Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

identification of primary site pending

1st line – supportive care

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INITIAL
|
identification of primary site pending
1st line – 

supportive care

Initial treatment strategies are aimed at controlling symptoms attributable to the underlying process, such as pain or local obstruction, and the focus should be on palliation of symptoms. Specific treatment will depend upon the site involved. Expedited diagnostic work-up allows initiation of appropriate chemotherapy in a timely fashion.[30]

Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines, as appropriate.

Plus – commence chemotherapy

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INITIAL
|
identification of primary site pending
|
investigations complete and good performance status
Plus – 

commence chemotherapy

Treatment recommended for ALL patients in selected patient group

Historically, chemotherapy has been the cornerstone of treatment of adenocarcinoma of unknown primary site (AUP), and has been used with palliative intent in unfavourable risk subtypes.[2][15]

Many chemotherapeutic regimens have been assessed, but systematic reviews and meta-analyses have failed to demonstrate superiority of one regimen over another.​[43][44][45]​ One meta-analysis reported a tendency towards improved survival with regimens containing platinum agents or taxanes.[45]

The majority of patients with AUP are older adults, with some functional impairment related to the advanced disease. US guidelines recommend that systemic therapy for patients with disseminated disease should be reserved for the following patients: symptomatic with performance status of 1-2; or asymptomatic with aggressive cancer and performance status 0.[15]

Supportive care should be initiated, ideally under the guidance of a palliative care physician or team.

ACUTE

multiple metastases: favourable clinico-pathological subtype not identified

1st line – chemotherapy

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ACUTE
|
multiple metastases: favourable clinico-pathological subtype not identified
1st line – 

chemotherapy

For the majority of patients in whom a favourable clinico-pathological subtype is not identified, the recommended initial chemotherapeutic regimen is a combination of agents, either platinum-based (cisplatin or carboplatin) or taxane/platinum-containing (e.g., docetaxel or paclitaxel with cisplatin or carboplatin).[3]

European guidelines suggest platinum-based doublets combined with either a taxane or gemcitabine as standard of care.[2]​ Responses are not durable (median survival approximately 12 months among patients with good performance status).[46][47]

There is no agreement on appropriate second-line therapy for patients previously treated with platinum-containing regimens; no single agent or combination has proven beneficial (response rate or median survival). Decisions about second-line therapy are based on oncologist preference, or on other patient characteristics that may prevent the use of certain cytotoxic drug classes.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

or

cisplatin

-- AND --

gemcitabine

OR

carboplatin

or

cisplatin

-- AND --

docetaxel

or

paclitaxel

Plus – supportive care

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ACUTE
|
multiple metastases: favourable clinico-pathological subtype not identified
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based upon the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

multiple metastases: women with isolated axillary lymphadenopathy (likely primary: breast cancer)

1st line – primary breast cancer management protocol

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ACUTE
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multiple metastases: women with isolated axillary lymphadenopathy (likely primary: breast cancer)
1st line – 

primary breast cancer management protocol

Female patients presenting with isolated axillary adenopathy and documented adenocarcinoma should undergo mammography and magnetic resonance imaging (MRI).

Retrospective studies indicate that breast MRI can help to identify the primary cancer in approximately two-thirds of patients with negative clinical examination and negative mammography.[48]​ Immunohistochemical markers for oestrogen receptor (ER) and progesterone receptor (PR) should be performed in all women with adenocarcinoma, especially in those with isolated axillary lymphadenopathy. Tumours exhibiting these receptors are sensitive to hormonal therapy.

Patients with likely breast primary should be managed according to primary breast cancer protocols.[2][15]​ See Primary invasive breast cancer.

Plus – supportive care

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ACUTE
|
multiple metastases: women with isolated axillary lymphadenopathy (likely primary: breast cancer)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

multiple metastases: women with papillary adenocarcinoma of the peritoneal cavity (likely primary: ovarian cancer)

1st line – ovarian cancer management protocol

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ACUTE
|
multiple metastases: women with papillary adenocarcinoma of the peritoneal cavity (likely primary: ovarian cancer)
1st line – 

ovarian cancer management protocol

Histologically analogous to stage III ovarian cancer.

