Download Unknown Primary Cancer - Northern England Clinical Networks

Carcinoma of unknown primary
Dr Syed Zubair
Consultant Medical Oncologist
The James Cook University Hospital
Overview
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Epidemiology
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NICE recommendations
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Definitions
Organisation of services
Diagnosis and management
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CUP subsets and its management
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Clinical trials in CUP
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Local pathways
Is this relevant ?
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In England, 9,778 new cases registered in 2006 (2.7%)
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4th most common cause of cancer death
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No discrete classification within the ICD nomenclature
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C77 to C80 usually cover registrations
Incidence by age
Use of resources
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HES (Hospital Episode Statistics) for England (06-07)
 25,318 episodes of care
 308,359 NHS bed-days
Admissions with CUP (2007): 365,197 patients
 72% as emergencies
 28% were elective admissions
Inpatient episodes
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Inpatient episodes per 1000 population per year (2000 – 2007)
 The highest rate was seen in the North East SHA.
Survival in CUP
Survival for solid tumours
Head and neck
Uterus (1.6)
Liver (3)
Kidney (3.8)
Ovary (4.4)
Bladder (4.8)
Stomach (5.2)
Oesophagus (7)
Pancreas (7.3)
Breast (12.4)
Bowel (16)
Lung (34)
0
5
(mortality/year/UK)
10
15
20
Months
CUP 7m
25
30
35
Experience of patients
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Lengthy diagnostic process with little new information discovered.
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Disquiet at a string of investigations which may cause discomfort,
adding little to care.
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Confusion - who is in charge of care.
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Long periods of inpatient stay with little perceived benefit.
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Feel lack of fitting into a defined system when they meet other
cancer patients.
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Absence of an organised research programme.
Patient journey
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Mr HR, 69 years old, previous history of prostate cancer on hormonal treatment
Presented to GP with intermittent dysphagia, clinically palpable nodes in the neck,
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2nd week July: Referred to Gastroenterology at North Tees
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18th July: OGD , soft tissue lesion around epiglottis
20th July : Referred to ENT by GP
25th July: Seen in ENT clinic, FNA of neck node
4th Aug: Nasolaryngoscopy and Panendoscopy.No epiglottic lesions and normal larynx
9th Aug: CT of TAP
15th Aug: ENT clinic
16th Aug: H&N MDT, NSC cancer, refer to upper GI MDT
19th Aug : Upper GI MDT, PET and US core biopsy
26th Aug: PET scan
2nd Sep: Upper GI MDT, Radiological no evidence of upper GI cancer
8th Sep: US guided neck node biopsy
23rd Sep: Upper GI MDT, Likely CUP
4th OCT H&N MDT:
06th Oct: Combined clinic
07th Oct: Referral to CUP team
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14th Oct : Seen in CUP clinic
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Diagnosis and management of
metastatic malignant disease
of unknown primary origin
Implementing NICE guidance
July 2010
NICE clinical guideline 104
Why are we still failing patients ?
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Lack of a system for clinical care
Site-determined Cancer
Unknown Primary Cancer
• Specialist Oncologist
• Specialist Nurse
• Multi-disciplinary team
• MDT management approach
• Rapid systematic investigation
• Site-specific protocols
• Site-specific audit
• Site-specific research
• Cancer measures
• Site-specific information + support
• Accurate epidemiology
• No Specialist Oncologist
• No Specialist Nurse
• No Multi-disciplinary team
• No MDT management approach
• No Rapid systematic investigation
• No Site-specific protocols
• No Site-specific audit
• No Site-specific research
• No Cancer measures
• No Site-specific information + support
• No Accurate epidemiology
NICE Recommendations
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Definitions
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Epidemiology
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Organisation of services and support
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Diagnosis
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Factors influencing management decisions
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Managing specific presentations
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Systemic treatment
Definitions
Based on clinical course, clinical findings and investigations
Detection of metastatic malignancy on clinical examination
or by imaging, without an obvious primary site
MUO
Metastatic epithelial / neuro-endocrine malignancy on
histology. No primary detected despite initial investigations.
