Phase III Study of Efaproxiral As an Adjunct to Whole-Brain Radiation Therapy for Brain Metastases

Suh, John H.; Stea, Baldassarre; Nabid, Abdenour; Kresl, John J.; Fortin, A.; Mercier, Jean Philippe; Senzer, Neil; Chang, Eric L.; Boyd, Adam P.; Cagnoni, Pablo J.; Shaw, Edward G.

doi:10.1200/jco.2004.00.1768

Cited by 176 publications

(94 citation statements)

References 45 publications

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“…Median survival 3.4 mo, 1-y survival 12%, ie, comparable results Survival of the contemporary cohort analyzed here is comparable to representative large cohorts from the current decade Knisely et al, 16 Rades et al, 17,18 Suh et al 19 These studies confirm the survival results obtained with SRS, surgery, or WBRT in the current analysis clear, statistically significant observation was the increase in female patients with brain metastases in the contemporary cohort (57% vs 30%, P < .0001), resulting primarily from an increase in the number of female patients with lung cancer (56% of the contemporary lung cancer patients were females compared with 11% in the historical cohort, P < .0001). This shift could be driven by 2 factors, one being an obvious increase in the absolute numbers of women developing lung cancer and therefore subsequent brain metastases, as has been reported in other studies, but also possibly by a worrisome preliminary observation that women with lung cancer may be more susceptible to developing brain metastases compared with men.…”

Section: Argument References Commentsupporting

confidence: 81%

Presentation, patterns of care, and survival in patients with brain metastases

Nieder

Spanne

Mehta

et al. 2010

Cancer

181

106

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. RESULTS: Patterns of care have changed significantly. Contemporary patients received focal treatments such as stereotactic radiosurgery and surgical resection far more frequently. Furthermore, systemic treatment was used more often in contemporary patients, both before and after diagnosis of brain metastasis. Improved survival was observed in the contemporary cohort (P ¼ .03). The 1-year survival rate increased from 15% (95% confidence interval [CI], 7%-25%) to 34% (95% CI, 25%-44%). However, this improvement was largely driven by patients with favorable prognostic features. More than 40% of the patients still belong to unfavorable prognostic groups with limited median survival and little improvement. CONCLUSIONS: Contemporary patients were managed on a much more individualized basis, requiring multidisciplinary case discussion and thorough assessment of prognostic features. Progress has been made, but the overall outcome needs to be improved further. Avoiding overtreatment in patients with poor prognosis is as important as aggressive treatment in patients who might survive for several years. Cancer 2011;117:2505-12.

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Section: Argument References Commentsupporting

confidence: 81%

Presentation, patterns of care, and survival in patients with brain metastases

Nieder

Spanne

Mehta

et al. 2010

Cancer

181

106

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“…The goal of the current analysis was to evaluate efficacy in relation to efaproxiral exposure in the REACH study (Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009) (Suh et al, 2006). This REACH study was a randomised, Phase 3, multinational, clinical trial in patients with brain metastases from various primary cancers, which tested whether the addition of efaproxiral to WBRT (plus supplemental O 2 ) would improve survival compared to WBRT (plus supplemental O 2 ) alone.…”

Section: Received 1 March 2006; Revised 18 April 2006; Accepted 19 Apmentioning

confidence: 99%

“…The primary efficacy analyses were performed on all eligible patients, as well as all eligible patients with primary tumours of either non-small-cell lung cancer (NSCLC) or breast cancer. Using unadjusted log-rank analysis, the REACH efficacy results for the co-primary populations of lung or breast primary cancer suggested an improvement in median survival time (MST) in favour of the efaproxiral arm (Suh et al, 2006) (although not statistically significant). After adjusting for protocol-defined prognostic factors by Cox multiple regression, the results showed a statistically significant survival advantage for efaproxiral-treated patients in both primary cancer populations compared to control patients.…”

Section: Received 1 March 2006; Revised 18 April 2006; Accepted 19 Apmentioning

confidence: 99%

“…All patients received a standard 2-week course of WBRT (3 Gy/ fraction Â 10 days), plus supplemental O 2 (4 l/min via nasal cannula) as described previously (Suh et al, 2006). Efaproxiral administration began on the first day of WBRT and continued every day of WBRT, for a total of 10 doses.…”

Section: Treatmentmentioning

confidence: 99%

“…Patients were required to have an SpO 2 measurement (resting and exercise) X90% and no prior treatment for brain metastases (other than resection with measurable lesion(s) remaining). Additional eligibility criteria were presented previously (Suh et al, 2006).…”

Section: Eligibility Criteriamentioning

confidence: 99%

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Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

et al. 2006

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Efaproxiral (Efaproxynt, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O 2 ) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction Â 10 days), plus supplemental O 2 (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (X483 mg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.

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Clinical Management of Multiple Melanoma Brain Metastases

et al. 2015

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Importance The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery and whole brain radiation. Several new classes of agents have revolutionized the treatment of metastatic melanoma allowing for subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. Objective To review the current evidence regarding the treatment of MBM from melanoma. Evidence Review The Pubmed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy and targeted therapy published between January 1, 1995 and January 1, 2015. Articles were selected for inclusion based on targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 76 articles were included. Findings Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of radiosurgery alone, whole brain radiation therapy (WBRT), and radiosurgery with WBRT. Though the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have reported to have high response rates and deserve further attention in the setting of larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Conclusions and Relevance At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or combination of both. Emerging data exists to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for whole brain radiation and prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.

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Phase III Study of Efaproxiral As an Adjunct to Whole-Brain Radiation Therapy for Brain Metastases

Abstract: The addition of efaproxiral, a noncytotoxic radiation sensitizer, to WBRT may improve response rates and survival in patients with brain metastases, particularly metastases from breast cancer. A confirmatory trial for breast cancer patients has been initiated.

Cited by 176 publications

References 45 publications

Presentation, patterns of care, and survival in patients with brain metastases

Presentation, patterns of care, and survival in patients with brain metastases

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

Clinical Management of Multiple Melanoma Brain Metastases

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