eMedicine Specialties > Oncology > Special Topics in Oncology
Metastatic Cancer, Unknown Primary Site: Treatment & Medication
Updated: Mar 4, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
The treatment of cancer of unknown primary origin continues to evolve.15,16 The most common scenario is a patient with progressive, metastatic adenocarcinoma with multiple organ involvement.17 The treatment of this group of patients remains suboptimal.
The overall prognosis of patients with cancer of unknown primary origin with multiple organ involvement and poor performance status is grave; the median survival is only 3-4 months. The 1-year survival rate is less than 15%, with a 5-year survival of 5-10%. Certain clinical factors, like male sex, multiple brain metastases, pleural/lung involvement, liver involvement, adrenal involvement, and adenocarcinoma histology are poor prognostic markers. Others, like lymph node involvement and neuroendocrine histology, are associated with a longer survival.
In contrast, some favorable subsets have been identified that respond well to certain specific treatment strategies. These are discussed below.
Metastasis to cervical lymph nodes
A histologic diagnosis of metastatic carcinoma in the cervical nodes warrants a careful evaluation of the upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus. Most of these tumors are squamous cell carcinoma on histology, but adenocarcinoma, melanoma, or anaplastic tumors can also be seen in this location. In patients with squamous or undifferentiated carcinoma, tonsillectomies should be considered.18 Cervical adenopathy can be the primary disease manifestation in 2-5% of patients with primary squamous cell carcinoma of the head and neck region. In the absence of localization of a primary site, aggressive local therapy is indicated. This may involve any of the following:
- Radical radiation therapy with curative intent to the neck and possible site of origin
- Preoperative radiation therapy followed by radical neck dissection
- Radical neck dissection
- Radical neck dissection followed by radiation to possible sites of origin
Five-year survival rates as high as 30-50% have been achieved with this approach. Role of chemotherapy is debated. One randomized study showed improved response rate and median survival with cisplatin and 5-fluorouracil—based chemotherapy when compared to radiation alone. A single adenocarcinoma-involved lymph node in either the cervical or inguinal areas with no evidence of disease elsewhere may be managed with surgical excision alone and watchful expectation.19 Radiation therapy to the involved and local fields may be provided as well. Combination therapy may be superior to monotherapy with 5-year survival rates of 35% reported.
Patients with cervical nodes metastases from squamous cell carcinoma from cancer of unknown primary have an overall survival comparable to that of patients with known primary. In a retrospective study of 89 patients cancer of unknown primary treated with curative intent at a single institution, Mistry et al showed that the overall 5-year and 8-year survival rates were 55% and 51%, respectively. All patients were treated with surgery, and 70 patients received more than 40 Gy postoperative radiotherapy.20
Isolated axillary adenopathy in women
Metastatic adenocarcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer.2 Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70% cases. Immunohistochemical stains with estrogen and progesterone receptor should be performed in this setting, as they may aid in diagnosis.
Modified radical mastectomy with axillary node dissection has been advocated. A study with 42 patients, however, showed improved survival with systemic chemotherapy and improved local control with breast and axillary radiation. When these patients are treated with local excision or as having primary breast cancer, 50% of patients achieve 2-10 year survival. Currently, management is based on the guidelines for stage II breast cancer.
See related CME at Poorly Differentiated Carcinoma of Unknown Primary Involving the Axilla and Advances in the Treatment of Metastatic Breast Cancer.
Peritoneal carcinomatosis in women
Women with peritoneal carcinomatosis with adenocarcinoma have similarities with patients with ovarian cancer. They often have papillary histology with elevation of CA 125 and a good response to platinum-based chemotherapy, but a primary tumor is not revealed on exploratory laparotomy.
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. They should be treated with radical lymph node dissection. Survival, surprisingly, is slightly better than that for stage II melanoma in patients with a known primary site.
Poorly differentiated and undifferentiated carcinoma
One third of patients with cancer of unknown primary origin have poorly or undifferentiated carcinoma. A subpopulation of these can be potentially curable. This subgroup includes patients with lymphomas, germ cell tumors, or neuroendocrine tumors. The features that point toward a treatment-responsive tumor include the following:
- Patient younger than 50 years
- Midline distribution, with elevated levels of beta-HCG or AFP
- Beta-HCG/AFP positive on immunohistochemistry
- Neuroendocrine granules
- Rapid tumor growth
- Iso-chromosome 12p in midline tumors
Platinum-based combination chemotherapy regimens specific for germ cell tumors have been employed in these patients with a response rate of 63%, a complete response rate of 26%, and a 10-year survival rates of 16%.
Poorly differentiated neuroendocrine carcinomas
These tumors are characterized by positive histochemical stains for chromogranin or neuron-specific enolase. These patients often present with extensive liver or bone metastases. In a series of 29 patients, 19 were treated with intensive cisplatin-based chemotherapy, and 6 others received doxorubicin-based combinations. Complete responses were achieved in 6 patients, and 4 of these patients were alive 19-100 months after diagnosis.
