Focus on past conferences ecc - introduction

ESTRo conferences

European Cancer Congress 27 September - 01 October 2013 Amsterdam, The Netherlands The European Cancer Congress in Amsterdam provided superlative surroundings for all participants to leverage knowledge, promote education and build awareness about oncology - reinforcing multidisciplinarity to work towards ensuring that every patient does indeed receive the best. The recognised multidisciplinary setting of the ECC 2013 featured a strong balance of representation from all cancer stakeholders, and a marked increase in attendance from the different disciplines. This shows our community’s: 18% increase in Basic & Translational Scientists 7% increase in Radiation oncologists 23% increase in Surgical oncologists 18% increase in Patient advocates

The ECCO-ESMO-ESTRO congress has demonstrated the power of multidisciplinarity towards cancer prevention, treatment and care over the years, and Amsterdam proved no exception: More than 18 000 delegates from 120 countries 3 306 abstracts (38% increase from Stockholm 2011) 800 invited speakers 1 000 presentations 300 sessions in 17 parallel rooms 168 oral presentations 2 200 poster presentations 126 late-breaking abstracts

Focus on past conferences ecc - Highlight of papers

ESTRo conferences

Highlight of papers Philip Poortmans Institute Verbeeten Tilburg, The Netherlands Co-authors: H. Struikmans, C. Kirkove, V. Budach, P. Maingon, M. C. Valli, S. Collette, A. Fourquet, H. Bartelink, W. Van den Bogaert for the EORTC radiation oncology and breast cancer groups

Philip Poortmans

Locoregional radiation therapy (RT) improves overall survival in patients with involved lymph nodes (LN). EORTC trial 22922-10925 investigates how much RT to the internal mammary and medial supraclavicular LN (IM-MS) contributes to this effect (Clinicaltrials.gov NCT00002851).

Between 1996 and 2004, 4004 patients participated in a trial to investigate how much RT to the internal mammary and medial supraclavicular lymph nodes (IM-MS LN) contributes to overall and disease free survival. Eligible patients had involved axillary LN (55.6% of the cases) and/or a central or medially located primary tumour. The majority (76.1%) was treated with breast conserving therapy. Nearly all LN-positive (99.0%) and 66.3% of LN-negative patients received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients have died. IM-MS RT improved outcome at 10 years: 82.3 vs. 80.7% OS (HR=0.87 (95%CI: 0.76, 1.00), Logrank p=0.056); 72.1 vs. 69.1% DFS (HR=0.89 (95%CI: 0.80, 1.00), Logrank p=0.044);

78.0 vs. 75.0% DMFS (HR=0.86 (95%CI: 0.76, 0.98), Logrank p=0.020). The treatment effect on OS was independent from the number of involved LN: HR = 0.79 (95%CI: 0.61, 1.02) for LN-negative; 0.89 (95%CI: 0.73, 1.09) for 1-3; 0.85 (95%CI: 0.61, 1.18) for 4-9 and 1.00 (95%CI: 0.59, 1.71) for 10+ involved axillary LN (p>0.1 for heterogeneity). In the IM-MS group 382 patients died vs. 429 patients in the no IM-MS group. The causes of death were similar except for breast cancer (259 vs. 310). No increase in lethal complications has been observed so far. Further analyses will be done after 15 and 20 years of follow-up. In the meantime, combined with the earlier report of good tolerance and limited toxicity up to 3 years, we advise RT to the IM-MS lymph nodes for patients with involved axillary LN and/ or a central or medially located primary tumour. Importance for radiation oncology: this trial confirms that elective regional treatment decreases the risk for development of distant metastases and, as a second level effect, of death due to breast cancer (“stopping metastases at their source”). A –not yet significant- impression exists that this effect is stronger in lower risk patients as well as in patients who receive both chemotherapy and hormonal treatment. This supports the importance of a multidisciplinary approach: collaboration and combination instead of competition!

