CANCER OF UNKNOWN PRIMARY TUMOUR SITE SPECIFIC GROUP

Transcription

1 ST. LUKE S CANCER ALLIANCE CANCER OF UNKNOWN PRIMARY TUMOUR SITE SPECIFIC GROUP Constitution

2 Cancer of Unknown Primary Group Agreement Cover Sheet The Constitution has been agreed by: Position Cancer of Unknown Primary Group Chair Name Dr May Teoh Organisation Royal Surrey County Hospital NHS Foundation Trust/Ashford and St Peter s Date Agreed 13 th May 2015 Constitution Review Agreed by Cancer of Unknown Primary Group: 13 th May 2015 Review date: May 2016 Originator of this evidence item: Name Becky Clack Title Alliance Groups Manager Organisation St. Luke s Cancer Alliance Address Royal Surrey County Hospital Guildford Surrey GU2 7XX beckyclack@nhs.net Telephone ext 4671 Version Control: Date Version Status Author Summary of changes September Draft Becky Clack Original document. October Draft Becky Clack Updated with comments from Helen Bennett and Dr May Teoh. November Draft Becky Clack Updated with comments from Dr Eirini Thanopoulou, Dr John de Vos and Becky Clack. December Draft Becky Clack Inclusion of referral form and update of membership list. January Draft Becky Clack Updated after comments from Dr Nita Patel and further amendments from Dr Teoh. March Draft Becky Clack Updated after further review from Dr Eirini Thanopoulou. 6 th May Draft Becky Clack Minor changes to formatting and changes to brain mets pathway 13 th May Final Becky Clack Final, minor changes made at the TSSG and agreement by the group. 1

3 Contents 1 St Luke s Cancer Alliance 1.1 Population 1.2 Alliance Boundaries and Designated Hospital Trusts 1.3 Stakeholders Measure 2 Network Configuration 14-1C-101m 6 Page Network Group Membership 3.1 Core Membership of the Group 3.2 Extended membership of the Group 3.3 Terms of Reference 3.4 Responsibilities of the CUP TSSG Chair 3.5 Network Group Meetings 4 Clinical Guidelines and Patient Pathways 4.1 Introduction 4.2 Patient Referral Pathways 4.3 Patient Investigation Policy and Pathways 4.4 Histological Assessment 14-1C-102m 14-1C-102m 14-1C-102m 14-1C-103m 14-1C-107m 14-1C-105m & 108m Patient Management Policy (including Treatment 14-1C-106m & 108m 18 Pathways) Appendix

4 1. St Luke s Cancer Alliance (Formerly Surrey West Sussex and Hampshire Cancer Network) The Surrey, West Sussex and Hampshire (SWSH) Cancer Network was established in the summer of 2001, as a 3rd wave Cancer Network. SWSH Cancer Network team was disbanded in March 2013 as part of the NHS reforms. In April 2014 St Luke s Cancer Alliance clinical network was established to replace the SWSH Cancer Network Under NHS Reforms from April 2013 the responsibility for commissioning publicly funded healthcare services has moved to the National Commissioning Board NHS England (represented by Area Teams) and Clinical Commissioning Groups. St Luke s Cancer Alliance comprises of 8 Clinical Commissioning Groups and the Surrey/Sussex Specialist Commissioning Area Team. The boundaries of the St Luke s Cancer Alliance lie within the South East Coast Strategic Clinical Network Population St Luke s Cancer Alliance has a resident population of approximately 1.4 million across East and West Surrey, parts of West Sussex, and North and Mid Hampshire. Table 1 below illustrates the total population of the Clinical Commissioning Groups (CCGs) that St. Luke s Cancer Alliance cuts across. Table 2 shows the population covered within the St. Luke s Cancer Alliance catchment area. St Luke s Cancer Alliance population in Table 2 does not include the Basingstoke and North Hampshire NHS Foundation Trust population; Head & Neck and Urology patients from this area have their treatments in St Luke s Cancer Alliance. Table 1: Total Population by CCG Clinical Commissioning Group (CCG) Number of GP Practices Registered population Surrey North West Surrey ,176 Surrey Downs ,698 Guildford and Waverley ,935 East Surrey ,875 Surrey Heath 9 94,099 West Sussex Horsham and Mid Sussex ,327 Crawley ,302 Hampshire North East Hampshire and Farnham ,753 Total 185 1,635,165 3

