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Carcinoma Unknown Primary Louise Medley Medical Oncologist Overview: Malignancies of Undefined Primary Origin Overview Definitions Challenges faced Priorities Meaningful investigations Evidence based treatment? RUH experience and………….the future Carcinoma Unknown Primary 3-5% all cancers (>10,000 cases per year) 2% of all cancer patients in hospital 72% admitted as an emergency Length of stay 8-10 days 4th largest cause of cancer deaths Median survival 11weeks -11 months No change in survival over last 15 years Appropriate management depends on ability to recognise the subset of these patients whose tumours have a favourable prognosis and those which are highly responsive to therapy Terminology (as per draft NICE guidance) Community referral Malignancy of Metastatic (or suspected) disease based on undefined primary minimal tests without obvious primary site origin (MUPO) Eg USS Liver/CXR/limited CT scan Emergency presentation Provisional CUP Metastatic epithelial or NET identified on basic histology, prior to specialist review Eg Liver biopsy/FNA lymph node mass Specialist referral Confirmed CUP ONCOLOGICAL DIAGNOSIS Metastatic epithelial or NET identified on final histology with no obvious primary following specialist guided investigations and specialist review Since the tests that have been run fail to turn up a location, and since I haven‟t presented any symptoms that would indicate the presence of cancer elsewhere, they have just chalked it up to a mystery. For me that is probably the scariest part. The image that often comes to mind is a time bomb ticking away somewhere. You know that a bomb may exist but you don‟t know if it really does nor do you know where it is and when it will go off My late wife‟s journey could have been so much better and handled much better The whole time, my symptoms were getting increasingly worse and I did not have any symptom control. What will (would) also make a huge difference is early oncology and palliative care input Clinically meaningful and Cost-effective Investigations (Initial assessment) •History and physical Inc breasts, nodes, genital, rectal and pelvic examination examination •FBC, U+E, LFT, Ca, LDH, urinalysis •CXR •CT chest, abdo, pelvis •Symtom directed No evidence for routine use to diagnose primary endoscopy •Mammography Only if clinical or pathological features are consistent with breast primary (‘routine’ use has pick up of only 6-14%) •PET directed by the CUP MDM Evidence for whether PET can improve diagnosis AND prognosis not clear Evidence needed on impact of early use reducing investigations Diagnostic Yield: Basic tests = 60% (restricted panel of tests can identify most primaries) Additional tests = 30% Exhaustive tests = high rate of false +ve results may delay diagnosis Clinically meaningful and Cost-effective Investigations (Tumour Markers) Occasionally early use of these tests can facilitate speedy diagnosis and prompt treatment with significant clinical gain In general inappropriate ordering of these markers leads to: Unnecessary and costly investigations Incorrect management Needless distress and worry for patients AFP and HCG Presentations consistent with germ cell tumours (esp midline nodal / retroperitoneal disease) AFP HCC PSA Men with presentations compatible with prostate cancer Ca125 Women with presentations compatible with ovarian cancer (inc inguinal nodes, chest, pleural, peritoneal and retroperitoneal presentations) CEA and CA19.9 low specificity for primary site in patients presenting with provisional CUP and are unlikely to be helpful when diagnosing a primary site (DUKES D: 65% elevation of CEA) Carcinoma Unknown Primary 2010 ….the role of molecular profiling Molecular profiling (mRNA PCR) on paraffin- embedded tissue (sensitivities 85-90%, specificities 99%) GRECO: 84 patients known primary + 38 patients unknown primary: 75% predictions correct* Patients with MUPO who subsequently are given a ‘defined’ primary often present with atypical patterns of spread NOT SUPPORTED IN NICE GUIDANCE * Horlings et al J Clin Oncol 2008;26;4435-4441 Management decisions Do not investigate further to identify primary site if patient unfit for treatment Perform investigations ONLY if: Results are likely to affect treatment decisions Patients understand why investigations are necessary Patient understands the risks/benefits of investigations and treatment AND is prepared to accept treatment Provide