Focus on past conferences ecc - Highlight of papers

ESTRo conferences

Highlight of papers Michael Baumann Department of Radiation Oncology, OncoRay National Center for Radiation Research in Oncology, Institute of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany, Helmholtz-Zentrum Dresden -Rossendorf, Germany

Michael Baumann

ECCO 2013 Clinical Research Award Keynote Lecture: Improved cure through personalised radiation oncology – basis and perspectives Radiotherapy has a proven curative potential in many cancer types, due to its high efficacy to inactivate those tumour cells which have capacity to cause recurrences of the primary tumour and regional metastases (i.e. cancer stem cells or tumour recurrence initiating cells). Today, radiation oncology is already highly personalised based on anatomical imaging, space-resoluted radiation dose models, TCP- vs. NTCP-data-based-models and clinical parameters. Most of these advances in personalised radiation oncology can be attributed to detailed dose-distribution-outcome analysis, prospective clinical trials and the revolutionary progress in high-precision radiation delivery and planning technology during the past decades. These innovative technologies have been rapidly translated into clinical practice and allowed the development of novel more efficient clinical strategies. Despite these substantial advances, today

approximately 35% of all tumours treated using radiotherapy with curative intent will recur in the treated volume. This usually leads to incurable local progression but also increases the risk of distant metastases. Furthermore, large volumes are irradiated in a significant proportion of patients which may lead to early, late and very late normal tissue damage. One of the most promising research avenues for further improvement of radiotherapy is the integration of biological information on the specific tumour and on surrounding normal tissues in individual patients. It is well recognised that both TCP and NTCP show substantial heterogeneity even in stratified populations. Because of spatially resolved information, biological imaging is of particular relevance for advancing biology-driven individualisation of radiation oncology, but other predictive and prognostic markers also demonstrate high potential in preclinical and clinical studies. Examples covered in the lecture include dose prescription based on surrogate markers of the cancer stem cell number in individual tumours (tumour volume and cell surface markers) and stratification of patients for treatment intensification by PET hypoxia imaging before and during radiotherapy. Assays of the cellular radiosensitivity, by determination of residual DNA

Focus on past conferences ecc - Highlight of papers

double strand breaks in tumour specimens using histological techniques, may substantially add to discrimination. Combination of radiation with specific molecular targeted drugs may increase local tumour control. However this is only true when the drugs are active on cancer stem cells and not only on the bulk of tumour cells which may not cause recurrence. If not active on stem cells, only tumour regression and growth delay are improved but local tumour control, i.e. the curative potential of radiotherapy, remains unchanged. Therefore systematic evaluation of novel drugs in the context of radiotherapy

using relevant endpoints is an important research field for the radiation oncology community. The heterogeneity of the efficacy of molecular drugs combined with irradiation on tumour control adds another level of complexity to biological individualisation, requiring parallel investigations in biomarkers specific for combined treatments in radiation oncology. Progress in these areas will not only need significant research programmes, but also close interaction between radiation oncologists, medical physicists and biologists. Radiation oncology can,

however, capitalise on the unique situation that even broad biological stratification of patients in two or a few groups can substantially enhance individualisation, as this new information adds a power-function to the anatomicallypersonalised dose-distributions achieved today. Therefore radiation oncology should be in pole position to translate research on personalised cancer treatment to applications which are improving care of patients.

Focus on past conferences ecc - Highlight of papers

ESTRo conferences

Highlight of papers Jesper G Eriksen DAHANCA, Denmark Co-authors: Maare C, Johansen J, Primdahl H, Evensen J, Kristensen CA, Andersen LJ and Overgaard J

Jesper G Eriksen

A randomized phase III study of primary curative (chemo)radiotherapy and the EGFRinhibitor zalutumumab for squamous cell carcinoma of the head and neck (HNSCC) Antibodies against the Epidermal Growth Factor Receptor (EGFR-I) are suggested to increase tumour control and survival of patients with Head and Neck Squamous Cell Carcinomas (HNSCC) when combined with radiotherapy (RT).

The EGFR-I zalutumumab is a fully human IgG1 antibody directed against the external part of the receptor and has preclinically shown similar efficacy as cetuximab, as well as promising results in phase I-II trials. The aim of this study was to evaluate whether concomitant treatment with zalutumumab during (chemo-) RT would improve outcome in patients with HNSCC. The primary endpoint of the study was locoregional control (LRC). 612 eligible patients were accrued from November 2007 to June 2012. The majority of patients had tumours of oropharyngeal origin (69%), locally advanced disease (90%) and 75% of the oropharyngeal tumours were HPV/p16 positive. Patients were randomized to control-arm or zalutumumab-arm. The control-arm consisted of primary accelerated RT (predominantly 66-68Gy, 2Gy/fx, 6 fx/wk) and concomitant daily hypoxic radiosensitisation with nimorazole. Stage IIIIV carcinomas received weekly cisplatin 40 mg/ m2 during RT. Elective neck-dissection were not performed. The zalutumumab-arm was identical with the control-arm plus zalutumumab 8 mg/kg. First dose was given one week before start of RT and continued weekly during irradiation. Analyses were performed as intention-to-treat.