Specialist review and possible further investigations pending
pCUP
Metastatic epithelial / neuro-endocrine malignancy on
histology. Specialist review and all relevant investigations
completed. No primary detected.
cCUP
Organisation of services
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Site specific group
Every hospital with a cancer centre or a
cancer unit should establish
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CUP team
CUP specialist nurse
Outpatients and inpatients with CUP
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O/P : rapid referral pathway(2W).
I/P : assess by end of the next working day.
Local and network CUP MDT??
Diagnosis
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Initial Diagnostic Phase
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Comprehensive history and examination
Bloods: FBC, U &E, LFT, Calcium and LDH
Chest X-ray
CT of the chest, abdomen and pelvis
Cytology / Histology
Diagnosis
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Second diagnostic phase
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Tumour markers
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AFP and hCG : Germ-cell tumours or mediastinal/retroperitoneal masses in
young men
AFP : Hepatocellular cancer
PSA : Prostate cancer.
CA125 : Women with ovarian cancer.
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Upper or lower GI endoscopy: If symptoms, histology or radiology suggestive
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Myeloma screen: Isolated or multiple lytic bone lesions
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Mammography: Clinical or pathological features compatible with breast cancer
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Breast MRI: Adenocarcinoma of axillary node to identify lesions for targeted
biopsy.
Investigations
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PET-CT
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Cervical lymphadenopathy with no primary.
For extra-cervical presentations, discussion with the
CUP team.
Gene expression based profiling
Histology
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Well differentiated adenocarcinoma (60%)
Squamous cell carcinoma (5%)
Poorly differentiated adenoca (15%)
Poorly differentiated carcinoma (20%)
20
Immunohistochemistry
Tumor type
Immunohistochemistry
Carcinoma
CK, EMA
Lymphoma
CLA
Melanoma
S-100, vimentin, HMB-45
Sarcoma
Vimentin, desmin
Neuroendocrine tumor
Lung Cancer
Prostate
Synaptophysin and chromogranin
TTF1
PSA
Immunohistochemistry
Varadhachary GR et al. Diagnostic strategies for unknown primary cancer. Cancer.
2004 May 1;100(9):1776-85
When to stop investigations
Perform investigations only if:
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Results are likely to affect a treatment decision
Patient understands potential benefits and risks.
Patient is prepared to accept treatment.
Do not offer: If unfit for treatment.
Favourable subsets
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Women with isolated axillary adenopathy
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Women with papillary serous adeno Ca of the peritoneal cavity
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Sq cell carcinoma involving cervical lymph nodes
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Isolated inguinal adenopathy from squamous cell Ca
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Men with bone metastases, elevated serum PSA.
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Men with poorly differentiated carcinoma of midline distribution
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Poorly differentiated neuroendocrine carcinoma
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Single, small and potentially resectable metastatic site
Potential radical treatment
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Squamous carcinoma upper or mid neck nodes
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Adenocarcinoma involving the axillary nodes
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Breast cancer MDT
Squamous carcinoma confined to inguinal nodes
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Head and neck MDT
Specialist surgeon in an appropriate MDT
Solitary mets in liver/brain/lung
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Appropriate MDT
Unfavourable subsets
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Adenocarcinoma metastatic to the liver or other organs
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Non-papillary malignant ascites (adenocarcinoma)
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Multiple cerebral metastases
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Multiple lung/pleural metastases
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Multiple metastatic bone disease
Systemic treatment
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Chemotherapy for confirmed CUP with no
features of a specific treatable syndrome,
inform patients about the potential benefits
and risks.
Opportunity to enter clinical trials.