5 Table 2: Total Population covered by the St. Luke s Cancer Alliance CCGs Total Population % in SLCA SLCA normal population % of SLCA Surrey CCGs 1,096, , West Sussex CCGs Hampshire CCGs 813, , ,376, , TOTAL 3,287,401 1,351, Alliance Boundaries and Designated Hospital Trusts The SLCA spans a large geographical area with both urban and rural communities centred on the main towns of Ashford, Chertsey, Crawley, Farnham, Frimley, Guildford, Redhill and Reigate. Please see map 1 for the boundaries of the SLCA. Data from the Office for National Statistics suggest the population size of SLCA is likely to increase to 1,498,528 by 2018 and to 1,646,547 by SLCA is committed to improving the outcomes and quality of cancer services for our growing population by bringing together commissioners, providers and patients to plan, commission and monitor cancer services. Map 1: SLCA boundary and Designated Hospitals locations 4

6 1.3. Stakeholders Table 3: SLCA key stakeholders There are also a number of community hospitals in the area covered by SLCA. 5

7 2. Network Configuration (14-1C-101m) There are two Cancer of Unknown Primary (CUP) MDTs within the St. Luke s Cancer Alliance (SLCA). These include all four of the relevant hospitals that fall within the SLCA. - MDT 1 - Ashford & St Peter s Hospitals NHS Foundation Trust/Royal Surrey County Hospital NHS Foundation Trust/Surrey & Sussex NHS Healthcare Trust - MDT 2 - Frimley Health NHS Foundation Trust Both MDTs meet on a weekly basis. Each hospital provides a CUP service. The Royal Surrey County Hospital (RSCH) provides oncology tertiary treatment services (including radiotherapy and chemotherapy) for CUP patients from Frimley Park Hospital (FPH), Ashford & St Peter s Hospitals (ASPH) and Surrey and Sussex Healthcare (SASH). It has been agreed by the SLCA that the Cancer of Unknown Primary Tumour Site Specific Group (CUP TSSG) will be part of the Alliance Acute Oncology and Metastatic Spinal Cord Compression (AO/MSCC) Group. As 3 groups have been amalgamated into one, it has been agreed that the Oncologists will cover lead roles within the single group. Dr Teoh will be the Chair of the single group and will also be AOS Lead. Dr Patel will be MSCC Lead and Dr Thanopoulou will be CUP Lead. They will lead on any service development for these areas and for Peer Review. 3. Network Group Membership (14-1C-102m) 3.1 Core Membership of Group There is a single Alliance CUP Group which includes membership from the two MDTs within the SLCA. Core member role Organisation Individual Consultant Clinical Oncologist/Chair ASPH/RSCH Dr May Teoh Consultant Clinical Oncologist/MDT Lead Clinician FPH/RSCH Dr Nita Patel Consultant in Palliative Medicine RSCH Dr Andrew Davies Consultant in Palliative Medicine FPH Dr Nicholas Dando Consultant Radiologist FPH Dr Dhruv Patel Consultant Radiologist RSCH Dr Sarah Watson Consultant Histopathologist FPH Dr Maria Bahhadi-Hardo AOS Clinical Nurse Specialist/User Issues FPH Shobana Srinivasan/Joseph Peralta AOS Clinical Nurse Specialist/User Issues RSCH Aga Kehinde/Sam Russell Secretarial/Administrative Support SLCA Becky Clack 6

