Cancer of unknown primary site represents approximately 3% to 5% of all new cancer diagnoses. Adenocarcinomas account for 60% of all unknown primary cancers and poorly differentiated carcinomas or adenocarcinomas, for 30%. Historically, the prognosis for most patients with unknown primary tumors has been poor, with survival often less than 6 months from diagnosis. Recent advances in diagnostic techniques, including immunocytochemical and molecular genetic methods, have increased the probability of identifying a likely underlying tumor type. Based on clinical and pathologic features, approximately 40% of patients can be categorized within subsets for which specific treatment has been defined. Empiric therapy is an option for the remaining 60% of patients. In these patients, favorable prognostic factors for treatment response include tumor location in lymph nodes, fewer sites of metastases, younger age, and poorly differentiated carcinoma histology. Although experience remains limited, the incorporation of a taxane into empiric regimens appears to improve response rates and survival. A recent study of paclitaxel (Taxol), carbo-platin (Paraplatin), and etoposide in 55 patients with cancer of unknown primary site reported an overall response rate of 47% and a median overall survival of 13.4 months. Investigations continue to explore new diagnostic techniques and novel therapeutic approaches. [ONCOLOGY 14(4);563-575, 2000]
Management of Specific Patient Subsets
Approximately 40% of all patients with unknown primary cancer fit into a defined patient subset with specific treatment implications (Figure 1). Most of these patient groups are easily recognized after a routine clinical and pathologic evaluation.
Women With Adenocarcinoma in Axillary Lymph Nodes—Women with axillary adenopathy containing metastatic adenocarcinoma should receive treatment according to the guidelines for breast cancer. Patients in whom the axillary nodes are the only identifiable site of disease have a substantial chance for long-term survival. Positive immunoperoxidase staining for estrogen and/or progesterone receptors provides further evidence for the diagnosis of breast cancer. Even when a breast examination and mammography are unrevealing, a mastectomy will identify an occult breast primary in approximately 60% of patients.
Primary treatment should include either modified radical mastectomy or axillary node dissection plus radiation therapy to the breast.[17,18] Adjuvant treatment should follow the standard guidelines for the treatment of stage II breast cancer, based on the number of lymph nodes involved, estrogen receptor status, and patient age.
Women With Peritoneal Carcinomatosis—Women with adenocarcinoma or poorly differentiated carcinoma involving the peritoneal surfaces should be treated according to the guidelines for stage III ovarian cancer. In many of these women, histologic features resemble those of ovarian cancer, including papillary or serous cystadenocarcinoma features. This syndrome has been reported in women who have histologically normal ovaries or who have undergone a previous oophorectomy. Serum CA-125 levels are usually elevated.
Optimal treatment for women with peritoneal carcinomatosis is identical to that currently recommended for those with advanced ovarian cancer; namely, initial laparotomy with maximal surgical cytoreduction followed by chemotherapy with paclitaxel (Taxol) and a platinum agent,[20,21] Several series report the 5-year survival rate in this patient group to be from 15% to 25%.[22-26] This syndrome has also been reported in men.
Men With Osteoblastic Bone Metastases and/or Elevated PSA—All men with metastatic adenocarcinoma and elevated serum PSA levels, or positive tumor staining for PSA, should be treated for advanced prostate cancer. Responses to hormonal therapy have been documented in such patients, even when sites of metastases were atypical for prostate cancer (eg, mediastinal adenopathy, lung metastases).[28,29] Consideration should also be given to a trial of hormonal therapy in men with predominantly blastic bone metastases, even if their serum PSA level is normal.
Patients With a Single Metastatic Lesion—In some patients, only one metastatic lesion can be found, even after a complete staging evaluation. Many locations of such lesions have been reported, including lymph nodes, liver, lung, adrenal gland, brain, or bone. The possibility of a primary cancer in an unusual site, rather than a metastasis, should always be considered (eg, apocrine, eccrine, or sebaceous carcinoma presenting as skin or subcutaneous lesions; a single liver “metastasis” actually representing a hepatoma).
