy. Secondary endpoints are late side-effects including change in breast appearance. 1,766 breast cancer patients have been recruited to date with standardized documentation of toxicity and QoL. Among patients who completed radiotherapy so far, 21.6% of patients developed grade 2 skin toxicity (brisk erythema) and 1.3% grade 3 (moist desquamation). The ability of patient, treatment and genetic variables to predict clinical outcomes and QoL will be examined. The REQUITE study includes the largest radiogenomics cohort of breast cancer patients to date recruited under a single standardised protocol. Findings of the REQUITE-AB project are likely to inform the development of interventional biomarker trials and personalise breast cancer care in the future. [1] Talbot et al, Br J Cancer, 2012; 107: 748-53. [2] Seibold et al, Int J Radiat Oncol Biol Phys, 2015; 92: 1084-92. Citation Format: Rattay T, Johnson K, Azria D, Chang-Claude J, Davidson S, Dunning A, de Ruyscher D, Guiterrez-Enriquez S, Lambin P, Rancati T, Rosenstein B, Seibold P, Symonds RP, Thierens H, Valdagni R, Vega A, Webb A, Wenz F, West C, Talbot C. The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-51.