8 3.2. Extended Membership of Group On top of the core membership the circulation list includes an extended list of members who are invited to each meeting to strengthen knowledge and relationships across the trusts. This table outlines the extended membership of the group. Consultant Clinical Oncologist FPH/RSCH Dr Ajay Mehta Consultant Medical Oncologists ASPH/RSCH SASH/RSCH Dr Alaeeldin Shablak Dr Eirini Thanopoulou Associate Specialty Doctor RSCH Dr Simon Page AOS Nurses Cancer Services Managers ASPH ASPH SASH SASH RSCH RSCH ASPH RSCH FPH SASH Faithe Cockcroft Sian Wing Lisa Jacques Tina Dela-Cruz Amanda Houston Julia Whittle Sarah Dawson Helen Bennett Simon Gifford Tina Brown AOS/CUP Secretary RSCH Stephanie Wynter Alliance Team SLCA Lorraine Sime Marianne Illsley 3.3 Terms of Reference (14-1C-102m) The Alliance CUP Group will be the SLCA s primary source of advice and clinical opinion on issues relating to CUP services. The group has responsibility for the development of patient pathways and clinical guidelines for CUP services for the SLCA. The group has responsibility for ensuring co-ordination and consistency across the SLCA for CUP policy, practice guidelines, audit, research, and service development relating to CUP services. The group is responsible for consulting with the relevant cross cutting SLCA Groups on issues involving chemotherapy, radiotherapy, radiology, histopathology, cytology, acute oncology and specialist palliative care. The group has responsibility for ensuring co-ordination and consistency across the SLCA for implementing the CUP Peer Review measures. The group, in consultation with the relevant tumour site-specific group chairs will agree the network CUP guidelines and algorithms on the systemic therapy of treatable syndromes. 7

9 The group will agree a network policy which underpins the on-going investigation and subsequent management of all patients presenting as cases of Malignancy of Unknown Origin (MUO). The group will review patient feedback associated with each CUP MDT and actions implemented, and should agree an improvement programme with them. The group will review, at least annually, the Clinical Lines of Enquiry and any Cancer Outcome Indicators associated with CUP MDTs, agree an improvement programme with them and monitor progress. The group will agree Alliance audits. The progress of audits will be reviewed at least once a year. Completed audits will be presented and improvement programmes agreed and monitored. The group will discuss at least annually CUP MDTs research reports on recruitment to trials and any barriers to achieve agreed SLCA targets and agree an improvement programme with them and monitor progress. The group will produce an annual Work Programme in discussion with the Strategic Clinical Networks and agreed with the Medical Director of the NHS England Area Teams (14-1C-104m). The group will produce an Annual Report for the Strategic Clinical Network and the NHS England Area Teams (14-1C-104m). 3.4 Responsibilities of the Chair of the CUP TSSG Group Work with SLCA s management team to ensure all stakeholders representing the patient journey across the Alliance are involved and the group is multi-professional in nature. Responsible for ensuring recommendations made by the cross cutting Alliance Groups and the Alliance CUP Group are implemented within the SLCA. Foster a network approach to issues. Provide strategic leadership. 3.5 Network Group Meetings (14-1C-103m) The group will meet four times per year. The meetings will be minuted and a record of attendance for each meeting will be kept. For meetings to be quorate there must be a representative from each CUP MDT in the SLCA. 4. Clinical Guidelines and Patient Pathways (14-1C-105m, 106m, 107m, 108m) 4.1 Introduction MUO/CUP represents a very broad spectrum of presentations where evidence of a metastatic malignancy is apparent without a primary tumour identified. NICE Clinical Guideline 104 sets out 8

10 clearly the definition (Table 4) for MUO and the two refinements of this diagnosis following further investigations; namely provisional and confirmed carcinoma of unknown primary (pcup and ccup). Table 4: Definitions of MUO and CUP Presentation Malignancy of undefined primary origin (MUO) Provisional Carcinoma of Unknown Primary (pcup) Confirmed Carcinoma of Unknown Primary (ccup) Definition Metastatic malignancy identified on the basis of a limited number of tests, without an obvious primary site, before comprehensive investigation. Metastatic epithelial or neuroendocrine malignancy identified on the basis of histology/cytology, with no primary site detected despite a selected initial screen of investigations, before specialist review and possible further specialised investigations. Metastatic epithelial or neuroendocrine malignancy identified on the basis of final histology, with no primary site detected despite a selected initial screen of investigations, specialist review, and further specialised investigations as appropriate. Historically, MUO/CUP patients have been poorly managed with excessive and unnecessary investigation, poor information giving and delays in referral to oncology or palliative care. The establishment of CUP MDTs has allowed for the streamlining of investigative processes and timely triage to further specialist care. In the SLCA, local Acute Oncology teams contribute to these MDTs and are responsible for the provision of local CUP services in line with network CUP guidelines. These Clinical Guidelines/Patient Pathways provide an agreed framework within SLCA for the investigation and management of all patients presenting with MUO/CUP. Several MUO/CUP syndromes are exempted from this pathway as they are best managed via different site- specific MDTs: - Squamous cell carcinoma affecting the upper/mid cervical lymph nodes should be managed through the local head and neck MDT. - Adenocarcinoma of the axillary nodes in women +/- bone metastases only should be managed through the local breast MDT. - Squamous carcinoma involving inguinal lymph nodes only should be considered for resection and referred to the most appropriate surgical specialist, which may include discussion at a lower GI MDT (anal). - A solitary metastasis should be discussed at an appropriate site specific MDT (with the involvement of a member of the CUP MDT for advice) and considered for radical treatment. - Poorly differentiated midline carcinoma (mediastinum, retroperitoneal) with raised AFP, bhcg in men and women <40y should be referred to the relevant germ cell MDT. - Women with peritoneal adenocarcinoma and elevated Ca125 should be managed through the local gynaecology MDT. - Male with (osteoblastic) bone metastases and elevated PSA should be managed through the local Urology MDT. - Generalised lymphadenopathy only should be referred to the local haematology MDT. - Neuroendocrine carcinoma should be managed through neuroendocrine MDT To minimise the risk of delayed site-specific referral for patients who are suspected to have a specific primary, patients considered as having MUO/CUP are further defined as follows: 9