information about CUP to patients and carers Always consider early referral to Palliative care team/clear communication with GP to reduce emergency re-admission Systemic therapy Unclear as to the benefit of chemotherapy in confirmed CUP presentations Data from 29 phase II trials of 39 regimens [Adenis et al 2009]: -objective RR of 10-30% -median survival 5-7 months, 2 year survival rare [prognosis = advanced NSCLC/pancreatic cancer] On the assumption that the commonest primaries identified in CUP patients are Lung, Pancreas and UGI….and palliative chemotherapy in these situations prolongs survival by 3-6 months over BSC alone ? = benefit of chemotherapy in confirmed CUP Favourable Prognostic Subsets (clinical or pathological features) Poorly differentiated carcinoma with a midline distribution Suspicion of germ cell tumours 25% Complete remission, long term survival possible Women with predominately peritoneal adenocarcinoma Median survival up to 24 months Long term survival 5-25% Women with adenocarcinoma of axillary nodes Outcome = Stage II breast cancer Squamous cell carcinoma of cervical neck nodes 5 year OS 75-80% if treated radically (chemo-rad + surgery) Poorly differentiated neuroendocrine carcino ma Doubling of median survival to apporx 14 months Challenges….. Lack of agreed definitions of the clinical entity and lack of an overall organisational structure to ensure high-quality care NICE Guidance August 2010 No referral guidelines for suspected cancer relevant to patients without an obvious or strongly suspected primary Local guidelines in development August 2010 Lack of a team structure to efficiently care for and manage initial diagnostic phase of newly presenting patients Lead Clinician, key worker, MDM, SSG Lack of support and information for the defined patient group. No research organisation MUPO flow chart Symptoms or radiological Patient pre se ntsto GP and evidence of cance r, found to have symptoms s me dical/ urgical take or o or radiol gical evidence of tie ward pa nt cance r Initial tests have be e nunde rta ken with results available whe re possible Full examination (including neurological, lymph nodes, external genitalia, rectal examination) Full blood count, urea and electrolytes, liver function tests, CRP, LDH, calcium (serum and urine electrophoresis in case of isolated lytic bone lesions) CT chest/abdomen/pelvis (skeletal survey in isolated lytic bone lesions) Biopsy Fill in Ņp rovisional carcinoma of unknown primary MDT referral formÓand fax urgently to 2 week wait office (outpatient referrals) or CUP administrator (inpatient) What to expe ct Non-Malignant from CUP te am Primary identified Outpatient re fe rrals Inpatie nt re fe rrals Outpatient appointment with CUP Review of patient by end of next Confirmed CUP BSC team within 2 weeks of referral working day (this will usually be in person, but due to clinical Consideration of commitments may be over the phone and advice given on how therapy best to proceed CUP-One Trial MUPO: RUH Experience January-September 2010 36 referrals (average 1 per week) Mean age = 70.8 years (range 37-90) Mean survival = 56 days (range 3*-151) MUPO Referral Source (Jan-Sept 2010) 10 9 8 4 referred between 18th 7 June - 12th July 2010 6 Number of 5 Referrals 4 3 2 1 0 A A A W n P t en ow G P P P W O O O ti t 2 en n pa m t gy nk an rg ae In lo U lt U co H su n on O C Referral Source Diagnosis and Staging Investigations Investigations for MUPO 100% 90% Undergoing Investigation 80% Percentage of Patients 70% Image 60% guided Series4 Biopsy Series3 50% Series2 40% Series1 30% 20% Not Indicated 10% ? Not Done 0% C T Scan Biopsy Investigation No single point of discussion MDM where Case Discussed 18 16 14 12 Number of 10 Patients 8 6 4 Series1 2 0 t g I I y ae y as G G og g n U yn lo Lu re er ol ro G B w at U Lo m ae H MDM Speciality Diagnosis Following Specialist Review 100% 1 90% 1 1 80% Gynae 1 Number of Patients Renal 70% 2 Neuroendocrine 60% Gastric 2 50% 20 Lymphoma 40% 2 Colorectal Cholangiocarcinoma 30% 2 Pancreas 20% Lung 10% 3 0% Confirmed CUP Suspected Diagnosis Diagnosis Management Decision following Specialist Review 100% 1 90% 80% 4 70% 60% Surgery 50% 15 8 Radiotherapy C hemotherapy 40% 30% 8 20% 10% 0% BSC Active Treatment Unknown Response to Active Treatment 3 1 2 Number 3 1 2 2 1 0 Response Complete Response Progressive Treatment Partial Disease On Lym phoma Neuroendocrine Questions ?
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