Treatment in this group of patients should include definitive local therapy, using surgical resection, radiation, or the two modalities combined, based on the location of the single metastasis. Many patients have a substantial disease-free interval before other metastatic lesions develop, and occasional patients enjoy long-term survival.[30,31]
The role of systemic chemotherapy, in addition to local therapy, in patients with a single metastatic lesion is undetermined. We have empirically added chemotherapy to the treatment of patients with poorly differentiated carcinomas.
Squamous Cell Cancer Involving Cervical Nodes—In most patients with squamous cell cancer presenting in cervical lymph nodes, a primary site located in the head and neck can be found after a careful endoscopic examination of the head and neck areas (ie, nasopharynx, oropharynx, hypopharynx, and larynx). Squamous cell lung cancer should be suspected in patients with involvement of low cervical or supraclavicular lymph nodes, and bronchoscopy should be considered.
In approximately 15% of patients, no primary site can be identified. In these patients, treatment should follow the guidelines for locally advanced head and neck cancers.
Recently, concurrent chemotherapy plus radiation therapy has improved treatment results in patients with locally advanced head and neck cancers.[32,33] These treatment programs should also be considered in patients with cervical adenopathy and no identified primary site.
Even with local treatment modalities alone (radiation with or without radical neck dissection), 5-year survival rates of 30% to 60% have been reported in this patient group.[34-36] As in patients with known head and neck cancers, the prognosis depends on the extent of cervical adenopathy.[37,38]
Squamous Cell Cancer Involving Inguinal Nodes—In most patients presenting with squamous cell cancer in the inguinal nodes, an evaluation of the perineal structures will reveal a primary site. All patients should undergo sigmoidoscopy; female patients should have careful pelvic examinations, with colposcopy. Cystoscopy should also be considered.
If no primary site is identified, treatment should include inguinal node dissection. Patients with extensive nodal involvement should be considered for radiation therapy. About 25% of patients have prolonged survival after definitive local therapy. The role of systemic therapy in this patient subset is undefined. However, with the now firmly established roles of combined-modality treatment in cancers of the cervix and anus, systemic therapy with platinum-based regimens should be considered.
Young Men With Features of Extragonadal Germ-Cell Tumors—Young men with poorly differentiated carcinoma involving the mediastinum or retroperitoneum should be treated according to the guidelines for extragonadal germ-cell tumors. Many of these patients will have elevated serum levels of HCG or AFP.
Molecular genetic analysis can establish a definitive diagnosis in some of these patients by identifying the pathognomonic I (12p) chromosomal abnormality. The recent development of a genomic hybridization technique that can detect extra 12p material using paraffin-embedded tissue specimens may make this procedure more clinically applicable by avoiding the need to obtain fresh tissue by rebiopsy. Treatment with four cycles of cisplatin (Platinol), etoposide, and bleomycin (Blenoxane) is curative in approximately 30% to 40% of these patients.
Patients With Poorly Differentiated Neuroendocrine Carcinoma—The diagnosis of neuroendocrine carcinoma has been improved by the routine availability of relatively specific immuno-peroxidase stains for chromogranin and synaptophysin. In some patients with neuroendocrine carcinoma, light microscopic features suggest the diagnosis; in others, the diagnosis is made solely on the basis of immunoperoxidase staining.
Patients in this group present with diverse clinical characteristics; however, these tumors share an aggressive biology and are usually sensitive to chemotherapy with platinum/etoposide combinations. In our experience, over 75% of patients had major responses, and long-term survival was achieved in 15% to 20% of patients. Recently, the combination of paclitaxel, carbo-platin (Paraplatin), and etoposide also showed marked activity in the treatment of these cancers.
Patients With Well-Differentiated Neuroendocrine Carcinoma—Most patients with well-differentiated neuroendocrine carcinoma have pathologic features of carcinoid or islet cell tumors, and most present with multiple liver metastases. As opposed to poorly differentiated neuroendocrine carcinomas, these tumors are relatively indolent and relatively unresponsive to systemic chemotherapy.