11 - Liver metastasis/metastases and other intra-abdominal masses identified as likely metastatic malignancy on initial imaging, without evidence of a probable primary site. - Brain metastasis/metastases identified as likely metastatic malignancy on initial imaging, without evidence of a probable primary site. - Lung metastasis/metastases identified as likely metastatic malignancy on initial imaging, without evidence of a probable primary site. - Pleural and/or pericardial effusion(s) diagnosed as malignant on cytology, without evidence of a probable primary site. - Any malignant ascites diagnosed on cytology, without evidence of a probable primary site. - Skin tumour(s) confirmed as malignant on histology when primary skin cancer excluded and no obvious primary from histology or imaging. It is important to consider the multiple physical and psychosocial factors that may influence treatment decisions in individual cases and in particular, the futility of exhaustive investigations or potentially toxic therapies with little proven benefit in patients who are approaching end of life. In such cases, provision of early holistic needs assessment and specialist palliative care must be prioritized and effectively delivered. Continuing investigations should only be carried out if: - The patient is fit for treatment if the primary is found (PS <2, minor co-morbidities). - The results are likely to affect a treatment decision. - The patient understands why the investigations are being performed and the potential risks and benefits of investigation and treatment. - The patient is prepared to accept treatment. 4.2 Patient Referral Pathways (14-1C-107m) The majority of MUO/CUP presentations occur via radiology flagging systems or via an emergency admission to secondary care. Less commonly, patients may be referred as outpatients from GP referrals, secondary care clinics or other site-specific MDTs. Primary care referrals may be accepted by local arrangement with the host Trust s CUP team. All patients with suspected MUO/CUP should be referred to one of the hospital s designated members of the local CUP team. These patients should be assessed face to face by a core member of the CUP MDT: - For outpatients, ideally within 2 weeks of the diagnosis of MUO/CUP. However, it is acknowledged that MUO is a much wider clinical entity than any site-specific cancer, and it may be challenging to set clearly definable and detailed clinical boundaries to enable appropriate and timely referral and review for these patients. - By the end of the next working day for inpatients. Patients presenting on Friday or during the weekend should be assessed by the end of the normal working day on Monday. It is expected that these patients will be reviewed by the local Acute Oncology service. For inpatients, the local CUP team will advise on further investigations (bloods, including relevant tumour markers, any scans etc.) and arrange a fast-track outpatient appointment in the local CUP clinic (if appropriate). It is the responsibility of the admitting secondary care team to arrange the investigations as advised and they have the overall responsibility of the patient until a named Consultant Oncologist takes over the care of the patient. 10

