Management of Patients With Cancer of Unknown Primary Site

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]

Introduction

Cancer of unknown primary site accounts for 3% to 5% of all cancer diagnoses.[1] This syndrome occurs with equal frequency in men and women and increases in incidence with advancing age. Numerous clinical presentations and histologic tumor characteristics are represented in this heterogeneous group of patients. Common sites of metastases include the liver, bone, lung, lymph nodes, pleura, and brain. The majority of patients have metastases present in two or more sites.[2] Patients are diagnosed with cancer of unknown primary site after an initial standard evaluation fails to identify a primary tumor site.

Historically, patients with an unknown primary tumor have responded poorly to empiric therapy, and median survival from diagnosis has usually been less than 8 months. The limited activity of early chemotherapeutic regimens and short median survival have contributed to clinical nihilism about patients with cancer of unknown primary site.

A number of patient subsets with specific treatment implications have now been described, however. These subsets, identified by specific clinical or pathologic criteria, account for approximately 40% of all patients with unknown primary tumors. In the remaining patients, recent studies of empiric taxane-containing therapies have produced higher response rates, and have probably extended survival. Ongoing evaluations of other new regimens and approaches to the treatment of cancer of unknown primary may result in additional treatment advances.

Diagnosis and Evaluation

Approximately 60% of patients with cancer of unknown primary site have well-differentiated or moderately well-differentiated adenocarcinoma. Poorly differentiated carcinomas or poorly differentiated adenocarcinomas are diagnosed in approximately 30% of patients. Squamous cell carcinomas and poorly differentiated neoplasms account for 5% of diagnoses. Clinical presentation, evaluation, prognosis, and treatment options differ for these four histologically distinct groups. The presence of specific clinical features or the use of specialized pathologic studies can identify subsets within these broad categories of patients who may benefit from tumor-specific therapy.

Clinical Evaluation

In most patients, the clinical evaluation, including the search for the primary site, should be brief and focused. A careful history should be taken and a complete physical examination should be performed (including pelvic and rectal examinations), with routine laboratory evaluation (hematologic and chemistry profiles), chest radiography, and computed tomography (CT) of the abdomen and pelvis.[2] Computed tomographic scans of the abdomen may identify a primary site in 10% to 35% of patients; CT scans may also locate additional sites of metastatic disease.[3,4] Tumors identified by CT scans of the abdomen and pelvis include those arising from the pancreas, kidney, hepatobiliary tract, and ovary.

Additional procedures (eg, radiologic imaging and/or endoscopic examinations) are warranted to evaluate specific presenting signs or symptoms. Positron emission tomography (PET), performed with fluorine-18-deoxyglucose, is a noninvasive technique that has identified primary sites in a few patients, although its role in the evaluation of patients with cancer of unknown primary site is incompletely defined.[5,6]

Certain additional diagnostic evaluations should be performed in specific patient subsets. For example, mammography should be performed in women with clinical features suggestive of metastatic breast cancer. All men with adenocarcinoma of unknown primary site should have their serum prostate-specific antigen (PSA) levels measured, as well as PSA staining of the biopsy specimen. Serum levels of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) should be measured in young men with poorly differentiated carcinoma.

The diagnostic yield of other additional diagnostic procedures is low[7,8] (Table 1) and can add considerable expense to the initial evaluation. Extensive radiologic or endoscopic investigations of asymptomatic areas are rarely useful in identifying a primary site.

Measurement of various commonly used serum tumor markers (eg, carcinoembryonic antigen [CEA], cancer antigen 15-3 [CA 15-3], cancer antigen 125 [CA-125], and cancer antigen 19-9 [CA 19-9]) also is not useful in providing clues to the location of the primary site. All of these markers are frequently elevated in patients with carcinoma of unknown primary site, and thus, provide no diagnostic or prognostic information.[9] Modest elevations of HCG or AFP (ie, levels of either marker < 100) are also of no diagnostic or prognostic utility in this patient population.[10] If levels of any of these markers are elevated, serial measurement may be useful in assessing response to treatment.

Pathologic Evaluation

An accurate pathologic evaluation of tumor tissue is an essential part of the diagnostic process. A biopsy of the most accessible lesion should be performed. A fine-needle biopsy is least invasive but may not yield enough tissue for specialized pathologic studies, which are required for all patients with poorly differentiated tumors. Close collaboration with the pathologist is therefore necessary to ensure that optimal diagnostic studies are performed. The pathologist should be informed about all of the clinical information to assist in the selection of specialized pathologic studies.

