Should patients with malignant intracranial space occupying lesions (M-ICSOLs) be excluded from phase I trials? The Royal Marsden Hospital Drug Development Unit experience.

Papadatos-Pastos, D.; Blanco-Codesido, Montserrat; Carden, Craig P.; Fehrmann, Rudolf S.N.; Trani, Leonardo; Molife, L. Rhoda; Brunetto, Andre Tessainer; Sandhu, Simarjot Kaur; Massard, Christophe; Banerji, Udai

doi:10.1200/jco.2010.28.15_suppl.2516

Cited by 6 publications

(3 citation statements)

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“…Main reasons to exclude patients from phase I clinical trials are (a) their poor prognosis, (b) risk of intracranial bleed especially when an angiogenesis inhibitor is involved, and (c) intracranial disease, which might complicate assessment of toxic effects. A recent retrospective study in patients that participated in phase I trials at a single institution, demonstrated that there is no significant difference in PFS between patients with BM at screening (n = 24) when compared to the rest of the phase I patient population (n = 861) [91]. All patients with BM at screening had to have controlled intracranial disease and be asymptomatic.…”

Section: Discussionmentioning

confidence: 98%

Revisiting the role of molecular targeted therapies in patients with brain metastases

Papadatos-Pastos

Banerji

2011

J Neurooncol

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Brain metastases (BM) are treated with surgical resection when feasible. Unfortunately this occurs only in a small subset of patients. The optimal treatment for patients with intracranial metastases non amenable to surgical resection has not been identified. Radiotherapy improves symptom control and survival but long-term local control has been poor. Conventional chemotherapies have generally produced disappointing results possibly due to their limited ability to penetrate the blood brain barrier. Therefore, newer treatments are required for patients with unresectable BM. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review we will present current data on targeted therapies that have been approved for the treatment of malignant tumours and we discuss the evidence of their use in patients with BM.

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Section: Discussionmentioning

confidence: 98%

Revisiting the role of molecular targeted therapies in patients with brain metastases

Papadatos-Pastos

Banerji

2011

J Neurooncol

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“…Initially, the Royal Marsden Phase I unit reported that the progression-free survival of patients with malignant intracranial lesions was not different from the rest of the patients who participated in Phase I trials at the same time period [61]. More recently, a second study, which interestingly included 30 patients with melanoma, confirmed that it is safe and clinically relevant to include selected patients with BM in early trials [62].…”

Section: Clinical Trialsmentioning

confidence: 96%

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

Papadatos-Pastos

Januszewski

Dalgleish³

2013

Expert Review of Anticancer Therapy

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The CNS is a common site of metastasis in patients with malignant melanoma. Locoregional control either with surgery or radiotherapy is first-line treatment for patients with brain metastasis should they be suitable candidates. For those patients who are not and those who progress after previous treatment, there is an unmet clinical need for effective systemic therapies. Systemic cytotoxics, such as temozolamide and fotemustine, have only modest activity, resulting in a median progression-free survival ranging from 1-2 months, in patients with metastatic melanoma to the brain. Newer systemic treatments such as vemurafenib and ipilimumab have been approved for the treatment of melanoma, but evidence regarding their activity in brain metastases is inconclusive due to the limited access of patients to clinical trials. This is now being revised and more data are emerging supporting the inclusion of patients with brain metastasis in trials. In this review, the authors present data regarding the efficacy of systemically administered therapies in patients with metastatic melanoma to the brain.

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“…This series reports on a neglected topic in experimental oncology and follows on the heels of an abstract detailing the Royal Marsden Hospital experience (2) and an excellent editorial (3). More than 170,000 patients with brain metastases are identified annually, and treatment of such patients poses a significant clinical challenge due to the confined anatomic location of the tumors, the blood-brain barrier (BBB), and variant tumor biology (4).…”

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confidence: 99%

Inclusion of Patients with Brain Metastases in Phase I Trials: An Unmet Need

Gounder

Spriggs

2011

Clinical Cancer Research

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Patients with brain metastases are increasing in number; however, these patients are often excluded in phase I/II trials due to perceived poor prognosis, risk of hemorrhage, inefficient drug delivery, and confounding toxicities. Tsimberidou and colleagues demonstrate that selected patients can be appropriately enrolled in phase I trials and have outcomes representative of the general cancer population. Clin Cancer Res; 17(12); 3855-7. Ó2011 AACR.In this issue of Clinical Cancer Research, Tsimberidou and colleagues (1) report their single-institution experience of patients with brain metastases treated in various phase I clinical trials. This series reports on a neglected topic in experimental oncology and follows on the heels of an abstract detailing the Royal Marsden Hospital experience (2) and an excellent editorial (3). More than 170,000 patients with brain metastases are identified annually, and treatment of such patients poses a significant clinical challenge due to the confined anatomic location of the tumors, the blood-brain barrier (BBB), and variant tumor biology (4).The goal of phase I studies is to establish the safety, dose, toxicity, and pharmacokinetics of a new drug or regimen (5). In identifying appropriate patients, clinicians must weigh on one hand the scientific and clinical benefits, and on the other hand the risk of delay from unrelated toxicity and early patient drop-out. A metaanalysis of phase I trials showed overall response rates, stable disease, and toxicity-related deaths of approximately 10%, 34%, and 0.5%, respectively (6). Although these are surrogate endpoints, in selected patients (e.g., those with EGFR mut non-small cell lung cancer) this can be used to predict a survival benefit. Eligibility criteria serve as objective guidelines to identify low-risk, appropriate patients, and typically exclude patients with poor performance status, organ dysfunction, a life expectancy of <12 weeks, concomitant medications that interfere with metabolism, and comorbidities (e.g., brain metastases). Brain Metastases and Clinical TrialsPatients with brain metastases represent a heterogeneous population with a wide range of outcomes. Gaspar and colleagues (7) retrospectively analyzed 1,200 patients with brain metastases who presented with neurological symptoms and were enrolled in Radiation Therapy Oncology Group randomized trials from 1979 to 1993. The authors evaluated various radiation doses, schedules, and radiosensitizers, and on the basis of a recursive partitioning analysis proposed 3 prognostic classes. Class I patients had a Karnofsky performance status (KPS) greater than 70, age under 65 years, controlled primary disease with brain-only metastatic site, and a median overall survival of 7.1 months. Class III patients had a KPS less than 70 and survival of 2.1 months. Class II patients had a survival of 4.5 months and were neither class I nor class III. To further refine the model, other investigators have used prognostic indices incorporating age, control of primary disease, response to st...

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Should patients with malignant intracranial space occupying lesions (M-ICSOLs) be excluded from phase I trials? The Royal Marsden Hospital Drug Development Unit experience.

Cited by 6 publications

References 0 publications

Revisiting the role of molecular targeted therapies in patients with brain metastases

Revisiting the role of molecular targeted therapies in patients with brain metastases

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

Inclusion of Patients with Brain Metastases in Phase I Trials: An Unmet Need

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