BRCA1/2 germline mutations may be present and CA 125 is typically elevated, consistent with an ovarian cancer profile. First-line therapy includes optimal surgical debulking and systemic chemotherapy, generally a taxane/platinum doublet.[2]​​ There is some evidence, although not consistent, to support the use of intraperitoneal chemotherapy for advanced-stage ovarian cancer; its potential role in the management of papillary adenocarcinoma of the peritoneal cavity has not yet been evaluated.[49][50][51]

Patients with ovarian-like cancer of unknown primary (CUP) are treated per ovarian cancer guidelines.[2][15]​​ See Ovarian cancer.

Plus – supportive care

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ACUTE
|
multiple metastases: women with papillary adenocarcinoma of the peritoneal cavity (likely primary: ovarian cancer)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

multiple metastases: poorly differentiated carcinoma with neuroendocrine features (likely primary: small cell lung cancer)

1st line – small cell lung cancer management protocol

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ACUTE
|
multiple metastases: poorly differentiated carcinoma with neuroendocrine features (likely primary: small cell lung cancer)
1st line – 

small cell lung cancer management protocol

A significant minority of poorly differentiated or undifferentiated carcinomas have neuroendocrine features identified by histological assessment. Favourable neuroendocrine carcinoma subtypes are not considered in European guidelines because an elusive primary cancer is a common finding.[2]

Combination chemotherapy with paclitaxel, carboplatin, and etoposide was associated with a major response rate of 53% (median survival 14.5 months; 2- and 3-year survival rates of 33% and 24%, respectively) in one phase 2 clinical trial of treatment-naive patients with metastatic poorly differentiated neuroendocrine carcinoma.[52]​ In a subsequent phase 2 study, irinotecan and cisplatin was not inferior to etoposide and cisplatin in patients with poorly differentiated gastroenteropancreatic neuroendocrine carcinoma.[53]​ Enrolment to the study was terminated early (n=66 patients) because initial analyses reported similar response rates.[53]

Poorly differentiated neuroendocrine tumours are treated per small cell lung cancer guidelines.[15][54]​ See Small cell lung cancer.

Plus – supportive care

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ACUTE
|
multiple metastases: poorly differentiated carcinoma with neuroendocrine features (likely primary: small cell lung cancer)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

multiple metastases: well-differentiated neuroendocrine tumours

1st line – neuroendocrine tumour management protocols

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ACUTE
|
multiple metastases: well-differentiated neuroendocrine tumours
1st line – 

neuroendocrine tumour management protocols

Neuroendocrine tumours include islet cell tumours, carcinoid tumours, and gastrinomas, among others. Favourable neuroendocrine carcinoma subtypes are not considered in European guidelines because an elusive primary cancer is a common finding.[2]

If feasible, surgical debulking or chemoembolisation is preferred as an initial therapy, as control of tumour bulk appears to delay progression of systemic disease. Chemotherapy is variably effective, depending on the underlying tumour type, with pancreatic neuroendocrine tumours exhibiting much better response rates than carcinoid tumours derived from other primary sites. Treatments appropriate for well-differentiated metastatic neuroendocrine tumours should be considered, including somatostatin analogues (e.g., octreotide, lanreotide), everolimus, sunitinib, or peptide receptor radiotherapy.[3]

Well-differentiated neuroendocrine tumours should be treated as carcinoid tumours.[15]​ See VIPoma.

Plus – supportive care

Back
ACUTE
|
multiple metastases: well-differentiated neuroendocrine tumours
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

multiple metastases: adenocarcinoma with colorectal immunohistochemistry (likely primary: colorectal cancer)

1st line – colorectal cancer management protocol

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ACUTE
|
multiple metastases: adenocarcinoma with colorectal immunohistochemistry (likely primary: colorectal cancer)
1st line – 

colorectal cancer management protocol

Patients with immunohistochemistry suggestive of colorectal primary site (CDX2-positive, CK20-positive, CK7-negative) may benefit from chemotherapy regimens used for treatment of metastatic colorectal cancer (e.g., fluorouracil/folinic acid with oxaliplatin [FOLFOX or FLOX] or irinotecan [FOLFIRI], with or without bevacizumab).[2][15][55]​ See Colorectal cancer.