Light microscopic examination results in the identification of several subgroups, including poorly differentiated neoplasms, well-differentiated and moderately well-differentiated adenocarcinomas, squamous cell carcinomas, and poorly differentiated carcinomas (with or without features of adenocarcinomas). Histochemical staining for mucin may facilitate identification of some adenocarcinomas.[11]

In patients with well-differentiated or moderately differentiated adenocarcinoma, further pathologic studies rarely identify a primary site and are only indicated in selected patient subgroups. Staining for PSA occasionally identifies a prostate primary site in men with metastatic adenocarcinoma, and positive staining for estrogen/progesterone receptors is useful in women with clinical features compatible with metastatic breast cancer.

As opposed to their limited utility in patients with adenocarcinoma, additional pathologic studies frequently add useful information to the evaluation of poorly differentiated tumors. Immunocytochemical stains are now widely available and should be routinely performed. Although definitive diagnoses can be made only in a minority of patients, a number of diagnoses can be suggested with this technique, including lymphoma, melanoma, sarcoma, and neuroendocrine carcinoma (Table 2). Several of these diagnoses have specific therapeutic implications.

A number of “tumor-specific” antibodies or antibody panels have been evaluated. However, none of these is sufficiently specific to reliably identify a primary site.[12-15]

Electron microscopy is also a valuable tool in the evaluation of poorly differentiated tumors. Since it is less widely available and often requires rebiopsy with special tissue preparation, electron microscopy should be reserved for use in tumors of uncertain lineage following immunoperoxidase studies. Definitive diagnoses of lymphoma, neuroendocrine tumors, melanoma, and a variety of sarcomas is possible with electron microscopy.

Therapy

When a primary site is definitively identified by either clinical or pathologic evaluation, treatment should proceed according to the guidelines for that type of cancer. In the large majority of patients, however, no primary site can be identified. In these patients, it is probably best to avoid the temptation to “guess” at a primary site based on either suggestive clinical or pathologic features.

For example, patients with mucin-positive adenocarcinoma involving the liver may have an unidentified gastrointestinal primary, and yet empiric treatment with gastrointestinal regimens (eg, fluorouracil [5-FU]/leucovorin)

has shown very little benefit in this group.[16] Therefore, empiric treatment for carcinoma of unknown primary site should be employed (see below), rather than relatively ineffective treatment for a presumed insensitive primary site.

While, as mentioned above, it is not particularly helpful to label patients with a presumed primary site, it is important to identify patients who fall into certain treatable subsets, based on either clinical or pathologic features (see below). Specific treatment guidelines are available for these subsets. In the remainder of patients, empiric treatment designed for cancer of unknown primary should be employed.

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.[17]

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.[19] 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.[27]

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.[39] 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.[40] 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.[41] 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.[42] Recently, the combination of paclitaxel, carbo-platin (Paraplatin), and etoposide also showed marked activity in the treatment of these cancers.[43]

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.[44]

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.[47] 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]

Empiric Therapy

Approximately 60% of patients with carcinoma of unknown primary site do not belong to any of the subgroups described above. Most of these patients have adenocarcinoma.

Various empiric chemotherapy regimens have been tested in this patient group. Many of these have consisted of 5-FU–based regimens or other regimens developed for the treatment of advanced gastrointestinal cancers. Large, randomized, phase III trials have not been performed in this group of patients, and therefore, most available data regarding empiric treatment have been derived from relatively small phase II trials.

Older Agents-Several drugs, including 5-FU, cisplatin, oral etoposide, and mitomycin (Mutamycin), have been evaluated as single agents. All of these agents have produced response rates of 10% to 20%.[50-53]

Table 4 summarizes the results with empiric combination regimens; individual phase II trials of similar or identical combinations have been pooled, and composite efficacy results are provided.[43,54-74] Most regimens produced low response rates (20% to 33%) and similar median survival durations (4 to 7 months).

In patients with adenocarcinoma of unknown primary site, results with cisplatin-based regimens have not been superior to other regimens; however, response rates have been slightly higher. Because of their increased toxicity, cisplatin-based regimens are not considered to be standard therapy in this group of patients (as opposed to patients with poorly differentiated carcinoma of unknown primary site).[54,67-71]

New Agents-The availability of several new antineoplastic agents with broad clinical activity (paclitaxel, docetaxel [Taxotere], gemcitabine [Gemzar], vinorelbine [Navelbine], irinotecan [Camptosar]) offers the possibility for the development of empiric regimens with improved efficacy in patients with carcinoma of unknown primary site. Evaluation of these drugs in this group of patients has only just begun. At present, paclitaxel is the only new drug that has been evaluated as a component of empiric chemotherapy for patients with carcinoma of unknown primary site.

Our first clinical experience with paclitaxel in this group of patients was in combination with carboplatin and etoposide.[43] Table 5 provides details of this regimen and summarizes the results of our initial phase II trial.

