How an Acute Oncology service can help with managing Cancer of unknown primary

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1 How an Acute Oncology service can help with managing Cancer of unknown primary Dr Pauline Leonard MD FRCP Consultant Medical Oncologist Lead Cancer Clinician Whittington Health

2 Definitions Patients who have cancer of unknown primary origin have metastatic malignant disease without an identifiable primary site Only epithelial lineage so lymphoma, sarcoma excluded CUP refers to those with proven epithelial, neuroendocrine or undifferentiated carcinoma Provisional CUP after initial investigations MUO refers to those who present with clinical or radiological features without an obvious primary site

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5 National Cancer Intelligence Network CUP Updated Briefing 2014 First briefing in 2012 described ICD-codes used to capture data C76-C80 CUP accounts for 3.3% of all newly diagnosed cancers 40% in those> 80 years + 5% < 50yrs European age standardised rate of 11.5 per 100,000 Males > females (12.2 vs per 100,000) Statistically increased incidence in the most socioeconomically deprived 21% v 17%

6 Challenges in care In England & Wales over 10,000 cases annually No clear referral pathway accepted Lack of consensus on appropriate diagnostic tests Lack of dedicated key worker Lack of support and specific information Referral to inappropriate site specific teams Uncertainty about optimal treatment Patients often present unwell via the emergency route Not all Trusts have robust AOT/CUP services

7 Routes to Diagnosis: Cancer unknown Primary 57% of all CUP/MUO present via ED Compared with 23% all cancers 45% were older than 85 years 4% under 50 yrs CUP accounts for 9% of all ED presenting cancers Compared to 23% Lung 11% CRC 1 year survival is 16% Better survival via managed routes 24-37%

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9 What is acute oncology? Chemotherapy toxicity + safety Malignancy of unknown origin MUO/CUP Urgent symptom control and End of Life Acute Oncology Urgent diseaserelated problems Metastatic spinal cord compression Admission Avoidance (Transforming Inpatient Care) Venn diagram donated by Dr Richard Osborne

10 A key recommendation from NCAG report 2009 Development of an Acute Oncology Service Management of patients who develop severe complications following chemo or as a consequence of their cancer Management of patients who present as emergencies with previously undiagnosed cancer AOS brings together expertise from oncology disciplines, emergency medicine, and general medicine and general surgery

11 Three types of Cancer emergencies Type 1 Patients who present who a new diagnosis of cancer Type 2 Patients who present with toxicities of treatment - Chemotherapy - Radiotherapy Type 3 Patients who present with symptoms from disease

12 Our experience at WH Four not three types of patient presentations 53% of all patients who present to ED with a diagnosis of cancer have an unrelated problem Survivors of disease Living with disease but present Accident Exacerbation of co-morbidity New pathology Type 1 28% Type 2 22% Type 3a 50% 20% EOLC

13 Data to understand the usual pathway King et al BMJ Qual Saf 2011;20: Process mapping the patient pathway for medical presentations 59% self referral Delay awaiting procedure Delay awaiting report Delay awaiting MDT A&E Admit Radiology report suggests cancer Refer for endoscopy/ biopsy for tissue diagnosis Cancer confirmed on histology MDT review imaging And histology Refer to oncology 41% GP referral 9 days 1.6 days 34 medical patients presented via ED 2008 and found to have a new cancer diagnosis MedianLos 19 days Blood tests 42 Number of tests 3 47% referred to palliative care 26% Oncology 60% upper GI/HPB

14 Relative one year survival: by cancer type Malignant registrations, South West 2007, excluding multiples and DCOs Cancer type GP/OP referral (+TWW) Relative 95% CIs Survival Emergency Relative 95% CIs Survival Other route Relative 95% CIs Survival Acute leukaemia 39.7 ( ) 39.4 ( ) 40.4 ( ) EUROCARE Relative Survival Bladder 78.3 ( ) 34.0 ( ) 79.2 ( ) 85.3 Brain & CNS 68.4 ( ) 34.0 ( ) 60.6 ( ) 39.1 Breast 97.7 ( ) 50.8 ( ) 98.2 ( ) 95 Colorectal 84.5 ( ) 48.4 ( ) 79.5 ( ) 74.7 Kidney 81.1 ( ) 24.0 ( ) 72.4 ( ) 74.7 Lung 39.8 ( ) ) 32.4 ( ) 36.1 Multiple myeloma 83.6 ( ) 53.1 ( ) 73.0 ( ) 70.5 Non-Hodgkin's lymphoma 86.6 ( ) 43.7 ( ) 80.9 ( ) 73.1 Oesophagus 43.8 ( ) 22.4 ( ) 45.5 ( ) 36.3 Other 81.1 ( ) 27.2 ( ) 77.8 ( ) Ovary 83.4 ( ) 38.8 ( ) 72.1 ( ) 70.7 Pancreas 21.0 ( ) 6.0 ( ) 22.3 ( ) 19.2 Prostate 98.0 ( ) 48.2 ( ) 98.3 ( ) 92.2 Stomach 49.1 ( ) 17.7 ( ) 47.6 (41-54) 44.1