Historical Post-mortem studies of CUP patients (1944-2000)
Unidentifiable Primary in ~30%
Commonest “primaries”: pancreas and lung (40%), GI, kidney
Autopsy-found primaries, N = 644 (%)
DNA-assigned primaries, N > 500 (%)
Lung
Pancreas
Liver/bile duct
Kidney/adrenals
Bowel
Genital system
Stomach
Bladder/ureter
Breast
Other
Lung
Pancreas
Liver/bile duct
Kidney/adrenals
Bowel
Genital system
Stomach
Bladder/ureter
Breast
Other
27
24
8
8
7
7
6
0.01
0.007
10
11.5
12.5
8
6
12
9
3
5
15
18
Platinum/Taxane chemotherapy
Author/year
Chemo
Patients
RR (%)
MS (mon)
Voog (00)
CpE
23
32
8
Briasoulis (00)
PCb
77
39
13
Greco (00)
DCb
47
22
8
Greco (00)
DCp
26
26
8
Park (04)
PCp
37
42
11
Berry (07)
PCb (weekly)
42
18
8.5
Pentheroudakis
(2008)
DCb
47
32 (46)
16.2 (22.6)
Cb –Carboplatin; Cp – Cisplatin; D – Docetaxel, E – Etoposide, P – Paclitaxel
Comparative survival with diverse chemotherapy
regimens for cancer of unknown primary site:
Multiple-treatments meta-analysis
Golfinopoulos et al, 2009
• Meta-analysis of 10 randomized phase 2 trials comparing
relative efficacy of various regimen
• Data on favorable subset CUP were excluded
• Overall 683 subjects
• No trials compared systemic treatment to BSC
Comparative survival with diverse chemotherapy
regimens for cancer of unknown primary site:
Multiple-treatments meta-analysis
Golfinopoulos et al, 2009
Comparative survival with diverse chemotherapy
regimens for cancer of unknown primary site:
Multiple-treatments meta-analysis
Golfinopoulos et al, 2009
• No significant benefit for any treatment group over others
• No type of chemotherapy has been solidly proven to prolong survival
• Regimens using either platinum or taxanes or both show some
trends for prolongation of survival
• A taxane/platimun combination may prolong survival by 1.5 months
• BSC may be considered for old or unfit unfavorable CUP
Triplet chemotherapy regimens
Author/year
Chemotherapy
Patients
RR (%)
MS (months)
Greco (2000)
PCbE
71
48
11
Greco (2002)
PCbG
120
25
9
Greco (2004)
PCbE
132
30
9
Schneider (2007)
CbGCAP
33
39
7.6
Cb –Carboplatin; E – Etoposide, G – Gemcitabine; P – Paclitaxel
Pentheroudakis
(2009)
Platinum
conining
regimens
918
32
9
Common chemo regimen
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ECF regimen
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epirubicin, cisplatin and 5FU
RR of 22%
median survival of 9 months
Parnis, F.X., et al., Phase II study of epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) for
carcinoma of unknown primary site. Ann Oncol, 2000. 11(7): p. 883-4.
7. Karapetis, C.S., et al., Epirubicin, cisplatin, and prolonged or brief infusional 5-fluorouracil in the
treatment of carcinoma of unknown primary site. Med Oncol, 2001. 18(1): p. 23-32.
Chemotherapy - summary
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Only phase II trials, few randomized
No randomized phase III trials to establish the efficacy of
combination chemotherapy over BSC
Unfavourable subsets: patients with good PS may benefit from
systemic chemotherapy
Chemotherapy: most commonly used regimens include platinum
and a taxane or ECX
The role for a third agent such as gemcitabine, irinotecan or
etoposide remains unclear
The CUP-ONE Trial
A multi-centre phase II trial to assess the
efficacy of ECX in CUP incorporating the
prospective validation of molecular
classifiers in diagnosis and classification
Chief Investigator: Harpreet S Wasan
Coordinated by:CRUK Clinical Trials Unit, Glasgow
Local pathways
CUP service rolled out to
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All patients from south NECN
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JCUH / Friarage
Darlington / Bishop
North Tees / Hartlepool
Friday AM CUP clinic (Specialist
CUP Nurse)
Inpatients
A and E
MAU
Medical/Surgical ward
Diagnostic/Referral pathways
Primary site unknown
Primary site identified
CUP team
Site specific MDT
Palliative care
Systemic Rx
Out patients
OPD
Liaise with CUP team
Primary care
Appropriate MDT
Palliative care
Appropriate MDT
CUP team
CUP team
Acknowledgements
Dr Nicola Storey
Nicky Hand
Any Questions
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Discussion
Thank you