Cancer of Unknown Primary Treatment Protocols

Treatment protocols for cancer of unknown primary (CUP) are provided below, including treatment for metastasis to cervical lymph nodes, in women with isolated axillary adenopathy, for metastatic melanoma to a single nodal site, and for cancer of unknown primary in unselected patients, as well as common chemotherapeutic agents in clinical practice. ^[1]

General treatment recommendations

See the list below:

• Chemotherapy for patients with cancer of unknown primary is aimed at prolonging survival and relieving any related symptoms.

• Chemotherapy should be considered for patients who are symptomatic or for asymptomatic patients with an aggressive cancer and should be based on the histologic type of the cancer. ^[2]

• Patients in whom combination therapy fails may benefit from single-agent treatment with gemcitabine, with median time to progression of 5mo.

• Patients with cancer of unknown primary should always be offered a clinical trial as an option for treatment.

• in some cases, determination of somatic mutations might be helpful, especially with the approval of tumor-agnostic drugs such as programmed death 1 inhibitors and neurotrophic kinase receptor inhibitors as treatment options. ^{[3, 4, 5, 6, 7, 8]}

Adenocarcinoma of unknown primary origin treatment recommendations

Adenocarcinomas respond to cisplatin-based combination chemotherapy. However, various studies have shown that treatment with carboplatin, gemcitabine, irinotecan, and docetaxel have also been effective. ^{[2, 9, 10, 11]}

Paclitaxel and carboplatin:

• Paclitaxel 175-200 mg/m ² IV infusion over 1h on Day 1 
• Carboplatin area under the curve (AUC) 5-6 on Day 1 (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator)
• Repeat cycle every 21d

Paclitaxel, carboplatin, and etoposide:

• Paclitaxel 175–200 mg/m ² IV on Day 1 
• Carboplatin AUC 5–6 IV on Day 1 
• Etoposide 50 mg/d PO alternating with 100 mg/d PO on Days 1–10
• Repeat cycle every 21d for 2-3 cycles, then restage (patients are often treated with 6 cycles up to best response or up to dose-limiting toxicities)

Docetaxel and carboplatin:

• Docetaxel 65 mg/m ² IV on Day 1 
• Carboplatin AUC 5-6 on Day 1
• Repeat cycle every 21d

Gemcitabine and cisplatin:

• Gemcitabine 1000–1250 mg/m ² IV on Days 1 and 8
• Cisplatin 75 mg/m ² IV on Day 1
• Repeat cycle every 21d

Gemcitabine and docetaxel:

• Gemcitabine 1000 mg/m ² IV on Days 1 and 8
• Docetaxel 75 mg/m ² IV on Day 8
• Repeat cycle every 21d

CapeOX:

• Oxaliplatin 130 mg/m ² IV on Day 1
• Capecitabine 850–1000 mg/m ² PO twice daily on Days 1–14
• Repeat cycle every 21d

mFOLFOX6:

• Oxaliplatin 85 mg/m ² IV on Day 1
• Leucovorin 400 mg/m ² IV on Day 1
• Fluorouracil  (5FU) 400 mg/m ² IV bolus on Day 1, then 1200 mg/m ²/d IV continuous infusion x 2 days (total 2400 mg/m ² over 46–48 hours)
• Repeat cycle every 2wk

Docetaxel and cisplatin:

• Docetaxel 75 mg/m ² IV on Day 1
• Cisplatin 75 mg/m ² IV on Day 1
• Repeat cycle every 3wk

Irinotecan and carboplatin:

• Irinotecan  60 mg/m ² IV on Days 1, 8, and 15
• Carboplatin AUC 5–6 IV on Day 1
• Repeat cycle every 4wk

Irinotecan and gemcitabine:

• Irinotecan 100 mg/m ² IV on Days 1 and 8
• Gemcitabine 1000 mg/m ² IV on Days 1 and 8
• Repeat cycle every 3wk

FOLFIRI:

• Irinotecan 180 mg/m ² IV on Day 1
• Leucovorin 400 mg/m ² IV infusion to match duration of irinotecan infusion on Day 1
• 5FU 400 mg/m ² IV bolus on Day 1, then 1200 mg/m ²/d x 2 days (total 2400 mg/m ² over 46–48 hours) continuous infusion
• Repeat every 2wk

Other regimen

Combination therapy with bevacizumab, erlotinib, paclitaxel, and carboplatin has been evaluated, showing activity as first-line therapy in previously untreated patients; response rate, progression-free survival time, and overall survival time achieved with this regimen are among the best reported to date in the first-line treatment of cancer with unknown primary; however, more data are needed. ^[12]