12 For outpatients, the local CUP team will take responsibility for arranging further investigations and assessing the patient in clinic prior to any definitive treatment. All referred patients (see appendix 1 for proforma) should be discussed at the next central/local CUP MDT, which will advise on further investigations required to identify the primary site and any treatment planning decisions including the suitability for active anticancer treatment (in this context, active anticancer treatment refers to any cytoreductive treatment or therapeutic surgical intervention). Any intervention for palliation should follow the local palliative care guidelines. The MDT outcomes and management plan for each case should be documented and implemented. The possible outcomes following MDT review include: - MUO/pCUP/cCUP fit (PS <2 and minor co-morbidities) for active therapy and requiring further investigation or treatment. - MUO/pCUP/cCUP classified as too frail for further therapy and requiring best supportive care. - Primary site identified or specific MUO/CUP syndrome (as specified in Section 4.1), to be referred for review at site-specific MDT. - Non-malignant diagnosis, requiring onward referral. Concomitant with a thorough medical assessment, the patients holistic needs should also be assessed. Symptom control and psychological support should be offered and appropriate referrals made. The patients and carers understanding of the situation should be assessed and information given in a clear and sympathetic manner. These processes are active and on-going throughout the patient s journey and the CUP Clinical Nurse Specialist (CNS) role here is fundamental. It is common for Specialist Palliative Care to be brought in during the diagnostic stage and for the majority of patients this will remain the most important intervention during their illness. Many patients can be managed as outpatients once the above needs have been met and therefore every attempt should be made to facilitate discharge. 4.3 Patient Investigation Policy and Pathways (14-1C-105m, 108m) The assessment of any MUO/CUP patient begins with a thorough history and physical examination. Most patients will be referred having had some imaging which is highly suggestive or confirmatory of malignancy. The minimum imaging should include a CT thorax, abdomen and pelvis. The bare minimum for further tests represents a full blood count and biochemical profile (including Renal Function Tests, Liver Function Tests and lactate dehydrogenase- LDH); in accordance to ESMO and NICE guidelines. The decision to embark on further tests from here will very much be influenced by the mode of presentation and the condition of the patient. Continuing investigations to find the primary should only be carried out if: - The patient is fit for treatment if the primary were found. - The results are likely to affect a treatment decision. - The patient understands why the investigations are being performed and the potential risks and benefits of investigation and treatment. - The patient is prepared to accept eventual treatment. It should be borne in mind that most oncology decisions can be made utilising three fundamental pieces of information: - The condition, functional status and co-morbidities of the patient (history and examination). Investigations should only continue if the patient is fully informed around risks/benefits of investigations and wants to consider therapeutic options. 11

13 - The stage of the cancer (cross-sectional imaging). - The type of cancer (histology). Frequently, an important component of the investigation pathway will involve a biopsy of a suitable metastatic lesion and standard histological examination (Section 4.3.2). Further specific investigations may be appropriate, as guided by the patient s symptoms and results of the initial diagnostic tests (Table 5). The general investigation pathway for MUO/CUP patients is illustrated in Figures 1 and 2. Table 5: Further specific investigations for MUO/CUP patients Test Tumour markers Upper and lower gastrointestinal (GI) endoscopy Mammography Postiron emission tomographycomputed tomography (18F-FDG PET-CT) Flexible bronchoscopy and video-assisted thoracoscopic surgery (VATS) Action Do not measure during diagnosis except for: AFP and bhcg in presentations compatible with germ-cell tumours (particularly mediastinal and/or retroperitoneal masses and in young men). AFP in presentations compatible with hepatocellular cancer. PSA in presentations compatible with prostate cancer. CA 125 in presentations compatible with ovarian cancer (including inguinal node, chest, pleural, peritoneal or retroperitoneal presentations). Carefully interpret the results because of limited test specificity. Do not carry out in patients with MUO/CUP unless the symptoms, histology or radiology suggest a GI primary tumour. Do not offer routinely to women with MUO/CUP unless clinical or pathological features are compatible with breast cancer. Offer to patients with provisional CUP and cervical lymphadenopathy if a primary tumour is not identified on ear, nose and throat panendoscopy and radical treatment is an option. Consider for patients with provisional CUP and extra-cervical presentations after discussion with CUP MDT/central PET radiologists. When percutaneous biopsy is unsuitable or inappropriate for intrapulmonary nodules of probable metastatic origin offer: Flexible bronschoscopy with biopsy, brushings and washings even when there is no endobronchial or central nodal disease on imaging. VATS exploration only after a negative bronchoscopic procedure Investigation of Specific Presentations Liver Lesions The finding of isolated liver metastases is a common MUO/CUP presentation and nearly half of all MUO patients will have liver involvement. A full staging CT scan of thorax, abdomen and pelvis should be performed after history taking and physical examination. A serum AFP should be checked if there are any risk factors or clinical/radiological signs to suggest chronic liver disease or HCC. 12