15 GP/OP referral Two Week Wait Emergency presentation Other outpatient Screen detected Inpatient elective DCO Unknown Total Number of patients Routes to Diagnosis Acute leukaemia 17% 3% 61% 12% 0% 4% 0% 4% 100% 380 Bladder 22% 36% 18% 13% 0% 6% 1% 5% 100% 1,167 Brain & CNS 18% 2% 49% 20% 0% 5% 0% 5% 100% 740 Breast 8% 40% 5% 5% 28% 2% 0% 13% 100% 5,646 Cervix 21% 17% 12% 8% 23% 3% 1% 15% 100% 308 Chronic leukaemia 26% 6% 45% 13% 0% 4% 1% 4% 100% 629 Colorectal 19% 29% 24% 12% 0% 8% 0% 7% 100% 4,515 Kidney 22% 26% 23% 16% 0% 5% 0% 8% 100% 928 Larynx 35% 34% 8% 14% 0% 5% 0% 3% 100% 216 Lung 15% 26% 38% 10% 0% 4% 1% 7% 100% 3,893 Melanoma 23% 39% 4% 8% 0% 5% 0% 22% 100% 1,686 Multiple myeloma 20% 14% 44% 13% 0% 4% 1% 5% 100% 606 Non-Hodgkin's lymphoma 25% 22% 25% 13% 0% 6% 1% 9% 100% 1,349 Oesophagus 15% 32% 21% 14% 0% 13% 0% 4% 100% 912 Oral 32% 27% 5% 14% 0% 4% 1% 17% 100% 458 Ovary 20% 29% 28% 11% 0% 3% 1% 8% 100% 853 Pancreas 13% 20% 45% 10% 0% 5% 1% 7% 100% 917 Prostate 26% 28% 11% 11% 0% 7% 0% 16% 100% 4,865 Stomach 14% 24% 31% 13% 0% 11% 1% 6% 100% 801 tbc (other) 21% 18% 34% 12% 0% 4% 1% 9% 100% 4,323 Testis 14% 47% 9% 15% 0% 4% 0% 11% 100% 259 Uterus 28% 36% 8% 12% 0% 5% 0% 12% 100% 918 Total 19% 28% 22% 11% 5% 5% 1% 10% 100% 36,369 All cancer Routes to Diagnosis: by cancer type All malignant registrations South West 2007 excluding C44 and multiples

16 Route of presentation by age

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18 What factors influence poor outcomes in this group of patients? Performance Status is usually poor 3-4 If PS 2 or higher Median survival usually measured in a few months when very symptomatic and unwell Evidence for most solid tumours PS 0 & 1 PS 2 must be individualised assessment Exceptions Chemosensitive disease Small cell Possibility of cure Metastatic Germ cell cancer

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21 SCLC: Survival by by Performance PS Status Median survival PS 0: 370 days Median survival PS 1: 286 days Median survival PS 2: 148 days Median survival PS 3: 57 days Median survival PS 4: 22 days N= y r Days PS 0 PS 1 PS 2 PS 3 PS 4 PS Unknown

22 Survival by Charslon Index at Diagnosis: All cases Kaplan-Meier; Charlson Index at diagnosis N=34,513 1 y r analysis time CI=0 CI=2-3 CI=1 CI=4+ Courtesy: Anna Rich et al, Nottingham University

23 Prospective audit of emergency admissions of cancer Dec 2012 March 2013 Cancer New ED diagnoses Total Dec Feb Percentage of diagnoses by ED (Dec Feb) National figure for percentage of diagnoses by ED (06-08) Examples of CUP pathways which ensure early triage to specific tumour MDT Lung % 39% Pancreas % 50% Hepatobiliary + GB % 48% NHL % 27% Myeloma % 37% MUO % 37% Gynae % 15% Colorectal % 26% CNS % 62% AML % 54% Bone sarcoma % 25% H&N- Oropharynx % 9% Mesothelioma % 36% Oesophagus % 22% Stomach % 33% Prostate % 10%

