Cancer of Unknown Primary Treatment Protocols 

Updated: Sep 13, 2019
  • Author: Winston W Tan, MD, FACP; Chief Editor: Wafik S El-Deiry, MD, PhD  more...
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Treatment Protocols

Treatment protocols for cancer of unknown primary 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

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, 3, 4, 5]

Paclitaxel and carboplatin:

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. [6]

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, 3, 4, 5]

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, 3, 4, 5] One regimen is as follows [7] :

  • 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 [8]

Isolated axillary adenopathy in women:

  • Currently, management is based on the guidelines for stage II breast cancer [9]
  • 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.