14 If the distribution of metastatic disease is confined to the liver and cross-sectional imaging suggests that it may be resectable (e.g. unilobar) then a referral to a hepatobiliary MDT is recommended prior to an image-guided biopsy. If it is likely to be resectable then colonoscopy, PET CT and MRI of liver should be considered to more accurately define the extent of disease prior to surgery. Most presentations are unlikely to be resectable and if tissue is needed an image-guided percutaneous biopsy of a lesion should be arranged. Consider the possibility of non-malignant conditions: - Cirrhosis. - Haemangiomata. - Focal nodular hyperplasia or hepatic adenomata Brain Lesions These are the presenting feature of around 10% of MUO/CUP presentations. They typically present as an emergency with stroke-like symptoms and are identified on CT scanning of the brain. Immediate management with dexamethasone (8mg po/iv bd with PPI cover) typically provides some relief. The key determinants of prognosis are performance status, response to corticosteroids and extent of extra-cerebral disease. Solitary lesions or less than 3 metastases should be discussed with neurosurgical services as possible treatment options may include surgical resection or radiosurgery. Patients who respond to steroids and are not surgical candidates should be considered for whole brain radiotherapy. Referral for whole brain or stereotactic radiosurgery should be made to the tertiary oncology centre. The patient pathway for the investigation and management of brain metastases presenting as MUO/CUP is shown in Figure 3. Consider the possibility of non-malignant conditions: - Brain abscesses. - Cerebral infarction. 13

15 Figure 1 MUO Investigation Pathway Outpatients with MUO (under named consultant) Inpatients with MUO (under care of non-oncology consultant) Advice from CUP Intra-trust referral Radiology alerts Intra-trust referral Review within 1 working day Local CUP team to advise - Complete history and examination (including breast, rectal, GU/pelvis) [Past history - any previous biopsies or malignancy; removed/ spontaneously regressed lesions] - Bloods: FBC/U+Es/LFTs/bone profile - CT TAP (? +/- Bone scan) - Hemoccult/symptom directed endoscopy PS: 3-4 OR Any PS + Significant comorbidities +/- Elderly (e-prognosis CGA) Patient wishes not to proceed with work up/anti-cancer Rx Non-malignant Adenocarcinoma (or poorly differentiated) Biopsy of most accessible site and 1 st line panel of IHC markers Patient to go to site specific MDT unless biopsy is inconclusive and then to CUP MDT Squamous Neuroendocrine Haematological malignancy - Melanoma - Sarcoma - Germ-cell tumour Site-specific MDT MDT Discussion only Referral to Palliative Care No further tests CUP Pathway Site-specific MDT Haematology MDT 14

16 Figure 2 CUP Investigation Pathway For other solitary mets send to relevant MDT HPB MDT Germ Cell MDT <40y Midline distribution (mediastinum, retroperitoneal) ADENOCARCINOMA OR SQUAMOUS CARCINOMA Solitary metastasis Liver Bone Bone MDT Brain Cervical/SCF lymph nodes Axillary lymph nodes Inguinal lymph nodes Peritoneal Neuro oncology MDT Head & Neck MDT Breast MDT Lower GI MDT Multiple metastases Gynaecology MDT Upper GI MDT Breast MDT (ILC) Fit for treatment Chemo Clinical trials Referral to palliative care Consider other treatment options (e.g. surgery, radiotherapy) Unfit for treatment Assess PS Discuss at CUP MDT Consider further investigations: Imaging Mammogram, PET/CT, Bone scan, testicular USS Tumour markers PSA, BHCG, AFP, CA19-9, CA125 Other e.g. urine cytology/cystoscopy, OGD, colonoscopy, bronchoscopy/vats, laparascopic biopsy, anal endoscopy Consider 2 nd line panel of IHC markers Multiple bone metastases and raised PSA Lung nodules Pleural effusion Mediastinal/hilar lymph nodes Urology MDT Consider discussion at lung MDT Referral to palliative care 15