Management should follow the established guidelines for advanced carcinoid tumors. At times, observation is the best treatment approach, and patients with slow-growing tumors sometimes have prolonged survival with few symptoms. Treatment with somatostatin analogs, 5-FU–based chemotherapeutic regimens, or local treatment (eg, hepatic resection, hepatic artery embolization) may also be appropriate in some instances.
Patients With Poorly Differentiated Carcinoma—Management of the larger, more heterogeneous group of patients with poorly differentiated carcinoma of unknown primary site is a subject of some controversy. Our experience with a large group of these patients who were treated with regimens effective in the treatment of germ-cell neoplasms, is summarized in Table 3. In this group of patients, 26% of patients had a complete response to treatment, and 16% remain continuously disease free after a minimum follow-up of 8 years.[45,46] Some, but not all, of the patients with excellent responses had clinical features of extragonadal germ-cell tumor.
In a retrospective analysis of a large group of patients studied at the University of Texas M. D. Anderson Cancer Center, a subset of patients with poorly differentiated carcinoma achieving long-term survival could not be identified. However, treatment was not uniform in these patients, and the group who received the cisplatin/etoposide–based regimens used in our series was not large.
Several prognostic factors have been identified that are helpful in predicting favorable treatment outcome. These include tumor location in lymph nodes, fewer metastatic sites, younger patient age, female gender, and poorly differentiated carcinoma histology.[45,48,49]
1. Greco FA, Hainsworth JD: Cancer of unknown primary site, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th ed, pp 2423-2443. Philadelphia, Lippincott-Raven, 1997.
2. Hainsworth JD, Greco FA: Treatment of patients with cancer of an unknown primary site. N Engl J Med 329:257-263, 1993.
3. Karsell PR, Sheedy PF II, O’Connell MJ: Computed tomography in search of cancer of unknown origin. JAMA 248:340-343, 1982.
4. McMillan JH, Levine E, Stephens RH: Computed tomography in the evaluation of metastatic adenocarcinoma from an unknown primary site: A retrospective study. Radiology 143:143-146, 1982.
5. Daugaard G, Lassen U, Eigtved A, et al: Whole body positron emission tomography (PET) with FDG in patients with unknown primary tumors (UPT) (abstract). Proc Am Soc Clin Oncol 17:290a, 1998.
6. Kole AC, Nieweg OE, Pruim J, et al: Detection of unknown occult primary tumors using positron emission tomography. Cancer 82:1160-1166, 1988.
7. Schapira DV, Jarrett AR: The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary carcinoma. Arch Intern Med 155:2050-2054, 1995.
8. Daugaard G: Unknown primary tumours. Cancer Treat Rev 20:119-147, 1994.
9. Pavlidis N, Kalef-Ezra J, Briasoulis E, et al: Evaluation of six tumor markers in patients with carcinoma of unknown primary. Med Pediatr Oncol 22:162-167, 1994.
10. Currow DC, Findlay M, Cox K, et al: Elevated germ-cell markers in carcinoma of unknown primary site do not predict response to platinum-based chemotherapy. Eur J Cancer 32A:2357-2359, 1996.
11. Hammar SP: Metastatic adenocarcinoma of unknown primary origin. Hum Pathol 29:1393-1402, 1998.
12. Brown RW, Campagna LB, Dunn JK, et al: Immunohistochemical identification of tumor markers in metastatic adenocarcinoma: A diagnostic adjunct in the determination of primary site. Am J Clin Pathol 107:12-19, 1997.
13. Kaufman NO, Deidesheimer T, Muehlenberg M, et al: Immunohistochemical differentiation of metastatic breast carcinomas from metastatic adenocarcinomas of other common primary sites. Histopathology 29:233-240, 1996.
14. Lagendijk JH, Mullink H, Van Diest PJ, et al: Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry: Differential diagnosis between colonic and ovarian carcinomas as primary sites. Hum Pathol 29:491-497, 1998.
15. Tot T: Adenocarcinomas metastatic to the liver: The value of cytokeratins 20 and 7 in the search for unknown primary tumors. Cancer 85:171-177, 1999.
16. Nole F, Colleoni M, Buzzoni R, et al: Fluorouracil plus folinic acid in metastatic adenocarcinoma of unknown primary site suggestive of a gastrointestinal primary. Tumori 79:116-118, 1993.