In our trial, a total of 55 patients were treated at the Sarah Cannon Cancer Center or at participating treatment sites in the Minnie Pearl Cancer Treatment Network. All 55 patients had carcinoma of unknown primary site (any histology was eligible), but patients were excluded if they fit into any recognized treatable subset. Most patients had multiple sites of metastatic disease, and a large majority had either adenocarcinoma or poorly differentiated adenocarcinoma. Patients received the combination of paclitaxel, carboplatin, and oral etoposide at 21-day intervals for a total of four to six courses.

Of the 53 patients evaluable for response, 25 (47%) had major objective responses, and 7 (13%) patients showed a complete response. Somewhat to our surprise, there was no difference in response rates when patients with adenocarcinoma were compared to those with poorly differentiated carcinoma (45% vs 48%). Median survival for the entire group was 13.4 months, with a 1-year survival rate of 58%. Survival was identical for patients with adenocarcinoma vs poorly differentiated carcinoma.

In general, this regimen was well tolerated in the outpatient setting. Grade 3 or 4 leukopenia accompanied 41% of treatment courses, but hospitalizations for treatment of neutropenia and fever were uncommon, and there were no treatment-related deaths. Other grade 3 or 4 toxicities, including peripheral neuropathy, arthralgia/myalgia, and nausea/vomiting, were uncommon.

We recently updated the results of this treatment program; the group now consists of 71 patients. With longer follow-up, median survival for the entire group was 11 months; the actual 2-year survival rate was 20%, and the actual 3-year survival rate was 14%.

Therefore, this treatment regimen has produced extended survival in a minority of patients with adenocarcinoma of unknown primary site. This subset of patients with adenocarcinoma who obtain major benefit from empiric chemotherapy has not been clearly demonstrated with previous regimens.

Pavlidis et al recently reported the results of a phase II trial evaluating the combination of paclitaxel and cisplatin in patients with cancer of unknown primary site.[74] This paclitaxel-based regimen also produced a high overall response rate of 41%; in an early report, the median survival had not yet been reached but was > 8 months.

In an ongoing phase II (not yet published), randomized, multicenter European trial, the combination of paclitaxel/carboplatin/etoposide is being compared to 5-FU/leucovorin. If this randomized trial can be completed, it will definitively address the role of paclitaxel-containing therapy for carcinoma of unknown primary site.

Ongoing or Recently Completed Clinical Trials

At present, we are evaluating several other new drugs in the treatment of carcinoma of unknown primary site. We have completed a trial of single-agent gemcitabine as second-line therapy. Most patients entering this trial had previously received paclitaxel and carboplatin. In this difficult-to-treat patient population, gemcitabine produced an 8% response rate, with an additional 25% of patients having stable disease or minor response with improved symptoms.[75] In an ongoing trial, we are evaluating oral topotecan (Hycamtin) as second-line treatment.

We recently completed phase II trials of first-line treatment with two different combinations: docetaxel/carboplatin and paclitaxel/carboplatin/gemcitabine. Results from of these completed clinical trials should be available in the near future.

Retrospectively, we have also evaluated a large group of patients with poorly differentiated carcinoma for HER-2 overexpression.[76] Overexpression of HER-2, as determined by immunoperoxidase testing, was reported in 10 (11%) of 94 patients. The efficacy of trastuzumab (Herceptin) in this patient group is a subject of further investigation.

Conclusions

Efforts to improve therapy for patients with cancer of unknown primary have been limited, due, in part, to widespread nihilism among clinicians regarding the prognosis of patients with this heterogeneous group of cancers. Improvements in pathologic diagnostic methods have resulted in a more accurate diagnosis of subsets of treatable cancers within this group. Advances in molecular genetics may further increase the proportion of patients in whom a specific diagnosis can be made, or may identify a subset of patients with tumors that are responsive to chemotherapy.

Management of the large group of patients who do not fit into any currently identified treatment subset continues to be an important concern. As chemotherapy for many advanced cancers evolves, the outlook for these patients should continue to improve.

Promising results have been obtained with first-line empiric paclitaxel/carboplatin/etoposide combination chemotherapy. The regimen is well tolerated and has become one of the standard approaches to the systemic management of cancer of unknown primary. Long-term follow-up of patients treated with this regimen documents a minority of patients (14%) alive at 3 years; all of these patients had major responses to initial therapy. Additional trials of paclitaxel/carboplatin–containing regimens are in progress.

Trials evaluating other new cytotoxic agents with broad antitumor activity, including docetaxel, gemcitabine, topotecan, and irinotecan, are being conducted. If these agents demonstrate activity, further evaluation of first-line combination regimens will be indicated. Other therapeutic approaches are also under development.

The potential to improve empiric therapy for patients with carcinoma of unknown primary site is promising. A broader scope of clinical trials in these patients is warranted.

References:

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).