1. Cancer of Unknown Primary Dr Chris Jones Consultant Medical Oncologist North of England Cancer Network Annual Conference 20 September 2013

2. Introduction what is cancer of unknown primary (CUP)?  metastatic epithelial or neuroendocrine malignancy on biopsy  no apparent primary site identified, despite investigations determined by specialist review how big a problem is it?  3% of total cancers registered  7% (men) and 9% (women) of all cancer-related deaths  fourth most common cause of cancer death (after lung, colorectal, breast ca.)  only 16% of patients survive for a year  2% of all cancer-related inpatient episodes, mostly emergencies NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20132

3. Where have we come from? How has CUP been managed in the past?  few, if any, specialist CUP teams  patients bounced between MDTs  patients over- or under-investigated  patients feeling “lost in the system”, “falling through the cracks”  best guess chemotherapy  empiric cover-all chemotherapy (domestos!) NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20133

4. What are we doing about this? NICE guidelines (CG104) 2010 NCAT peer review measures 2012  set up CUP assessment teams assess patient fitness for further investigation and treatment ensure initial investigations are performed  set up CUP multi-disciplinary teams rational use of further specialised investigations identify best treatments access to clinical trials  set up CUP NSSG standardise approach to investigating and managing CUP across the network NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20134

5. What are we trying to achieve? rational decision making to select: patients who are too unwell to benefit from further investigation and cancer treatment, and refer them early to palliative care patients with an identifiable primary, and refer them to a site-specific specialist team patients with a potentially curable presentation of CUP, and refer them to specialist teams for radical treatment  solitary metastases, resectable lymph node metastases, possible germ-cell tumours patients with incurable but highly treatable CUP syndromes, and offer them specific chemotherapy regimes  high-grade neuroendocrine CUP, peritoneal adenocarcinoma in women patients with CUP who might benefit from empiric chemotherapy NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20135

6. What have I achieved so far? prevented a lot of unnecessary investigations; about 20% of referrals were too unfit to justify further tests identified a primary site in about 50% of referrals even found a few non-cancers! confirmed a diagnosis of CUP in about 30% of referrals support, information, explanation about 1 in 7 treated radically palliative chemotherapy and radiotherapy recruitment to clinical trials NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20136

7. What would be the “Holy Grail” for CUP? if only we could identify the primary cancer in all CUP patients! access to best evidence-based treatments dedicated specialist team accurate information about prognosis at the moment, our best assessment involves scans, biopsy, endoscopy, specialist review what if there was a single test that could tell us exactly what this cancer of unknown primary actually is? NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20137

8. New technology for CUP New molecular tests for CUP may be the answer? different types of cancer tend to switch on certain parts of their DNA genetic code in a typical pattern (gene expression) new tests on a CUP biopsy can “peer inside” the cancer cell, read the gene expression pattern, and tell you what it is most likely to be early non-randomised data suggest that assay-directed site-specific therapy may result in longer survival than with empiric chemotherapy (Hainsworth, JCO 2012) subgroup of assay-identified colon cancer have similar response and survival with site-specific chemo compared with known metastatic colon cancer (Hainsworth, Clin Colorectal Cancer 2011) NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20138

9. Should we be using this new test for CUP? But… these tests are expensive not NICE approved as no randomised data to support their use several different versions of the test – which is best? are they really giving the true answer? is a cancer which presents with metastases but no primary going to respond to treatment in the same way as in a conventional presentation, or are they different diseases? is assay-directed site-specific chemotherapy actually better than empiric chemotherapy for CUP? NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 20139

10. UK national clinical trials for CUP CUP-1 study  part 1 –collecting biopsy samples from potential CUP patients, to validate the 3 different molecular diagnostic tests and pick a “winner”  part 2 –treating CUP patients with empiric chemotherapy with close follow up for response and survival to establish a “reference regime” CUP-2 study  (in planning stage)  randomise CUP patients to receive either empiric chemotherapy or assay- directed site-specific chemotherapy, to determine which approach gives the best results for response and survival NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 201310

11. Summary – what is on the horizon for CUP patients? CUP is on the agenda new teams to support patients new pathways to prevent delays rational use of investigations - to identify the primary - to select CUP patients who could benefit from specific treatment access to clinical trials NHS | Presentation to North of England Cancer Network Annual Conference – 20 September 201311