Inguinal node metastasis
Metastatic carcinoma in inguinal nodes from an unknown site can be found in 1-3.5% of patients. Squamous cell histology in this area is usually metastatic from the genital/anorectal area. The anorectal area should be carefully inspected in both sexes. Vulvar, vaginal, and cervical examination in women and penile examination in men is warranted. Treatment can involve groin dissection alone or with radiation and chemotherapy. In some patients, local excision with or without radiation may be adequate.
Cancer of unknown primary origin in unselected patients
The results from the favorable patient subsets do not apply to most of the patients with cancer of unknown primary origin. The most effective chemotherapy regimens for this group of patients involve combination therapy with a platinum compound (cisplatin or carboplatin) and a taxane (preferably paclitaxel). This combination gives a response rate of about 12-26% and a median survival of 5-7 months. Triple drug therapy does not appear to offer any additional benefit.
Docetaxel and carboplatin chemotherapy was found to be convenient, safe and effective outpatient palliative treatment for CUP. Pentheroudakis et al, in a phase II study of one hour infusion of docetaxel 75 mg/m2 and carboplatin AUC of 5 (30 min each) every 3 weeks, treated 47 patients with CUP. A median of 6 cycles were given, response rate was 32% (46% for favorable risk, 17% for unfavorable risk), and granulocyte colony stimulating factor support was used in a third of the patients. Toxicity was mild including grade 3-4 neutropenia (26%), febrile neutropenia (7%), and severe nonhematologic side effects in fewer than 8% of patients. Median time to progression and overall survival were 5.5 and 16.2 months, respectively. (Survival in the favorable risk was 22.6 months; visceral metastases had poor median survival 5.3 months.)
Patients in whom combination therapy fails may benefit from single-agent treatment with gemcitabine with median time to progression of 5 months. A recent phase II clinical trial with bevacizumab and erlotinib has given a median survival of 7-8 months with 33% of patients alive at 1 year.21 A confirmation and extension of this trial is anticipated within the next 1-2 years.
Newer agents, like sorafenib, bevacizumab, antineoplaston, CS-1008 (humanized anti-CD-5 antibody), BMS-690514, and ZD1839, are currently being tested in various clinical trials. Also, combinations of older drugs like capecitabine, carboplatin with weekly paclitaxel, and oxaliplatin with capecitabine are being evaluated in this group of patients.
Insights into the molecular biology of carcinoma of unknown primary (CUP) are needed for the development of targeted therapeutic approaches to the treatment of these patients.
Surgical Care
See Medical Care.
Medication
The goals of pharmacotherapy are to induce remission, prevent complications, and reduce morbidity. See Medical Care.
Antineoplastic Agents
These agents inhibit cell growth and differentiation.
Paclitaxel (Abraxane, Taxol)
Mechanisms of action are tubulin polymerization and microtubule stabilization, which in turn inhibits mitosis and may result in breakage of chromosomes.
Adult
175 mg/m2 IV over 3 h q3wk or 135 mg/m2 IV over 24 h q3wk
Pediatric
Not established
Coadministration with cisplatin may further increase myelosuppression
Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Premedicate with steroids, H1, and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmia may occur
Carboplatin (Paraplatin)
Analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.
Has same efficacy as cisplatin but with better toxicity profile. Main advantages over cisplatin include less nephrotoxicity and ototoxicity not requiring extensive prehydration, less likely to induce nausea and vomiting, but more likely to induce myelotoxicity.
Dose is based on the following formula: total dose (mg) = (target AUC) x (GFR+25) where AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR (glomerular filtration rate) is expressed in mL/min.
Adult
Combination therapy: 300 mg/m2 q4wk
Pediatric
Not established
Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
Documented hypersensitivity; bone marrow suppression
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Monitor bone marrow function
More on Metastatic Cancer, Unknown Primary Site |
| Overview: Metastatic Cancer, Unknown Primary Site |
| Differential Diagnoses & Workup: Metastatic Cancer, Unknown Primary Site |
 Treatment & Medication: Metastatic Cancer, Unknown Primary Site |
| Follow-up: Metastatic Cancer, Unknown Primary Site |
| References |
| « Previous Page | Next Page » |
References
American Cancer Society. Statistics for 2007. American Cancer Society Statistics. Available at http://www.cancer.org/docroot/stt/stt_0.asp. Accessed July 11, 2007.
Copeland EM, McBride CM. Axillary metastases from unknown primary sites. Ann Surg. Jul 1973;178(1):25-7. [Medline].
Merson M, Andreola S, Galimberti V, et al. Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer. Jul 15 1992;70(2):504-8. [Medline].
Davidson BJ, Spiro RH, Patel S, et al. Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg. Nov 1994;168(5):395-9. [Medline].
Levine MN, Drummond MF, Labelle RJ. Cost-effectiveness in the diagnosis and treatment of carcinoma of unknown primary origin. CMAJ. Nov 15 1985;133(10):977-87. [Medline].