17. Merson M, Andreola S, Galimberti V, et al: Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer 70:504-508, 1992.
18. Ellerbroek N, Holmes F, Singletary E, et al: Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 66:1461-1467, 1990.
19. Tobacman JK, Greene MH, Tucker MA, et al: Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian–cancer-prone families. Lancet 2:795-797, 1982.
20. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996.
21. Ozols RJ, Brundy BN, Fowler J, et al: Randomized phase III study of cisplatin/paclitaxel versus carboplatin/paclitaxel in optimal stage III epithelial ovarian cancer: A Gynecologic Oncology Group trial (GOG 158) (abstract). Proc Am Soc Clin Oncol18:356a, 1999.
22. Strnad CM, Grosh WW, Baxter J, et al: Peritoneal carcinomatosis of unknown primary site in women: A distinctive subset of adenocarcinoma. Ann Intern Med 111:213-217, 1989.
23. Ransom DT, Patel SR, Keeney GL, et al: Papillary serous carcinoma of the peritoneum: A review of 33 cases treated with cisplatin-based chemotherapy. Cancer 66:1091-1094, 1990.
24. Fromm GL, Gershenson DM, Silva EG: Papillary serous carcinoma of the peritoneum. Obstet Gynecol 75:89-95, 1990.
25. Bloss JD, Liao SY, Buller RE, et al: Extraovarian peritoneal serous papillary carcinoma: A case-controlled retrospective comparison to papillary adenocarcinoma of the ovary. Gynecol Oncol 50:347-351, 1993.
26. Piver MS, Eltabbakh GH, Hempling RE, et al: Two sequential studies for primary peritoneal carcinoma: Induction with weekly cisplatin followed by either cisplatin/doxorubicin/cyclophosphamide or paclitaxel/cisplatin. Gynecol Oncol 67:141-146, 1997.
27. Shah IA, Jayram L, Gani OS, et al: Papillary serous carcinoma of the peritoneum in a man: A case report. Cancer 82:860-866, 1998.
28. Gentile PS, Carloss HW, Huang TY, et al: Disseminated prostatic carcinoma simulating primary lung cancer: Indications for immunodiagnostic studies. Cancer 62:711-715, 1988.
29. Tell DT, Khoury JM, Taylor HG, et al: Atypical metastasis from prostate cancer: Clinical utility of the immunoperoxidase technique for prostate specific antigen. JAMA 253:3574-3575, 1985.
30. Nguyen LN, Maor MH, Oswald MJ: Brain metastases as the only manifestation of an undetected primary tumor. Cancer 83:2181-2184, 1998.
31. Salvati M, Cervoni L, Raco: A. Single brain metastases from unknown primary malignancies in CT-era. J Neurooncol 23:75-85, 1995.
32. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998.
33. Wendt TG, Grabenbauer GG, Rodel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol 16:1318-1324, 1998.
34. Jones AS, Cook JA, Phillips DE, et al: Squamous carcinoma presenting as an enlarged cervical lymph node. Cancer 72:1756-1761, 1993.
35. Carlson LS, Fletcher GH, Oswald MJ: Guidelines for radiotherapeutic techniques for cervical metastases from an unknown primary. Int J Radiat Oncol Biol Phys 12:2101-2110, 1986.
36. Reddy SP, Marks JE: Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: Results of bilateral neck plus mucosal irradiation vs ipsilateral neck irradiation. Int J Radiat Oncol Biol Phys 37:797-802, 1997.
37. Colletier PJ, Garden AS, Morrison WH, et al: Postoperative radiation for squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site: Outcomes and patterns of failure. Head Neck 20:674-681, 1998.
38. Fernandez JA, Suarez C, Martinez JA, et al: Metastatic squamous cell carcinoma in cervical lymph nodes from an unknown primary tumour: Prognostic factors. Clin Otolaryngol 23:158-163, 1998.
39. Guarischi A, Keane TJ, Elhakim T: Metastatic inguinal nodes from an unknown primary neoplasm: A review of 56 cases. Cancer 59:572-577, 1987.