24 Prospective audit of emergency admissions of cancer Dec 2012 March 2013 Cancer New ED diagnoses (RIP) Total Dec Feb Percentage of diagnoses by ED (Dec Feb) National figure for percentage of diagnoses by ED (06-08) Examples of CUP pathways which ensure early triage to specific tumour MDT Lung % 39% Pancreas % 50% Hepatobiliary + GB 3 (2) 5 60% 48% NHL % 27% Myeloma % 37% MUO % 37% Gynae % 15% Colorectal 2 (1) 14 14% 26% CNS % 62% AML 2 (1) 2 100% 54% Bone sarcoma % 25% H&N- Oropharynx % 9% Mesothelioma % 36% Oesophagus % 22% Stomach % 33% Prostate % 10%

25 Histological confirmation Treatment Frequency How many had histology? Radical chemo/radiotherapy 6 6 Potentially curative surgery 6 6 Palliative chemo/radiotherapy 10 9 Palliative surgery/ therapeutic intervention 2 1 Symptom control (75%) 33/44 patients had histological confirmation

26 MUO NICE guidance 2010

27 Why do clinicians over investigate? Fear of missing the treatable? Unwillingness that CUP is advanced disease? Do something is easier than having an honest discussion about poor prognosis? Belief that histological diagnosis a stronger determinant than prognosis determined by PS/co-morbidities

28 Role of Acute Oncology Team in CUP Sharing expertise in managing all presentations of CUP/MUO including emergencies irrespective of tumour type Sub-specialisation has eroded confidence in generic skills Sensitive communication to determine patients needs and preferences To help them make informed choices Advisory capacity in how best to proceed in patients who present with a new suspected cancer Where case does not fit into recognised established pathways Individualised treatment plans incorporating PS & co-morbidities

29 MUO /CUP MDT referrals April 2015 March 2016 We incorporated MUO/CUP MDT into Upper GI MDT meetings Run sequentially with own list 44 MDTs 25 meetings had patients with MUO/CUP added for discussion 35 new patients 17 female:18 male Age range yrs Median 62yrs

30 Monthly distribution of new cases presented April May June July Aug Sept Oct Nov Dec Jan Feb March

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32 Final diagnosis MUO Primary site identified CUP Benign MUO 7 Primary site identified 16(17) ccup* 6(5) Benign 6 35 * 1 patient PM treated as ccup first line then repeat Biopsy pre 2 nd line chemo immuno met CRC

33 Primary site identified Gynae Lung HPB Urological Upper GI Myeloma NHL Germ cell Naso-Pharygeal Anal CRC n=16 Gynae 4 Lung 2 Upper GI 1 HPB 2 Urological 2 NHL 1 Meyloma 1 Germ cell 1 Nasopharygeal 1 Anal 1 * plus CRC first treated as ccup Final n=17

34 Final histological sub-type ccup Patien t MS Immuno -profile + Ca 19.9 CEA CDX2 CK20 -CK7 TTF-1 WT1 ER/PR PAX8 HER-2 - Final histology Mod diff adenocarcinoma possible HPB primary site AV PM* SP SS + AE1/3 CK19 CEA CDX2 CK20 - TTF-1 ER/PR GCDFP-15 PAX8 WT1 +BerEP4 CEA CK19 CDX2 Ca TTF-1 CK5 CK7 +AE 1/3 CK7 CK 19 CEA CK5 Ber EP4 P63 - CK20 TTF-1 S100 WT1 Calretinin + CK19 PAX8 WT1 AE1/3 CEA BerEP4 MNF116 - CK 7 CK20 CDX2 CD5 TTF-1 Ca19.9 GATA3 CK5 p63 GCDFP-15 ER/PR CD30 CD45 *profile on initial ascitic fluid Necrotic adenocarcinoma Mod diff adeno carcinoma poss CRC primary site Poorly differentiated carcinoma Metastatic carcinoma

35 Benign cases Patient MS GP fast track referral investigation weight loss Patient JW GP fast track referral massive weight loss Patient CP Sepsis mimicking malignancy Patient AL Initial x-ray overcalled osteolytic metastases Patient SF GP suspected cancer referral Patient JR History of Anterior resection 2009 concern about lung nodule

