Elsevier

European Journal of Cancer

Volume 48, Issue 18, December 2012, Pages 3439-3447
European Journal of Cancer

Current Perspective
Trial design on prophylaxis and treatment of brain metastases: Lessons learned from the EORTC Brain Metastases Strategic Meeting 2012

https://doi.org/10.1016/j.ejca.2012.07.002Get rights and content

Abstract

Brain metastases (BM) occur in a significant proportion of cancer patients and are associated with considerable morbidity and poor prognosis. The trial design in BM patients is particularly challenging, as many disease and patient variables, statistical issues, and the selection of appropriate end-points have to be taken into account. During a meeting organised on behalf of the European Organisation for Research and Treatment of Cancer (EORTC), methodological aspects of trial design in BM were discussed. This paper summarises the issues and potential trial strategies discussed during this meeting and may provide some guidance for the design of trials in BM patients.

Introduction

Brain metastases (BM) represent a substantial health care problem in cancer patients. It is estimated that approximately 20–40% of patients with malignancy will develop BM during the course of their illness.1 The most common anatomic primary sites are breast and lung.2 Melanoma has however the highest percentage of BMs relative to other primary tumours, with 75% of patients with disseminated disease developing BM.3 With best supportive care, median survival time is approximately 1–2 months.4 Radiation therapy (RT) increases the median survival to 3–5 months. Surgery, stereotactic radiotherapy, whole brain radiotherapy (WBRT) and systemic methods have been integrated in the therapeutic armamentarium, depending on the number, the site and the size of brain secondary lesions.5, 6, 7 Delivering concomitant chemo-RT may improve tumour local control but does not improve overall survival (OS) and is thus not recommended for the routine treatment of BM patients.8

Although many patients with BM die as a result of extra-cranial disease progression, it is important to note that a substantial number suffer from the local tumour progression in the CNS.9 Optimising local control is thus of paramount importance. The development of symptomatic BM has a substantial impact on patient’s quality of life (QoL) and neuro-cognitive function.

However, these metrics are difficult to assess in BM patients, as the overall compliance rates of questionnaires and neuro-psychological tests decreases as patients’ condition deteriorates over time.10, 11, 12 Treatment may also induce drowsiness, alopecia and weakness that may consequently substantially affect the overall QoL of these patients.10, 12 Notwithstanding the overly optimistic estimation of the treatment’s clinical benefit of patients and referring physicians alike, palliative treatment should not be detrimental to the patients’ quality of life, notably when left with a limited life span.13, 14 Newer radiation techniques, e.g. with hippocampal sparing (Fig. 1), and the use of novel drugs may to some extent decrease the treatment-related toxicity and preserve neuro-congition.15, 16, 17

The main prognostic factors for BM patients are age, performance status, control of primary tumour, absence of extra-cranial disease and number of brain lesions.18 It is thus possible to identify a subset of patients in the heterogeneous BM population with favourable outcome potential, who may benefit from experimental therapeutic strategies. Additionally, some primary and secondary tumours may have unique biological signatures that may respond to targeted agents and biological modulation.19

The European Organisation of Research and Treatment of Cancer (EORTC) organised in February 2012 a multidisciplinary meeting to discuss issues with and strategies for trial development in patients with BM. In this report, we discuss some of the challenges of study conception and design discussed during this meeting. We hope that our report may provide guidance for the design of future trials in BM patients.

Section snippets

Challenges to developing a brain metastases trial

When developing trials for BM, there are a number of key aspects that require careful considerations like the trial organisation, the patient population, the safety assessment and the efficacy end-points.

Trial design

Two phase III randomised studies assessing cranial irradiation against appearance or recurrence of BM were recently published by EORTC (EORTC 22993-08993 and EORTC 22952-26001).20, 21, 22, 23 The following lessons can be learned from the data analysis and results of these two studies.

Trials addressing prophylaxis or treatments targeting cancer metastasizing to the brain, unlike other phase III clinical trials in oncology, rarely aim to substantially increase the overall or even progression-free

Study end-points

Several factors influence the choice of end-points in clinical trials on BM: the patient population, as there are significant differences in terms of natural history and outcome amongst different tumour types or even molecular subtypes; the trial setting (phase I, phase II, phase III); the type of intervention (local versus systemic treatments).

OS has been almost universally chosen as primary end-point in phase III trials on BM, as it is unambiguous and clinically meaningful, but, due to

Neurocognitive function

Since BMs are associated with poor prognosis, not only in terms of length of survival but also in terms of functioning, patient performance is of particular importance to evaluate treatment outcome. This is specifically the case for patients with BM for whom palliation of symptoms and sustained or improved QoL are equally important goals of treatment as prolonged survival and postponed metastases progression. Evaluation of treatment in patients with BM should therefore focus beyond oncological

Quality of life

During the last decades, QoL has become an increasingly important outcome measure in clinical cancer trials. It has been recognised that duration of survival is not the only goal of treatment, and that maintaining QoL is an important outcome as well. QoL of brain tumour patients is dependent on both tumour- and treatment-related factors.30 It is pivotal to avoid negative impact of treatment on QoL, but there always is a trade-off: a temporary drop in QoL might be acceptable when treatment

Biology of brain metastases: opportunities for targeted agents and translational research

BM is in principle a multifocal disease for which metastasizing cancer cells have to successfully master distinct mandatory steps to eventually grow to a clinically significant macrometastasis.42, 43 BM formation may be prevented by interfering with distinct steps of the brain-metastatic process, as demonstrated for inhibition of brain colonisation of NSCLC cell lines in a mouse model using bevacizumab.43 The following biological hallmarks of BM make it likely that judicious addition of

Summary and conclusions

Based on the discussion held at the EORTC Brain Metastases Strategic Meeting 2012, the following conclusions were made:

  • There is a strong need for well conducted trials on prophylaxis and treatment of BM.

  • New study initiatives should focus on specific tumour types/molecular subtypes instead of enrolling unselected BM patients with tumours of all histological types.

  • New trials should investigate the prophylaxis of BM based on insights into the pathogenesis of CNS involvement, e.g. by targeted

Conflict of interest statement

Matthias Preusser has received travel support (scientific meetings), research support (unrestricted grants) and lecture honoraria by Roche. Frank Winkler has received lecture honoraria by Roche, and research support restricted grants) by Roche and Genentech. Sven Haller has received travel support (scientific meetings) and research support (unrelated to the current manuscript). Riccardo Soffietti has received honoraria for Advisory Boards from Roche, Merck and MSD. Jaap Reijneveld received

Acknowledgements

The Meeting was kindly supported by Roche, Novocure, Merck Serono and the Comprehensive Cancer Center Vienna. The sponsors had no role or influence in the content of the meeting or this manuscript.

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