40. 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 13:274-282, 1995.
41. Summersgill B, Goker H, Osin P, et al: Establishing germ-cell origin of undifferentiated tumors by identifying gain of 12p material using comparative genomic hybridization analysis of paraffin-embedded samples. Diagn Mol Pathol 7:260-266, 1998.
42. Hainsworth JD, Johnson DH, Greco FA: Poorly differentiated neuroendocrine carcinoma of unknown primary site: A newly recognized clinicopathologic entity. Ann Intern Med 109:364-371, 1998.
43. 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 15:2385-2393, 1997.
44. Moertel CG, Kvols LK, O’Connell MJ, et al: Treatment of neuroendocrine carcinomas with etoposide and cisplatin: Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227-232, 1991.
45. 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 10:912-922, 1992.
46. Greco FA, Thomas M, Hainsworth JD: Poorly differentiated carcinoma (PDC) or adenocarcinoma (PDA) of unknown primary site: Long-term follow-up after cisplatin-based chemotherapy (abstract). Proc Am Soc Clin Oncol 16:274a, 1997.
47. Lenzi R, Hess KR, Abbruzzese MC, et al: Poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown origin: Favorable subsets of patients with unknown primary carcinoma? J Clin Oncol 15:2056-2066, 1997.
48. Pavlidis N, Kosmidis P, Skarlos D, et al: Subsets of tumors responsive to cisplatin or carboplatin combinations in patients with carcinoma of unknown primary site: A Hellenic Cooperative Oncology Group study. Ann Oncol 3:631-634, 1992.
49. Abbruzzese JL, Abbruzzese MC, Hess KR, et al: Unknown primary carcinoma: Natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 12:1272-1280, 1994.
50. Moertel CG, Reitemeier RJ, Schutt AJ, et al: Treatment of the patient with adenocarcinoma of unknown origin. Cancer 30:1469-1472, 1972.
51. Wagener DJT, de Mulder PH, Burghouts JT, et al: Phase II trial of cisplatin for adenocarcinoma of unknown primary site: The IKZ/IKO Clinical Research Group Eur J Cancer 27:755-777, 1991.
52. Van der Gaast A, Henzen-Logmans SC, Planting AS, et al: Phase II study of oral administration of etoposide for patients with well- and moderately differentiated adenocarcinomas of unknown primary site. Ann Oncol 4:789, 1993.
53. Falkson CI, Cohen GL: Mitomycin C, epirubicin, and cisplatin versus mitomycin C alone as therapy for carcinoma of unknown primary origin. Oncology (Basel) 55(2):116-121, 1998.
54. Eagan RT, Therneau TM, Rubin J, et al: Lack of value for cisplatin added to mitomycin/doxorubicin combination chemotherapy for carcinoma of unknown primary site. Am J Clin Oncol 10:82-85, 1987.
55. Kambhus SA, Kelsen D, Niedzwiecki D, et al: Phase II trial of mitomycin C, vincristine, and Adriamycin and predictive variables in the treatment of patients with adenocarcinoma of unknown primary site (abstract). Proc Am Assoc Cancer Res 27:185, 1986.
56. Milliken ST, Tattersall MH, Woods RL, et al: Metastatic adenocarcinoma of unknown primary site: A randomized study of two combination chemotherapy regimens. Eur J Cancer Clin Oncol 23:1645-1648, 1987.
57. Woods RL, Fox RM, Tattersall MH, et al: Metastatic adenocarcinomas of unknown primary: A randomized study of two combination chemotherapy regimens. N Engl J Med 303:87-89, 1980.
58. Goldberg RM, Smith FP, Ueno W, et al: 5-fluorouracil, Adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Oncol 1986;4:395-399, 1986.
59. Sulkes A, Uziely B, Isaacson R, et al: Combination chemotherapy in metastatic tumors of unknown origin; 5-Fluorouracil, Adriamycin, and mitomycin C for adenocarcinoms and Adriamycin, vinblastine, and mitomycin for anaplastic carcinomas. Isr J Med Sci 24:604-610, 1988.
