Table 3 summarizes the recommended treatment for various recognized clinicopathologic subsets.
When evaluating patients with adenocarcinoma of an unknown primary site, several clinical subsets should be identified and treated specifically. Empiric therapy for patients not included in any of these subsets is outlined in the final section of this chapter.
Women with isolated axillary adenopathy
Treatment appropriate for stage II breast cancer should be administered. Mastectomy reveals an occult primary cancer in 50% to 60% of these patients, even when findings from the physical examination and mammography are normal. Axillary dissection with breast irradiation is also a reasonable treatment, although there are no definitive comparisons of this approach vs mastectomy. Adjuvant systemic therapy, following standard guidelines for stage II breast cancer, is also indicated.
Women with peritoneal carcinomatosis
Often, the histopathology in these patients suggests ovarian cancer (ie, serous cystadenocarcinoma or papillary adenocarcinoma). However, all women with this syndrome should be treated as if they had stage III ovarian cancer. Initial cytoreductive surgery should be followed by chemotherapy with a taxane/platinum combination, as recommended for advanced ovarian cancer. In these patients, serum CA-125 can often be used as a tumor marker.
Men with bone metastasis
Metastatic prostate cancer should be suspected and usually can be diagnosed in patients with either an elevated serum PSA level or positive tumor staining for PSA. In such patients, androgen deprivation therapy, as recommended for advanced prostate cancer, is often of palliative benefit.
Patients with a colon cancer "profile"
Patients with a metastatic pattern (liver and/or peritoneal involvement) and pathologic findings (adenocarcinoma, CK20-positive/CK7-negative and/or CDX2-positive) strongly suggestive of metastatic colorectal cancer should be treated with modern regimens for advanced colon cancer (eg, fluorouracil(Drug information on fluorouracil)/leucovorin/oxaliplatin [Eloxatin]; FOLFOX/bevacizumab [Avastin]). The prediction of a colorectal tissue of origin by molecular gene profiling may also be useful in guiding therapy. In a recent series, 32 patients with unknown primary cancer and a molecular profiling prediction of a colorectal site of origin had a median survival of 22 months when treated with site-specific therapy, comparable to survival in patients with a known colorectal cancer.
Patients with a single metastatic site
Surgical resection or radiation therapy should be administered to patients who present with clinical evidence of a single metastasis. Before proceeding with local therapy in these patients, PET scanning should be considered to rule out additional metastatic sites. Some of these patients have prolonged survival after local therapy, particularly those who present with a sole metastasis in an isolated peripheral lymph node group. The role of "adjuvant" systemic therapy is undetermined in these patients.
Squamous cell cancer accounts for only 10% of light microscopic diagnoses in patients with unknown primary cancer. Isolated cervical adenopathy is the most common presentation for squamous cell carcinoma of an unknown primary site; other patients have isolated inguinal adenopathy at presentation. Specific management is essential for both of these subgroups, since both have the potential for long-term survival following treatment.
Patients with cervical lymphadenopathy
Patients with cervical lymphadenopathy in whom no primary site is identified should be treated as if they had a primary site in the head and neck. Concurrent treatment with chemotherapy and radiation therapy has recently proved superior to local treatment alone and to these treatment modalities used sequentially. Radiation therapy doses and techniques should be identical to those used in treating patients with known head and neck primaries. In addition to the involved neck, the nasopharynx, oropharynx, and hypopharynx should be included in the radiation field. Radical neck dissection should be considered in patients who have any evidence of residual cancer following combined-modality therapy.
Five-year survival rates with combined-modality therapy are 60% to 70% and appear superior to results with local modalities alone (30% to 50%). The extent of cervical lymph node involvement is the most important prognostic factor. (For additional discussion, see "Unknown Head and Neck Primary Site" in the "Head and Neck Tumors" chapter.)
Patients with inguinal lymphadenopathy
Identification of a primary site in the perineal area is important in patients with inguinal lymphadenopathy, because curative therapy is available for some patients, even after metastasis to inguinal lymph nodes. In the uncommon patient for whom no primary site is identified, inguinal node dissection, with or without radiation therapy, can result in long-term survival. Although limited data exist on this uncommon subgroup, the demonstrated superiority of combined-modality therapy vs local treatment alone for primary squamous cell cancers in the perineal area (eg, cervix, anus) has led to a suggestion that the addition of platinum-based chemotherapy may improve treatment results.
This heterogeneous group includes a minority of patients with highly responsive neoplasms and therefore requires special attention in initial clinical and pathologic evaluations. Specialized pathologic techniques can identify some patients with tumor types known to be treatable; these patients should be treated using standard guidelines for the appropriate tumor type.
