2Beacon Hospital, Sandyford, Dublin 18, Ireland
Keywords: Ipilimumab; Melanoma; Ipilimumab induced sarcoidosis; Bayes' theorem; Cancer immunotherapy; Immunerrelated adverse events; FDG PET CT
The decision to use Ipilimumab was partly influenced by the patients young age, therefore checkpoint inhibitors, such as Ipilimumab, may have durable complete responses (approximately 20% for Ipilimumab in metastatic melanoma). These durable complete responses are likely to emerge as the equivalent to a cure. Though drugs such as Vemurafenib or even combined BRAF and MEK inhibitors can improve progression free survival and overall survival, they do not have this effect. It is likely that melanoma is more aggressive in patients with BRAF mutant melanoma progressing on a BRAF inhibitor . Therefore conceptually it is possible that one could deny this young patient the opportunity of curative checkpoint inhibitor treatment with first line BRAF inhibition as post progression he may have a declining performance status. In addition, the kinetics of clinical benefit of Ipilimumab is delayed so the patient could die from progressive disease prior to benefit emerging .
A pre surgery MRI brain and 2'-[18F] fluoro-2'-deoxyglucose (18F FDG) PET was otherwise normal. A subsequent 18F FDG PET computed tomogram 6 weeks post completion of 4 cycles of Ipilimumab described FDG avid hilar and mediastinal adenopathy and bilateral FDG avid lung nodules. SUVmax of the most avid right hilar node was 14.1. There was low-grade uptake in sites of bilateral lower limb subcutaneous oedema. An ultrasound of an area of the lower limb swelling found local areas of subcutaneous oedema. Ultrasound guided fine needle aspiration of an area of low-grade uptake found blood but no malignant cells. In view of the distribution of the likely recurrent melanoma we considered the possibility of this radiology representing sarcoidosis as an immune related adverse reaction secondary to Ipilimumab. Clinically the lower limb findings were consistent with a distribution for erythema nodosum but not classical in clinical appearance. Prior to initiation of anti-PD1 we assessed the merit of undertaking a biopsy to confirm a second melanoma relapse.
p(R/E): sensitivity of the PET scan
p(e): complement of p(E)
p(R/e): false positive rate 
In a meta-analysis of published literature of the accuracy of PET detection of recurrent cutaneous melanoma the following values were determined [3-9].
Level B and C studies, 6 in total, n=714 patients
We separately determined the likely relapse rate of melanoma post Ipilimumabp(E) to be as follows: Phase II trials give a rate of 30% for ipilimumab treated patients having disease control at week 12 (CR, PR or SD). Potential sources of error include (i) Ipilimumab was administered in the context of a solitary resected metastasis (ii) there is also a difference between PET scan results weeks 12 and 18 with delayed Ipilimumab tumor kinetics and immune related response criteria of relevance . However the literature is a reasonable approximation. Therefore p(E)= 0.7
The published literature relevant to these values was assessed.
The accuracy of PET in determining recurrent melanoma: p (E/R)=
The value p(E) of 0.7 is a theoretical maximum at 18 weeks post initiation of Ipilimumab and is likely far lower. Reasons include relapse at sites other than those described in the PET scan. If even one further reduction of likelihood of relapse is made eg; that resected oligometastatic disease in the pre-Ipilimumab era had a 30% survival rate then the p(E) value is 0.4 with a p(E/R) of 0.974 and a 2.6 % chance the PET represents disease other than melanoma. As mentioned a long list of factor of intangible quantification will further increase the change of the PET being due to another cause. Partly on this rational an endoscopic biopsy of a station 7 and station 4R lymph nodes was undertaken.
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