Maisey MN, Ellam SV. Investigating the adenocarcinoma of unknown origin (ACUP): a cost benefit analysis. Rev Epidemiol Sante Publique. 1984;32(1):57-61. [Medline].
Schapira DV, Jarrett AR. The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary carcinoma. Arch Intern Med. Oct 23 1995;155(19):2050-4. [Medline].
Kole AC, Nieweg OE, Pruim J, et al. Detection of unknown occult primary tumors using positron emission tomography. Cancer. Mar 15 1998;82(6):1160-6. [Medline].
Battifora H. Recent progress in the immunohistochemistry of solid tumors. Semin Diagn Pathol. Nov 1984;1(4):251-71. [Medline].
Motzer RJ, Rodriguez E, Reuter VE, et al. Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol. Jan 1995;13(1):274-82. [Medline].
Feinmesser R, Miyazaki I, Cheung R, et a;. Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med. Jan 2 1992;326(1):17-21. [Medline].
Bosl GJ, Ilson DH, Rodriguez E, et al. Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst. Mar 2 1994;86(5):349-55. [Medline].
Sandberg AA, Meloni AM, Suijkerbuijk RF. Reviews of chromosome studies in urological tumors. III. Cytogenetics and genes in testicular tumors. J Urol. May 1996;155(5):1531-56. [Medline].
Garrow GC, Greco FA, Hainsworth JD. Poorly differentiated neuroendocrine carcinoma of unknown primary tumor site. Semin Oncol. Jun 1993;20(3):287-91. [Medline].
Hainsworth JD, Greco FA. Treatment of patients with cancer of an unknown primary site. N Engl J Med. Jul 22 1993;329(4):257-63. [Medline].
Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer. Sep 2003;39(14):1990-2005. [Medline].
Moertel CG, Reitemeier RJ, Schutt AJ, et al. Treatment of the patient with adenocarcinoma of unknown origin. Cancer. Dec 1972;30(6):1469-72. [Medline].
Righi PD, Sofferman RA. Screening unilateral tonsillectomy in the unknown primary. Laryngoscope. May 1995;105(5 Pt 1):548-50. [Medline].
Guarischi A, Keane TJ, Elhakim T. Metastatic inguinal nodes from an unknown primary neoplasm. A review of 56 cases. Cancer. Feb 1 1987;59(3):572-7. [Medline].
Mistry RC, Qureshi SS, Talole SD, et al. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary: Outcomes and patterns of failure. Indian J Cancer. Apr-Jun 2008;45(2):54-8. [Medline].
Hainsworth JD, Spigel DR, Farley C, et al. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol. May 1 2007;25(13):1747-52. [Medline].
Abbruzzese JL, Abbruzzese MC, Lenzi R, et al. Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol. Aug 1995;13(8):2094-103. [Medline].
Altman E, Cadman E. An analysis of 1539 patients with cancer of unknown primary site. Cancer. Jan 1 1986;57(1):120-4. [Medline].
Greco FA, Hainsworth JD. Cancer of unknown primary site. In: De Vita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice. 2005:2213-34.
Hainsworth JD, Erland JB, Kalman LA, et al. Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol. Jun 1997;15(6):2385-93. [Medline].
Hainsworth JD, Johnson DH, Greco FA. Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol. Jun 1992;10(6):912-22. [Medline].
Hess KR, Abbruzzese MC, Lenzi R, et al. Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res. Nov 1999;5(11):3403-10. [Medline].
Montero AJ, Varadhachary GR, Abbruzzese JL. Unknown Primary Carcinomas. In: Kantarjian HN, Koller CM, Wolff RA. MD Anderson Manual of Medical Oncology. McGraw Hill; 2006:937-954.
Neumann KH, Nystrom JS. Metastatic cancer of unknown origin: nonsquamous cell type. Semin Oncol. Dec 1982;9(4):427-34. [Medline].
Panagopoulos E, Murray D. Metastatic malignant melanoma of unknown primary origin: a study of 30 cases. J Surg Oncol. May 1983;23(1):8-10. [Medline].
Pavlidis N, Fizazi K. Cancer of unknown primary (CUP). Crit Rev Oncol Hematol. Jun 2005;54(3):243-50. [Medline].
Reintgen DS, McCarty KS, Woodard B, et al. Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet. Mar 1983;156(3):335-40. [Medline].
Ringenberg QS. Tumors of unknown origin. Med Pediatr Oncol. 1985;13(5):301-6. [Medline].
Further Reading
Keywords
metastatic cancer review article, cancer metastasis, metastases, cancer treatment, cancer diagnosis, cancer of unknown primary, CUP, carcinoma of unknown primary, tumor of unknown primary, cancer of unknown origin, carcinoma of unknown origin, unknown primary cancer, unknown primary carcinoma, metastatic carcinoma, metastatic tumor, occult primary malignancy
