CUP SSG May 2016 Dr Matt sephton PET-CT in CUP CUP SSG May 2016 Dr Matt sephton

Overview Current guidelines Quality of existing research Key points/themes Interesting facts Summary Discussion

Current Guidelines: PET in CUP NICE: Yes in cervical lymphadenopathy but no primary on ENT panendoscopy if for radical treatment. Consider in pCUP with extracervical disease after discussion with CUP team or network MDT. Further research is needed to determine whether the use of 18F- FDG PET-CT early in the CUP management pathway reduces the number of investigations that the patient is subjected to. ESMO: CT/FDG-PET may contribute to the management of patients with CUP tumors and especially those with cervical adenopathies and single metastasis (IV,B) NCCN: The panel does not recommend using PET/CT scans for routine screening. However, PET/CT scans may be warranted in some situations, especially when considering local or regional therapy.

Quality of Existing Research Majority retrospective studies Single centre, small numbers Significant population heterogeneity Non-uniform PET-CT protocols and interpretation Number of reviews & meta-analyses Lack of prospective studies of sufficient numbers with more uniform inclusion criteria.

Key Findings to Date Pawaskar & Basu, 2015 Inclusion of cervical and/or extra-cervical nodal disease

Cervical Nodal Disease More support & evidence in this subgroup; early research done in this group Rusthoven et al 2004: Overall sensitivity 88.3% Overall specificity 74.9% Accuracy rates in primary detection 78.8% Also FDG PET detected 24.5% tumours not apparent on conventional work-up and led to detection of previously unrecognised mets in 27.1% patients (regional 15.9%; distant 11.2%) Fleming et at 2007: Primary site found in 72.7% of patients Synchronous lesions found in 8.1% of patients by PET/CT Distant mets detected in 15.4% of patients

Cervical Nodal Disease Fletcher at al 2008: If suspected H&N primary and PET-CT negative, further effort should be made to find primary because of chance of false-negatives.

CUP with localised disease In extra-cervical CUP, PET-CT most useful in localised disease To determine the extent before loco-regional treatment Breuer et al 2014: Prognostic Relevance of FDG PET-CT in Carcinoma of Unknown Primary. Aim: to assess whether PET-CT findings have a prognostic value in patients with CUP. Retrospective study of 70 patients; looked at PET-CT findings & compared to survival OS: No residual disease on PET-CT>locoregional disease>extensive disease No sig difference in survival between pts with regionally confined disease without identification of primary and those in whom the primary was identified on PET-CT (p=0.25). Same case for extensive disease (p=0.26)

Extensive CUP with extra-cervical disease Møller et al 2012: Prospective study of CUP patients with extra-cervical disease. To evaluate diagnostic value of PET-CT and conventional CT in ability to detect primary tumour. Entry criteria: CUP= when ESMO diagnostic work up failed to identify primary. Excluded some better prognosis subsets. PET-CT and CTs reviewed by radiologist & NM expert to agree on primary or not and define number of metastatic sites. Blinded to initial PET/CT report and treatment decisions. This was then correlated with an MDT consensus regarding primary site identified or not False/true positives/negatives were then calculated.

Extensive CUP with extra-cervical disease Møller et al 2012

Extensive CUP with extra-cervical disease No statistically sig differences were observed between CT & PET-CT in regard to these parameters. PET-CT identified sig more CUP patients with bone mets than CT alone (28.1% vs 20%, p= 0.0045), but this didn’t change management decisions due to extensive nature of cancers in study. OS not looked at and no mention of treatment decisions. Concluded: in general CUP population with extensive extra-cervical mets, PET-CT does not represent a clear advantage over CT alone.

Interesting Facts Antemortem, primary is found in only 30% of CUP patients. Postmortem exams reveal a primary in 6-80% of CUP patients, most often lung, pancreas & hepatobiliary. Theories re CUP: Spontaneous regression of primary Immune destruction of primary Inherently small size of primary with metastatic spread favoured over local tumour growth) Breast and GI cancers appear to be the most common sites for false-negative PET-CT results. Keep in mind for axillary node mets or high CEA)

Summary Lack of prospective randomised data Lack of link to clinical outcomes More evidence for use of PET-CT in cervical node mets Consider in cases of locoregional disease amenable to radical treatment Less evidence in extensive disease

Discussion