Squamous cell carcinoma of unknown primary origin treatment recommendations

Treatments that include platinum-based chemotherapy are used in patients with squamous cell carcinoma. The most commonly used chemotherapeutic agents are 5-FU and cisplatin. Alternatively, docetaxel has also been used in combination with cisplatin. ^{[2, 9, 10, 11]}

Paclitaxel and carboplatin:

• Paclitaxel 175–200 mg/m ² IV on Day 1
• Carboplatin AUC 5–6 IV on Day 1
• Repeat cycle every 3wk

Cisplatin and gemcitabine:

• Cisplatin 75 mg/m ² IV on Day 1
• Gemcitabine 1000–1250 mg/m ² IV on Days 1 and 8
• Repeat cycle every 3wk

mFOLFOX6:

• Oxaliplatin 85 mg/m ² IV on Day 1
• Leucovorin 400 mg/m ² IV on Day 1
• 5FU 400 mg/m ² IV bolus on Day 1, then 1200 mg/m ²/d IV continuous infusion x 2 days (total 2400 mg/m ² over 46–48 hours)
• Repeat cycle every 2wk

Docetaxel, cisplatin, and fluorouracil:

• Docetaxel 75 mg/m ² IV on Day 1
• Cisplatin 75 mg/m ² IV on Day 1
• 5FU 750 mg/m ²/d IV continuous infusion on Days 1–5
• Repeat cycle every 3 wk

Paclitaxel and cisplatin:

• Paclitaxel 175 mg/m ² IV on Day 1
• Cisplatin 60 mg/m ² IV on  Day 1
• Repeat cycle every 3wk

Docetaxel and carboplatin:

• Docetaxel 75 mg/m ² IV on Day 1
• Carboplatin AUC 5–6 IV on Day 1
• Repeat cycle every 3wk

Docetaxel and cisplatin:

• Docetaxel 60 or 75 mg/m ² IV on Day 1
• Cisplatin 75 mg/m ² IV on Day 1
• Repeat cycle every 3wk

Cisplatin and fluorouracil:

• Cisplatin 20 mg/m ² IV on Days 1–5
• 5FU 700 mg/m ²/d IV continuous infusion on Days 1–5
• Repeat cycle every 4wk

Regimens for Other Conditions

Neuroendocrine tumors

Poorly differentiated neuroendocrine tumors are generally responsive to combination chemotherapy. Commonly used chemotherapeutic agents include paclitaxel, etoposide, and platinum agents. ^{[2, 9, 10, 11]} One regimen is as follows ^[13] :

• Etoposide 100 mg/m ² every day for 3d plus
• Cisplatin 45 mg/m ² on days 2-3 as a continuous IV infusion
• Repeated every 4wk

Metastasis to cervical lymph nodes:

• Radical radiation therapy with curative intent is administered to the neck and possible site of origin
• Preoperative radiation therapy is followed by radical neck dissection
• Radical neck dissection is followed by radiation to possible sites of origin ^[14]

Isolated axillary adenopathy in women:

• Currently, management is based on the guidelines for stage II breast cancer ^[15]
• Modified radical mastectomy with axillary node dissection has been advocated
• When these patients are treated with local excision or as having primary breast cancer, 50% of patients achieve 2-10y survival

Metastatic melanoma to a single nodal site:

• Five percent of patients with malignant melanoma may present with nodal metastasis in the absence of a documented primary site; these patients should be treated with radical lymph node dissection

Inguinal node metastasis:

• Treatment can involve groin dissection alone or with radiation and chemotherapy
• Some patients may benefit from local excision with or without radiation therapy

Various molecular panels are available for the clinician to use to help determine the primary cancer. ^[2] If the clinician believes this will help in tailoring the treatment for the patient, then those panels should be ordered. Such tests might show that a tumor is sensitive to a drug that does not make sense based on clinical findings; in such cases, it is important to use the best clinical judgement to treat the patient. How best to use this testing is still evolving at this time.

Microsatellite instability high or mismatch repair deficient

Pembrolizumab or nivolumab, or ipilumimab plus nivolumab  is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR). Regimens are as follows:

• Nivolumab 240 mg IV every 2wk or 480 mg every 4wk
•  Nivolumab 1 mg/kg over 30 min plus ipilumimab 3 mg/kg IV over 90 min
• Pembrolizumab 200 mg IV every 3wk

Tumor-agnostic therapy

Entrectinib and larotrectinib are approved for treatment of solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no alternative treatments or have progressed following treatment. Regimens are as follows:

• Entrectinib 600 mg PO qDay; continue until disease progression or unacceptable toxicity
• Larotrectinib 100 mg PO BID; continue until disease progression or until unacceptable toxicity