Focus on past conferences ecc - Highlight of papers

Patient and tumour parameters were well balanced and treatment was well tolerated. Threeyear LRC rate was 78% in the zalutumumab-arm vs. 79% in the control-arm, HR: 1.2 [95% CI: 0.81.7], see figure 1. Similar findings were observed for disease-specific and overall survival and out-

comes were not influenced by HPV/p16-status of the tumours. This study supports that addition of EGFR-I does not improve outcome in unselected HNSCC patients treated with primary chemo-radiothera-

py. Furthermore, the findings question that patients with HPV/p16-positive tumours might be the ones with benefit from treatment with EGFR-I.

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ESTRo conferences

Highlight of papers Pier Paolo Pandolfi M.D., Ph.D Beth Israel Deaconess Cancer Centre / Harvard Medical School, Boston, MA

Pier Paolo Pandolfi

The Mouse Hospital and the Co-Clinical Trial Project Tremendous advances in technology have allowed us to gain powerful insights into the molecular and genetic drivers of cancer. The rate at which this knowledge has been translated into effective therapeutics, however, has often been pitifully slow. To facilitate this process, we have launched a new platform and initiative, both nationally and internationally, that we refer to as “The Co-Clinical Project”. Its major goal is to accelerate the stratification of patients based on molecular and genetic criteria, and the identification of mechanisms of acquired resistance to specific treatments towards the development of novel therapies that overcome such resistances. This is achieved through integrated analyses of data obtained from preclinical trials performed in the “Mouse Hospital” in genetically engineered mouse models (GEMMs) of human cancer, as well as mouse models orthotopically transplanted with primary human cancers, and run in parallel and synchronicity with experimental clinical trials, as well as existing standard-of-care treatments in human patients ongoing in the “Human Hospital” (hence the term “CoClinical”).

Focus on past conferences ecc - Highlight of papers

ESTRo conferences

Highlight of papers J. Martin Brown, PhD

Vasculogenesis: A new target to improve the radiotherapy of solid tumours Functioning blood vessels are essential for tumours to recur after radiotherapy, A variety of studies have shown that tumour blood vessels can

derive from two sources: from angiogenesis, the sprouting of endothelial cells from nearby blood vessels, and from vasculogenesis, the formation of blood vessels by circulating cells. In most circumstances angiogenesis is the most important process for the formation of these vessels. However, in the case of radiotherapy we have shown

Department of Radiation Oncology, Stanford University, USA

J. Martin Brown

AMD3100 (inhibits SDF-1/CXCR4) prevents both CD11b influx and recurrence of the irradiated GBM

Focus on past conferences ecc - Highlight of papers

that angiogenesis is abrogated thereby forcing the tumour to use vasculogenesis to restore the vasculature. We have tested the hypothesis that the radiation response of tumours can be increased by blocking vasculogenesis using two human tumours (FaDu head and neck tumours and the U251 glioblastoma) transplanted into nude mice as well as an autochthonous tumour developing in the brains of rats treated while in utero with the carcinogen ethylnitrosourea (ENU). We show that CD11b+ monocytes/macrophages are

essential for vasculogenesis in irradiated tumours. These are recruited to the irradiated tumours by stromal cell-derived factor-1 (SDF-1) induced in the irradiated tumours. Importantly, a variety of ways of blocking this process (neutralising antibodies to CD11b, inhibition of the interaction of SDF-1 with CXCR4, antibodies against CXCR4, and inhibition of HIF-1) render tumours less able to recur following irradiation. This is particularly the case with the rat autochthonous brain tumours. The SDF-1 inhibitor NOX-A12, while having no effect alone, drama-

tically improves the survival time of rats given whole brain irradiation. We also show that blocking vasculogenesis does not increase the radiation damage to normal skin. Thus blocking circulating normal cells (monocytes/macrophages) that can reconstitute the tumour vasculature after irradiation can have a major positive impact on the response of solid tumours to irradiation, and potentially represents a new paradigm for the treatment of such tumours.

