Critical appraisal:Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, et al 2016

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Critical Appraisal

Article being appraised

Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol 2016 Dec;27(12):2288-2294 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27637745.


Applicable clinical question

Key Facts

Study Design

cohort study

Study aims:

To compare the intracranial control rate in patients treated with stereotactic radiosurgery for intact melanoma brain mets within 3 mo of the receipt of anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors or conventional chemotherapy.

Number of Patients:

96

anti-PD-1: n=21

anti-CTLA-4: n=25
BRAF/MEKi: n=12
BRAFi: n=18

Chemotherapy: n=20
Reported outcome(s):

distant melanoma brain metastases
local melanoma brain metastases
systemic progression-free survival
overall survival from SRS and cranial mets diagnosis

Results of outcome(s):

>distant melanoma brain metastases:
- Significant differences were noted among the groups in distant melanoma brain mets control rates following SRS, p=0.008.

6mo distant melanoma brain mets:
anti-PD-1: 61%
anti-CTLA-4: 26%
BRAF/MEK inibitor: 53%
BRAF inhibitor: 30%
conventional chemotherapy: 15%

12mo distant melanoma brain mets:
anti-PD-1: 38%
anti-CTLA-4: 21%
BRAF/MEK inibitor: 20%
BRAF inhibitor: 8%
conventional chemotherapy: 5%

- Treatment with BRAF/MEK inhibitors or anti-PD-1 was found to be significant for distant melanoma brain mets (univariate)
- Treatment remained significant (multivariate)

 - chemotherapy v anti-PD-1 HR 3.1 (95%CI 1.5-6.6), p=0.001
- chemotherapy v BRAF/MEK inhibitor HR 2.1 (95%CI 1.1-4.4), P=0.03

- No differences chemotherapy v BRAF inhibitor, p=0.27 OR chemotherapy v anti-CTLA-4, p=0.26 (multivariate)

improvement in distant melanoma brain mets in chemotherapy v immunotherapy (anti-PD-1 and anti-CTLA-4), HR 2.1 (95%CI 1.1-3.6), p=0.02 (multivariate)
no improvement in distant melanoma brain mets in chemotherapy v targeted (BRAF inhibitors and BRAF/MEK inhibitors, HR 1.2 (95%CI 0.71-2), p=0.51

>local melanoma brain metastases:
- No significant differences among the groups in local melanoma brain mets control rates, p=0.25

>systemic progression-free survival, p=0.04:

6mo systemic progression-free survival:
anti-PD-1: 41%
anti-CTLA-4: 36%
BRAF/MEK inibitor: 58%
BRAF inhibitor: 29%
conventional chemotherapy: 20%

12mo systemic progression-free survival:
anti-PD-1: 41%
anti-CTLA-4: 27%
BRAF/MEK inibitor: 39%
BRAF inhibitor: 12%
conventional chemotherapy: 5%

- Significantly improved OS on both univariate and multivariate:
(multivariate analysis)
anti-PD-1 v chemotherapy: 2.7 (95%CI 1.4-5.7), p=0.005
anti-CTLA-4 v chemotherapy: 2.5 (95%CI 1.3-5.0), p=0.007
BRAF/MEK inhibitors v chemotherapy: 2.5 (95%CI 1.2-5.5), p=0.02

>overall survival from SRS, p=0.01:
6mo OS from SRS:
anti-PD-1: 76%
anti-CTLA-4: 68%
BRAF/MEK inibitor: 83%
BRAF inhibitor: 52%
conventional chemotherapy: 60%

12mo OS from SRS:
anti-PD-1: 48%
anti-CTLA-4: 41%
BRAF/MEK inibitor: 65%
BRAF inhibitor: 24%
conventional chemotherapy: 10%

>overall survival from cranial mets diagnosis, p=0.004:
6mo OS from cranial mets:
anti-PD-1: 81%
anti-CTLA-4: 84%
BRAF/MEK inibitor: 83%
BRAF inhibitor: 71%
conventional chemotherapy: 70%

12mo OS from cranial mets:
anti-PD-1: 66%
anti-CTLA-4: 50%
BRAF/MEK inibitor: 75%
BRAF inhibitor: 29%
conventional chemotherapy: 15%

> Percentage, p=0.10:
Percentage demonstrating progression in the brain alone:
anti-PD-1: 16%
anti-CTLA-4: 19%
BRAF/MEK inibitor: 70%
BRAF inhibitor: 47%
conventional chemotherapy: 25%

Percentage demonstrating progression in systemic alone:
anti-PD-1: 33%
anti-CTLA-4: 19%
BRAF/MEK inibitor: 0%
BRAF inhibitor: 20%
conventional chemotherapy: 15%

Percentage demonstrating progression in both brain and systemic progression:
anti-PD-1: 50%
anti-CTLA-4: 63%
BRAF/MEK inibitor: 30%
BRAF inhibitor: 33%
conventional chemotherapy: 60%

Includes an economic evaluation

no

Evidence ratings

Level of evidence

III-2

Risk of bias
High risk of bias Comments: representative sample, most baseline variables were comparable, survival outcomes, all patients accounted for

Risk of bias assessment: cohort study

Subject selection
"New technology" group
Selected group
Comparison group
Selected group
Comparability of groups on demographic characteristics and clinical features
Not comparable and not adjusted for differences
Measurement of outcomes
Outcome measures blind to technology used
No, but objective measures used
Same method of measurement used across comparison groups
Yes
Completeness of follow-up
Was follow-up complete and were all patients included in the analysis?
Yes (follow-up >95%) or survival analysis using all patients
Size of effect
1 Reason for decision: p<0.01
Relevance of evidence
1 Additional comments: patient-related outcomes
Result of appraisal

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Completed by

Cecilia Taing


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Article
Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol 2016 Dec;27(12):2288-2294 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27637745.
Assigned to
User:Cecilia.taing
Topic area
Guidelines:Melanoma
Clinical question
Form
Form:Critical appraisal


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