36 Active treatment 12/15 patients with Primary site identified still alive 8/12 Anti-cancer treatment 3 debulking surgery 5 systemic anti-cancer chemotherapy 2/12 Active symptom control (ASC) 2/12 Unknown transferred to another Trust and no feedback 3/15 RIP Gall bladder & Naso-pharyngeal I patient with endometrial sarcoma died before OPA with Gynae OPA at UCLH 1 inappropriate biopsy as poor PS & co-morbidities 1 unfit ASC

37 MUO cases 7 cases MUO 5/7 RIP Median survival from presentation = 12 days Pt 1=11 days Pt 2 =29 days Pt 3 = 12 days Pt 4 = 17 days Pt 5 = 5 days 2/8 Alive One in Nursing home unwell from co-morbidities

38 CUP/MUO is about early symptom control 89 yrs female Short history fatigue, nausea & reduced appetite GP U/S Peritoneal cake CT done same day MUO MDT (D2) PL rang GP to offer fast-track OPA for assessment on (D6) Informed by GP for PP Saw HPB surgeon - biopsy Meets PL (D23) PS 2 Doesn t want chemo GFR 29 mls/min Dex& community Pall care

39 Liver metastases only How do we manage this case? -determine fitness -PS -renal & liver function -assess symptoms -explore wishes -Biopsy if chemo appropriate

40 DO NOT REFER FOR TOP & TAIL!

41 No role for routine use of screening tumour markers Unless Suspected germ cell tumour AFP, bhcg, LDH Hepatocellular carcinoma AFP Equivocal Pancreatic mass** Ca 19.9 MSCC PSA Medullary cell thyroid carcinoma Serum Calcitonin

42 Cerebral metastasis or primary brain cancer? Patient JM Patient AA

43 Next steps Assess patients fitness and wishes Trial 16mg dexamethasone stat then 8mg BD If keen and fit for treatment Needs full Thorax, Abdo & pelvis staging CT If no disseminated disease refer to neurosurgical centre or brain mets MDT Biopsy of brain mass Optimal surgical debulking

44 Actual pathway for AA 71yrs female history headaches & memory impairment Since Nov 2012 Urgent GP referral to Day 1 CT head Day 4 MRI head & Ct Thorax/Abdo/Pelvis Day 5 Discharged with appt Queens Square 6 days late Day 11 Saw 1 st Neurosurgeons advised MDT discussi Day 15 MDT outcome & met 2 nd neurosurgeon who offered all treatments Day 27 GP called PL as family confused Day 29 PL saw family & pt in OPA PATIENT HAD SIGNED AN ADVANCED DIRECTIVE SUMMER 2012 WANTED CLARITY OF WHAT WAS BEING COMMUNICATED

45 Managing emergency presentations of MUO/CUP

46 Metastatic Spinal cord compression 59yrs female Short history of weakness & loss of sensation right hand with pain in neck Contacted directly by MRI Vertebral collapse C7, T1,T2 & T3 with impending cord compression Organised by phone urgent RT & team approach Patient transferred UCLH and treated Post RT biopsy Metastatic breast ca

47 75% of all presentations of MSCC are from Breast, Lung & Prostate 5-10% will be myeloma or lymphoma

48 Superior venal caval obstruction 80 yrs Increasing SOB CT shows SVCO What about a diagnosis? First priority is patient safety and comfort?svc stent Steroids RT Biopsy confirmed adeno Lung EGFR WT

49 Learning Encouraging all teams to add the CT of any sick inpatient to MUO MDT if no clear primary site on CT or on examination before any further tests can expedite appropriate management Still examples of patients with poor PS undergoing unnecessary biopsy / ERCP if AOS/CUP not involved A clear primary site can be identified from a biopsy with a good panel of immuno from a metastatic site True ccup remain a small group of patients but fit OPA can receive active anti-cancer treatment with meaningful survival Unwell in-patients with multiple co-morbidities with MUO have a very poor prognosis

50 For patients not requiring admission - working with Ambulatory care has improved the pathway and patient experience for Type 1 presentations the person with a previously undiagnosed cancer