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ESTRo conferences

Highlight of papers Kristin Gurtner Department of Radiation Oncology and OncoRay – National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany Co-authors: C. Thurow, A. Yaromina, W. Eicheler, M. Baumann, M. Krause

EGFR-amplification correlates with response to combined treatment of fractionated irradiation and EGFR-inhibition in HNSCC tumour xenografts

Kristin Gurtner

With the aim to identify potential biomarkers for the improvement of local tumour control by simultaneous EGFR inhibition during fractionated irradiation, 10 different HNSCC tumour xenografts were evaluated for local tumour control after irradiation with or without EGFR inhibition, while simultaneously investigating factors that might influence the response. Results of the first

5 tumour models have already been published (Gurtner et al., Radiother Oncol 2011 (99):323330). Here we present an update of the data on a total of 8 tumour models and a comparison of EGFR gene amplified versus non-amplified tumours. For evaluation of local tumour control dose 50% (TCD50) 120 days after treatment tumours were treated with fractionated irradiation (RT) (30f/6 weeks) alone or combined with application of the monoclonal EGFR-antibody cetuximab (1mg, weekly, i.p.). For tumour growth delay and relative tumour volume, cetuximab was applied alone (once d0 or 4x d0, d2, d5, d7). Results were compared with molecular data

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on fluorescence-in situ-hybridisation (FISH) and immuno-histochemistry. A significant improvement of local tumour control could be observed for the combined treatment of RT and cetuximab compared to RT alone in all 3 tumours harbouring an EGFR gene amplification. The enhancement ratios for the TCD50 after irradiation alone versus irradiation plus cetuximab

were 2.0 (CAL-33), >40 (UT-SCC-14) and >44 (UT-SCC-8). In only 2 of the 5 tumour models without EGFR gene amplification local tumour control was improved by simultaneous cetuximab application. EGFR gene amplification appears as a promising biomarker for prediction of the improvement of local tumour control by combined fractionated irradiation and cetuximab treat-

ment. However, using this biomarker alone would result in some false-negative predictions, as the group of non-amplified tumours also contains some responder models. Thus, further biomarker evaluation is warranted to improve the validity especially in the latter subgroup of tumours.

Focus on past conferences ecc - Highlight of papers

ESTRo conferences

Highlight of papers Giuseppe Roberto D’Agostino Dept. of Radiation Oncology, Catholic University of the Sacred Heart Rome, Italy Co-authors: B. Diletto, A. Martino, G. De Dilectis, F. Catucci, L. Nardone, D. Pasini, V. Valentini, G. Mantini

Giuseppe Roberto D’Agostino

Prospective Gating

5-field IMRT

REDUCTION OF HEART DOSE DURING LEFT BREAST CANCER RADIOTHERAPY: COMPARISON BETWEEN RESPIRATORY GATING RT AND IMRT

early left breast cancer, referred for adjuvant radiotherapy to our Institution, were enrolled. For each patient, two simulation CT-scans were acquired (the first during free breathing, the second on prospective gating during deep inspiration breath-hold) and three treatment plans were performed: a 3D-CRT and an IMRT plans, based each on the free-breathing scan, and a PGRT plan based on the deep inspiration breathhold scan. Almost all patients underwent 4DCT-scan after no more than a 5 minute training in breathing techniques immediately before the dose-planning CT-scan, without any

Breast cancer survivors have a high risk of cardiac death as a consequence of heart irradiation during left breast tangential RT. In this study the cardiac dose delivered by a standard 3D tangential radiotherapy (CRT) was compared to that delivered by prospective gating radiotherapy (PGRT) or a 5 fields-IMRT. Fifty patients with

Focus on past conferences ecc - Highlight of papers

further coaching, and 84% of women performed simulation CT-scan in just one deep inspiration. The dose distribution to heart, lungs and contra-lateral breast delivered by PGRT proved to be more effective in reducing heart irradiation compared to CRT and IMRT. In fact, the median

MHD was 1.9 Gy in the PGRT plans, compared to 3 Gy in the CRT plans, and 4.5 Gy in IMRT plans (p