17 Bone Lesions Bone lesions are seen in about a third of MUO/CUP presentations and are typically lytic in nature. They typically present as an emergency with significant skeletal events such as pathological fracture, spinal cord compression or uncontrolled pain. In some cases, urgent treatment such as fixation of pathological fractures for stabilisation may be required. Patients presenting with spinal cord compression should be managed on the network agreed MSCC pathway. Men over the age of 40 should have a digital rectal examination and a PSA checked. All patients with lytic bone lesions should have a serum electrophoresis and urine collection for Bence-Jones proteins. If the patient presents with a pathological fracture and is scheduled for internal fixation then ensure that you request that the surgeon sends a pathological biopsy to the laboratory for histological analysis. Bone biopsies should be discussed with a member of the CUP MDT and following agreement should be arranged via the local orthopaedic services. If there is a suspicion of primary bone sarcoma on imaging, whose treatment is potentially with curative intent, the case should be discussed with the London and South East Sarcoma Network prior to an attempt at biopsy. Consider the possibility of non-malignant conditions: - Osteomyelitis. - Paget s disease of Bone. - Hyperparathyroidism (Brown Tumour). - Fibrous dysplasia Lung Lesions If there is any suspicion of a lung primary, such patients should be managed by the local lung MDT. Where the distribution and appearances suggest metastatic spread tissue can be obtained either by percutaneous needle biopsy, bronchoscopy or EBUS. Consider referral for video assisted thoracic surgery if no tissue is obtained via these routes. Consider the possibility of non-malignant conditions: - Sarcoidosis. - Wegener s granulomatosis. - Tuberculosis Peritoneal Carcinomatosis This typically presents with vague abdominal symptoms and ascites. In women it is reasonable to check a CA125 but it should be borne in mind that this will invariably be elevated even in nonmalignant causes for ascites. Diagnosis should be made with a formal biopsy, although the presence of malignant cells in peritoneal fluid (particularly if cell block is prepared) can sometimes be helpful. If an image guided procedure cannot access tissue then the patient should be considered for a laparoscopy +/- biopsy. 16

18 Figure 3 - Brain Metastases Pathway Imaging evidence of probable malignant brain tumour Fit for treatment? Early referral to Acute Oncology (inpatients) [Consider advanced age, comorbidity, poor performance status, unlikely to be improved with treatment and if the patient wants to be treated.] Yes No Full history and general examination MRI brain CT chest/abdo/pelvis staging FBC, U+E, LFT Tumour markers/myeloma screen only if relevant Start planning discharge Dexamethasone 8mg BD with PPI cover If large lesion and/or significant effects on patient please do not wait for staging before asking advice from St. George s Hospital Neurosurgery Unit Palliative care Symptom control at Home/Hospice Neuro-oncology MDT at SGH Multiple brain mets with unknown primary Solitary brain met or 3 mets with unknown primary Refer to CUP MDT Refer to SGH Neurosurgical Unit On call registrar (bleep 7242) Online referral system (referapatient.org) Treatment Options Surgery Radiotherapy Gamma Knife Chemotherapy Palliative Care SGH Neuroscience MDT discussion Urgent OPD if appropriate 17