60. Treat J, Falchuk SC, Tremblay C, et al: Phase II trial of methotrexate-FAM (m-FAM) in adenocarcinoma of unknown primary. Eur J Cancer Clin Oncol 25:1053-1055, 1989.
61. Van der Gaast A, Verweij J, Planting AS, et al: 5-Fluorouracil, doxorubicin, and mitomycin C (FAM) combination chemotherapy for metastatic adenocarcinoma of unknown primary. Eur J Cancer Clin Oncol 24:765-768, 1988.
62. Anderson H, Thatcher N, Rankin E, et al: VAC (vincristine, Adriamycin, cyclophosphamide) chemotherapy for metastatic carcinoma from an unknown primary site. Eur J Cancer Clin Oncol 19:49-52, 1983.
63. de Campos ES, Menasce LP, Radford J, et al: Metastatic carcinoma of uncertain primary site: A retrospective review of 57 patients treated with vincristine, doxorubicin, cyclophosphamide, (VAC) or VAC alternating with cisplatin and etoposide (VAC/PE). Cancer 73:470-475, 1994.
64. Valentine J, Rosenthal S, Arseneau JC: Combination chemotherapy for adenocarcinoma of unknown primary origin. Cancer Clin Trials 2:265-268, 1979.
65. Jadega J, Legha S, Burgess M, et al: Combination chemotherapy with 5-FU, Adriamycin, cyclophosphamide, and cisplatin in the treatment of adenocarcinoma of unknown primary and undifferentiated carcinoma (abstract). Proc Am Soc Clin Oncol 2:926a, 1983.
66. Pasterz R, Savaraj N, Burgess M: Prognostic factors in metastatic carcinoma of unknown primary. J Clin Oncol 4:1652-1657, 1986.
67. Gill I, Guaglianone P, Grunberg SM, et al: High-dose intensity of cisplatin and etoposide in adenocarcinoma of unknown primary. Anticancer Res 11:1231-1235, 1991.
68. Liu JM, Chen YM, Chao Y, et al: Continuous-infusion cisplatin and etoposide chemotherapy for cancer of unknown primary site (CUPS) in Taiwan, a region with a high prevalence of endemic viral infections. Jpn J Clin Oncol 28:431-435, 1998.
69. Raber MN, Faintuch J, Abbruzzese JL, et al: Continuous-infusion 5-fluorouracil, etoposide and cis-diamminedichloroplatinum in patients with metastatic carcinoma of unknown primary origin. Ann Oncol 2:519-520, 1991.
70. Lenzi R, Abbruzzese J, Amato R, et al: Cisplatin, 5-fluorouracil and folinic acid for the treatment of carcinoma of unknown primary: A phase II study (abstract). Proc Am Soc Clin Oncol 10:301, 1991.
71. Karapetis CS, Yip D, Virik K, et al: The treatment of carcinoma of unknown primary with epirubicin, cisplatin, and 5-fluorouracil (ECF) (abstract). Proc Am Soc Clin Oncol18:642a, 1999.
72. Warner E, Goel R, Chang J, et al: A multicentre phase II study of carboplatin and prolonged oral etoposide in the treatment of cancer of unknown primary site (CUPS). Br J Cancer 77:2376-2380, 1998.
73. Briasoulis E, Tsavaris N, Fountzilas G, et al: Combination regimen with carboplatin, epirubicin and etoposide in metastatic carcinomas of unknown primary site: A Hellenic Cooperative Oncology Group phase II study. Oncology 55:426-430, 1998.
74. Pavlidis N, Kalofonos H, Bafaloukos D, et al: Cisplatin/Taxol combination chemotherapy in 72 patients with metastatic cancer of unknown primary site: A phase II trial of the Hellenic Cooperative Oncology Group (abstract). Proc Am Soc Clin Oncol 18:195a, 1999.
75. Barton J, Hainsworth JD, Calvert SW, et al: Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: Phase II trial of the Minnie Pearl Cancer Research Network (abstract). Proc Am Soc Clin Oncol 18:450a, 1999.
76. Hainsworth JD, Lennington WJ, Greco FA: Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. J Clin Oncol, February 2000 (in press).