Plus – supportive care

Back
ACUTE
|
multiple metastases: adenocarcinoma with colorectal immunohistochemistry (likely primary: colorectal cancer)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

multiple metastases: poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years

1st line – testicular cancer management protocol

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ACUTE
|
multiple metastases: poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years
1st line – 

testicular cancer management protocol

These patients should be assessed for germ cell tumours (using alpha-fetoprotein [AFP] and beta-human chorionic gonadotrophin [hCG] serum tumour markers).​[3][15]​ Male patients should be considered for testicular ultrasound, particularly if tumour markers are elevated, and primarily treated with curative intent with a cisplatin-based regimen (e.g., bleomycin, etoposide, cisplatin [BEP]).[15] See Testicular cancer.

Historically, many patients with poorly differentiated carcinoma with midline distribution actually had extragonadal germ cell tumours. European guidelines, therefore, suggest that the poorly differentiated carcinoma with midline distribution subtype should no longer be used.[2]

Plus – supportive care

Back
ACUTE
|
multiple metastases: poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

blastic bone metastases with immunohistochemistry/serum prostate-specific antigen (likely primary: prostate cancer)

1st line – prostate cancer management protocol

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ACUTE
|
blastic bone metastases with immunohistochemistry/serum prostate-specific antigen (likely primary: prostate cancer)
1st line – 

prostate cancer management protocol

Blastic bone metastases in older men (aged ≥40 years) with elevated prostate-specific antigen (PSA) are most likely to be prostate carcinoma. Treatment with androgen deprivation therapy (with or without radiotherapy), or other treatments appropriate for newly diagnosed prostate cancer, should be administered.[3]​ See Prostate cancer.

Plus – supportive care

Back
ACUTE
|
blastic bone metastases with immunohistochemistry/serum prostate-specific antigen (likely primary: prostate cancer)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

single metastatic lesion

1st line – definitive local therapy

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ACUTE
|
single metastatic lesion
1st line – 

definitive local therapy

Patients presenting with a single metastatic lesion of unknown primary site are rare, and treatment should be individualised. However, the general consensus is to consider definitive local therapy, usually surgical; definitive radiotherapy may be appropriate depending on anatomical location.[2][15]​ Adjuvant chemotherapy may be considered to control metastatic foci that are not yet evident.[3]

Common sites of solitary lesions include the liver, adrenal gland, brain, and bone. Treatment varies depending on suspected primary. Cytokeratin staining and other immunohistochemical markers assist in determining the likely primary site of the tumour and thus the best treatment option. A chemotherapeutic regimen with broad activity across tumour types (encompassing most likely sites of disease, such as occult lung carcinoma, or gastrointestinal tumours) is often preferred.

Plus – supportive care

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ACUTE
|
single metastatic lesion
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

oligometastatic disease

1st line – ablative surgery and/or radiotherapy

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ACUTE
|
oligometastatic disease
1st line – 

ablative surgery and/or radiotherapy

European guidelines suggest that selected patients with oligometastatic disease may be managed using local ablative surgery and/or radiotherapy.[2][56]​​​ Candidate patients should satisfy the following criteria: local ablative treatment of all lesions by surgery and/or radiotherapy is deemed feasible; oligometastatic state has been confirmed by imaging including positron emission tomography/computed tomography and brain magnetic resonance imaging; number of metastases does not exceed five; no involvement of a diffuse organ, such as malignant pleural, peritoneal, or leptomeningeal carcinomatosis.[2]

Median event-free and overall survival of 15.6 months and 52.5 months, respectively, has been reported following local ablative treatment of single-site and oligometastatic carcinoma of unknown primary.[56]

Plus – supportive care

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ACUTE
|
oligometastatic disease
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.

Pain-control strategies can differ based on the site and character of pain.

Bone pain: typically requires treatment with a non-steroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.

Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

Local pain: can be treated with regional nerve blocks or radiotherapy.

Obstructive symptoms: are related to tumour mass or localised inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multi-disciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiotherapy, and medicines as appropriate.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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