19 4.4 Histological Assessment It is incumbent on the local CUP Assessment teams to work closely with their local pathology laboratories to provide sufficient background information to facilitate appropriate immunohistochemical analysis. For some patients the confirmation of cancer may be sufficient on haematoxylin and eosin (H&E) staining whereas others will require a more comprehensive immunohistochemical panel to categorise the tumour: - Undifferentiated malignancies. The panel of investigations will be influenced by the age and sex of the patient, the site of biopsy and morphological assessment of the H&E stained sections. In general, consider: Initial panel to cover possibilities of lymphoma, carcinoma, melanoma (CD45, MNF116, S-100) and germ cell tumour (OCT3/4, CD30). Second line panel depending on results of above. If probable carcinoma (CK7, CK20, CDX2, CA125, PSA, TTF-1, ER), melanoma (melan-a, HMB45), sarcoma (depends on suspected type, myogenin best for rhabdomyosarcoma). Suspected lymphomas should be sent directly to HMDS without further immunohistochemistry in order to preserve tissue. In the case of metastases to bone (and sometimes other sites) include TTF-1, CD10, renal carcinoma antigen, PSA. - Metastatic adenocarcinoma. Limited panel to refine possible primary site - CK7, CK19.9, CK20, TTF-1, PSA, ER, Her2, CDX2. CA125 and WT-1 may be helpful if a primary ovarian or primary peritoneal carcinoma is suspected. - Metastatic squamous cell carcinoma. Markers of squamous differentiation are not entirely specific but consider p63, CK5/6, CK14 or 34BE12. Site-specific markers for origin of squamous cell carcinoma are of very limited value. The only ones worth considering are in situ hybridisation for EBER (nasopharynx) and HPV (oropharynx) in patients with metastatic neck nodes, although PET-CT scanning in patients without an obvious primary lesion should be considered before (or in conjunction with) laboratory testing. - Identification of predictive markers of therapeutic response. After MDT discussion, consideration should be given to requesting additional biomarkers if any of the following are suspected but only if it will have a bearing on therapy: Breast: ER/PR/Her2 Lung: EGFR/ALK mutational status Colorectal: K-RAS mutational status Gastric/Junctional: Her2 4.5 Patient Management Policy (including Treatment Pathways) (14-1C-106m, 108m) The evidence base for optimal systemic treatment of those patients with confirmed CUP is poor. The initial decision to treat will be based on the patient s performance status and comorbidities but according to recent meta-analysis there is no evidence of superior efficacy of any chemotherapeutic regimen over another in CUP. Hence, low-toxicity convenient chemotherapy regimens should be administered to reasonably fit poor-risk CUP patients, always balancing potential side effects and benefits to ensure quality of life. The regimen used in practice therefore, typically is a best guess approach based on where the suspected origin of the cancer is. There is a clear need to develop an evidence base here and where possible patients should be managed in clinical trials. 18

20 Confirmed CUP patients who are being considered for chemotherapy should have the balance between the potential risks and benefits of treatment discussed with them. Table 7 shows the potential suitable regimens for treatable CUP syndromes (14-1C-106m) and other common CUP presentations. Table 7: Potential Regimens for Treatable CUP Syndromes Treatable CUP syndrome Poorly differentiated carcinoma with a midline distribution Women with predominant peritoneal adenocarcinoma Poorly differentiated neuroendocrine carcinoma Squamous cell carcinoma of lymph nodes in the neck Women with adenocarcinoma involving the axillary nodes Other common CUP presentations Treatable CUP syndrome Treatment option Liver or lung metastases adenocarcinoma or poorly differentiated carcinoma Squamous cell carcinoma Treatment option Refer to local Urology MDT. Chemotherapy Regimens can be found here: Refer to Gynaecology MDT. Chemotherapy Regimens can be found here: Refer to Neuroendocrine MDT. Chemotherapy Regimens can be found here: Referral for treatment under head and neck MDT. Chemotherapy Regimens can be found here: Referral for treatment under breast MDT. Chemotherapy Regimens can be found here: Refer to CUP MDT. Chemotherapy Regimens as follows: Gemcitabine and platinum Gemcitabine and irinotecan ECF/ECX/(E)OX Carboplatin and paclitaxel (or carboplatin and docetaxel) Capecitabine monotherapy Refer to CUP MDT. Chemotherapy Regimens as follows: Cisplatin and 5FU/capecitabine Oxaliplatin and 5FU/capecitabine 19

21 Appendix 1 NEW/SUSPECTED Metastatic Cancer of Unknown Primary Origin (CUP) Referral Form RSCH rsc-tr.acuteoncology@nhs.net Details/Sticker Name: NHS nr: Date of Birth: Hospital Number: Age: Consultant in Charge Referring Dr Date Referred Date of Admission Ward Name Bleep Grade Present complaint and HPC ( history of present complain) PS (performance status) PMH ( past medical history, any cancer history) DH ( drug history) O/E ( on examination/admission) SH ( social history) Blood tests: ( tumor markers) Imaging: X-rays: CT scans: MRI scans: PET/CT scans/ bone scans: Biopsy Scans: 20

22 Endoscopy: Histology/ Cytology: (please include also any past histological reports) CLINICAL ASSESSMENT / ADVICE WILL BE IN THE NOTES AOS TO COMPLETE PLAN: Date Referral Received Follow up/take Over Date Seen 21

23 PS score 0 Asymptomatic (Fully active, able to carry on all activities without restriction) 1 Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work) 2 Symptomatic, <50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours) 3 Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours) 4 Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair) 5 Death Version October