A Phase II Trial of Capecitabine Concomitantly With Whole-Brain Radiotherapy Followed by Capecitabine and Sunitinib for Brain Metastases From Breast Cancer

Niravath, Polly; Tham, Yee Lu; Wang, Tao; Rodriguez, Angel Augusto; Foreman, Claudette; Hilsenbeck, Susan G.; Elledge, Richard M.; Rimawi, Mothaffar F.

doi:10.1634/theoncologist.2014-0278

Cited by 12 publications

(9 citation statements)

References 15 publications

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“…Our review of the literature identified seven published studies of WBRT for brain metastases (melanoma or otherwise) in the last 10 years that failed to reach their recruitment target (Roos et al , 2006; Neuhaus et al , 2009; Chua et al , 2010; Hassler et al , 2013; Robins et al , 2013; Sperduto et al , 2013; Niravath et al , 2015). It is reasonable to expect there are more that have not been published.…”

Section: Resultsmentioning

confidence: 99%

“…Study entry criteria in this patient group are generally quite strict, which can limit successful accrual (Neuhaus et al , 2009; Chua et al , 2010; Niravath et al , 2015). In a phase 3 study of WBRT vs WBRT plus thalidomide, a short window between diagnosis of brain metastases and need to start treatment, and a requirement for follow-up with MRI scans every 2 months to assess PFS brain were noted to affect recruitment at some study sites (Knisely et al , 2008).…”

Section: Resultsmentioning

confidence: 99%

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RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases – results and lessons learnt

et al. 2016

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Background:Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases.Methods:In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials.Results:Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6–5.6) in the vandetanib group and 2.5 months (90% CI: 0.2–4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6–6.3) and 2.5 months (90% CI: 0.2–7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments.Conclusions:The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases – results and lessons learnt

et al. 2016

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“…The results from most single-arm studies have suggested that systemic therapy following WBRT is tolerable. [ 7 8 9 10 ] Several control studies have found that systemic therapy can improve the response rate of intracranial lesions and prolong patients’ progression-free survival and even OS. [ 11 12 13 ] However, the results from other studies have not found that systemic therapy has clinical benefits.…”

Section: Discussionmentioning

confidence: 99%

Systemic Therapy after Radiotherapy Significantly Reduces the Risk of Mortality of Patients with 1–3 Brain Metastases

Dai

Chen

et al. 2017

Chinese Medical Journal

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Background:For patients with a brain metastasis (BM), systemic therapy is usually administered after the completion of radiotherapy, especially in cases of multiple BMs. However, the role of systemic therapy in patients with a limited number of BMs is not clear. Therefore, we conducted a retrospective study to explore this question.Methods:Consecutive patients with a pathologically confirmed malignancy and 1–3 intracranial lesions that had been documented within the last decade were selected from the databases of three hospitals in China.Results:A total of 250 patients were enrolled; of them, 135 received radiotherapy alone and 115 received radiotherapy plus systemic therapy. In patients receiving whole-brain radiation therapy (WBRT) as radiotherapy, 28 received WBRT alone and 35 patients received WBRT plus systemic therapy. Of the patients treated with stereotactic radiosurgery (SRS), 107 received SRS alone and 80 received SRS plus systemic therapy. Multivariate analysis revealed that systemic therapy significantly reduced the risk of mortality compared with radiotherapy alone (hazard ratio [HR] = 0.294, 95% confidence interval [CI] = 0.158–0.548). Further, when the analysis was conducted in subgroups of WBRT (HR = 0.230, 95% CI = 0.081–0.653) or SRS (HR = 0.305, 95% CI = 0.127–0.731), systemic therapy still showed the ability to reduce the risk of mortality in patients with BMs.Conclusion:Systemic therapy after either SRS or WBRT radiotherapy may significantly reduce the risk of mortality of patients with 1–3 BMs.

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“…One study reported overall mild toxicity and no high‐grade neurotoxicity . A second study, a phase II trial, in which capecitabine was combined with WBRT followed by sunitinib, closed early because of low efficacy and excessive toxicity, although no high‐grade neurotoxicity was mentioned . Neurocognitive impairment and QoL, both salient endpoints, were not separately scored in these studies.…”

Section: Resultsmentioning

confidence: 99%

Use of Systemic Therapy Concurrent With Cranial Radiotherapy for Cerebral Metastases of Solid Tumors

et al. 2017

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The incidence of brain metastases of solid tumors is increasing. Local treatment of brain metastases is generally straightforward: cranial radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) or resection when feasible. However, treatment becomes more complex when brain metastases occur while other metastases, outside of the central nervous system, are being controlled with systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies). It is known that some anticancer agents can increase the risk for neurotoxicity when used concurrently with radiotherapy. Increased neurotoxicity decreases quality of life, which is undesirable in this predominantly palliative patient group. Therefore, it is of utmost importance to identify the compounds that should be temporarily discontinued when cranial radiotherapy is needed.This review summarizes the (neuro)toxicity data for combining systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies) with concurrent radiotherapy of brain metastases. Because only a limited amount of high-level data has been published, a risk assessment of each agent was done, taking into account the characteristics of each compound (e.g., lipophilicity) and the microenvironment of brain metastasis. The available trials suggest that only gemcitabine, erlotinib, and vemurafenib induce significant neurotoxicity when used concurrently with cranial radiotherapy. We conclude that for most systemic therapies, the currently available literature does not show an increase in neurotoxicity when these therapies are used concurrently with cranial radiotherapy. However, further studies are needed to confirm safety because there is no high-level evidence to permit definitive conclusions. The Oncologist 2017;22:222-235 Implications for Practice: The treatment of symptomatic brain metastases diagnosed while patients are receiving systemic therapy continues to pose a dilemma to clinicians. Will concurrent treatment with cranial radiotherapy and systemic therapy (chemotherapeutics, molecular targeted agents, and monoclonal antibodies), used to control intra-and extracranial tumor load, increase the risk for neurotoxicity? This review addresses this clinically relevant question and evaluates the toxicity of combining systemic therapies with cranial radiotherapy, based on currently available literature, in order to determine the need to and interval to interrupt systemic treatment.

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A Phase II Trial of Capecitabine Concomitantly With Whole-Brain Radiotherapy Followed by Capecitabine and Sunitinib for Brain Metastases From Breast Cancer

Cited by 12 publications

References 15 publications

RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases – results and lessons learnt

RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases – results and lessons learnt

Systemic Therapy after Radiotherapy Significantly Reduces the Risk of Mortality of Patients with 1–3 Brain Metastases

Use of Systemic Therapy Concurrent With Cranial Radiotherapy for Cerebral Metastases of Solid Tumors

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