51 Referred by GP on 20/3/15 (Friday) 32 yrs female c/o Increasing fatigue 3/12 & abdominal pain Day 1 examined in Ambulatory care Blood tests & liver ultrasound booked for after weekend home with analgesia Day 4 Ultrasound showed multiple liver metastases & blood tests showed abnormal liver function Day 6 CT Thorax/Abdo & Pelvis Acute Oncology team called due to CT findings

52 In Ambulatory care Day 6 Consultant Oncologist met patient with partner with AOS CNS present Bad news broken Plan for moving forward shared Patient wanted to take planned holiday Further analgesia & steroids started Day 7 Liver biopsy performed Day 15 Discussed at Malignancy unknown Origin (MUO) MDT Metastatic Breast Cancer Further testing requested HER2 Dr L booked OPA chemo slot & New patient appt for Specialist colleague Day 19 Dr L met patient with partner to discuss biopsy findings Day 20 Biphosphonates started as Calcium raised Day 27 Further pre-treatment investigations performed & met Specialist Consultant Day 28 Tailored chemotherapy started

53 What was value added? Improved patient experience safe in your hands Improved pace in pathway including planned holiday

54 What about potentially curative disease? Referral to AOT should not just be associated with Palliative treatment Small percentage of patients with favourable histology or isolated disease Same principles Establish fitness & wishes If CT staging shows isolated disease e.g. neck nodes, axillary nodes, isolated liver metastasis Role for FDG PETCT If no distant metastases radical treatment options Liaise with specialist MDT

55 From Audit patients who had a PETCT N=4 overall but just 2/5(4) ccup Patient KM pre-op HPB recommendation inoperable Patient BR staging NHL Patient SS isolated LN on CT Patient SP isolated LN on CT Advanced widespread LN and no primary

56 The Whitt MUO referral pathway PS = Performance Status AOS = Acute Oncology Service AOT = Acute Oncology team MUO= Malignancy unknown origin OPA = out-patient appointment Patient presents as an emergency with alarm symptoms or suspicious imaging Make a decision to admit or fast track to OPA assessment Communicate suspicion of cancer Needs admission Assess PS 0-1 or >2 Measure renal & liver function Determine patient preferences for possible treatment interventions Arrange discharge NO obvious primary site or unclear if fit for further intervention book to fast track AOS OPA within week Clear primary site refer site specialist team for OPA Good PS & fit and willing for further interventions refer site specific or MUO MDT involve AOT to help tailor timely & appropriate investigations Poor or borderline PS/comorbidities/patient or physician unsure refer AOS within 24hrs of suspicious scan Refer MUO or site specific MDT for completeness OPA review Good PS with good renal, haem & liver function & willing to undergo biopsy arrange biopsy of site which maximises staging information if unclear from imaging Refer MUO MDT

57 ICD-10 code Description UK incidence % of total recorded incidence CUP C76 Secondary and unspecified malignant neoplasm of head, face & neck?? C77 C78 C79 C80 Total Secondary and unspecified malignant neoplasm of lymph nodes Secondary malignant neoplasm of respiratory & digestive organs Secondary malignant neoplasm of other and unspecified organs Malignant neoplasm without specification of site Cancer of Unknown Primary 972 9% 3,163 30% 1,230 12% 5,105 49% 10, %

58 When cancer is suspected All cases are initially MUO unless clear primary site on imaging Before referral to site specialist team consider? What route did patient present? ED v 2WW What are their wishes for further investigations? In-patient v out-patient v none Assess patient for performance status/fitness for treatment Including renal & liver function Need histological confirmation before treatment can be given How best to get tissue? Suggest if in doubt about any of above to request Oncological opinion first Do not waste time hunting the primary if symptoms do not indicate where primary is Present all cases including clinical diagnosis to CUP MDT

59 Take home messages All patients who present with an abnormal scan with widespread disease suggestive of malignancy have MUO until site specific disease confirmed If biopsy proves cancer and no primary site identified then patient has CUP To undergo systemic anti-cancer treatment Need histological/cytological confirmation Assessment of liver & renal function The primary site does not have to be found!! Urgent treatment with RT can be offered without histology

60 Take home messages (2) Always ask yourself is this patient fit and willing to undergo any Oncological treatments If not then not fair to work them up any further Patients can go home if fit as long as someone takes responsibility for following them up Involve Oncology team earlier in patient pathway Avoid duplication of suspected lung/colorectal or breast cancer Bring all cases to most appropriate MDT for discussion and advice

61 In essence Careful provision of care by teams who communicate well