In the remaining patients, several investigators have documented an increased responsiveness to platinum-based chemotherapy when compared with patients with adenocarcinoma of an unknown primary site. In addition, several series have described a small cohort of long-term survivors following platinum-based treatment. Patients with poorly differentiated adenocarcinoma have usually been included in this group when making treatment decisions. Although most patients in this group should receive an empiric trial of treatment, several specific subsets can be recognized.
Men with extragonadal germ cell cancer syndrome
Young men with a predominant tumor location in the mediastinum and retroperitoneum and/or high levels of serum hCG or AFP should be treated as if they had a poor-prognosis germ cell tumor (ie, four courses of chemotherapy with cisplatin(Drug information on cisplatin)/etoposide/bleomycin, followed by surgical resection of residual radiographic abnormalities).
Molecular genetic analysis can identify an i(12p) chromosomal abnormality diagnostic of a germ cell tumor in some of these patients, even when the diagnosis cannot be made by any other pathologic evaluation. Patients with germ cell tumors diagnosed in this manner have been shown to be as responsive to treatment as patients with extragonadal germ cell tumors of typical histology.
Patients with poorly differentiated neuroendocrine carcinoma
With the improved immunoperoxidase stains now available, neuroendocrine features are recognized more frequently in patients with poorly differentiated carcinoma. These tumors are distinct in biology and therapeutic implications from well-differentiated neuroendocrine tumors (eg, carcinoid tumors, islet cell tumors) of an unknown primary site, which almost always present with multiple liver metastases. In contrast to typical carcinoid tumors, poorly differentiated neuroendocrine tumors are difficult to recognize by light microscopic examination alone, although some of the latter tumors have neuroendocrine or "small-cell" features.
Patients with poorly differentiated neuroendocrine carcinoma of an unknown primary site should receive a trial of chemotherapy containing a platinum and etoposide. In a group of 51 such patients, the complete response rate was 28% following treatment with cisplatin and etoposide, with or without bleomycin(Drug information on bleomycin); the overall response rate was 71%. Eight patients (16%) had durable complete remissions.
The combination of paclitaxel(Drug information on paclitaxel), carboplatin(Drug information on carboplatin) (Paraplatin), and etoposide(Drug information on etoposide) is also highly active in the treatment of poorly differentiated neuroendocrine tumors (response rate, 53%; 2-year survival, 33%). However, the addition of paclitaxel increases myelosuppression and is not clearly superior to platinum/etoposide therapy.
Although the identity of most poorly differentiated neuroendocrine tumors remains unknown, this group of chemotherapy-responsive patients can be reliably identified using specialized, but widely available, pathologic evaluation.
Other patients with poorly differentiated carcinoma
Most patients with poorly differentiated carcinoma do not have neuroendocrine features or clinical features of germ cell tumor. Patients in this group should receive an empiric trial of chemotherapy, unless an extremely poor performance status precludes this possibility. In a group of 220 such patients treated at a single institution with cisplatin-based regimens effective for germ cell tumor, the overall response rate was 64%, with 27% complete responses. Median survival in this group was 20 months, and 13% of patients have been disease-free for more than 8 years and are considered cured. Although the young median age of 39 years indicates that this was a select patient group, the extreme chemosensitivity of some patients in this large, heterogeneous group is clearly demonstrated.
Approximately 80% of patients with unknown primary cancer do not fit into any of the favorable treatment subsets previously discussed. The current standard of therapy for these patients, assuming an adequate performance status, is a trial of empiric combination chemotherapy. The overall impact of such treatment is modest, although some patients have sensitive tumors and derive major benefit. In larger trials with modern combination regimens, median survival ranges from 8 to 11 months. In a compilation of results from multiple trials conducted between 1997 and 2007 (928 patients), the median survival was 8.9 months.
An absence of randomized, comparative trials in this area makes it difficult to determine an optimum treatment regimen. Several combination chemotherapy regimens have produced similar results, as detailed in Table 4. Taxane/platinum and gemcitabine(Drug information on gemcitabine)/platinum combinations have been best studied and are widely used.
The treatment of patients with unknown primary cancer is evolving, and the era of empiric chemotherapy is nearing its end. With improved diagnostic methods, including better immunohistochemical stains and molecular tumor profiling, most patients in the future will receive site-specific therapy based on the predicted tissue of tumor origin. Although the optimum uses of these new diagnostic methods are still being defined, current evidence already strongly supports their accuracy and their success in identifying patients who benefit from site-specific therapy. With an increasing number of targeted agents available or in clinical development, routine evaluation of these tumors for critical molecular abnormalities is also likely to play a future role in directing therapy.