Commentary (Lenzi/Yalcin): Management of Patients With Cancer of Unknown Primary Site

The article by Drs. Hainsworth and Greco is a timely review of the management of patients presenting with metastatic cancer in the absence of a documented site of origin (cancer of unknown primary site). These patients constitute a significant proportion (approximately 5%) of all patients with cancer.

The uncertainty regarding the primary site poses difficult diagnostic and therapeutic challenges for the physician. Often, this uncertainty is a source of additional anxiety for the patient, who may feel that the diagnostic evaluation has been inadequate, and that treatment could be more effective and the prognosis more favorable, if the metastatic disease could be traced to a specific site.

Observations of a large series of patients who were referred with a diagnosis of metastatic carcinoma with an occult primary have confirmed, however, that even a careful diagnostic evaluation will detect the primary cancer in only a minority (approximately 20%) of patients.[1] Therefore, as Drs. Hainsworth and Greco point out, a carefully planned, focused diagnostic strategy is paramount for avoiding redundant testing and unnecessary treatment delays.

Pathologic Evaluation

The diagnostic potential of a careful pathologic evaluation cannot be overemphasized.[2] The widespread availability of less invasive fine-needle aspiration techniques has resulted in a number of patients being diagnosed on the basis of cytology.

Although fine-needle aspiration is often adequate, Drs. Hainsworth and Greco appropriately note that it may not yield adequate material for the evaluation of malignancies with poorly differentiated histology, which require multiple special studies. In some cases, obtaining additional biopsy material may be the key to the diagnosis. Electron microscopy has a definite role in some patients with poorly differentiated neoplasms, eg, those in whom immunohistochemical studies are not diagnostic because of the nonspecificity of positive markers, or those in whom all immunohistochemical markers tested are negative (a finding not uncommon in patients with morphologically undifferentiated neoplasms).

Molecular and cytogenetic analyses have an established role in the diagnosis of certain patient subsets.[3] Given the number of available special studies, communication between clinician and pathologist is essential for ensuring that appropriate tests are selected, as Drs. Hainsworth and Greco note.

Clinical Evaluation

The history, physical examination, and systems review often provide the most significant clues to the primary site. The history should include a careful cancer history. The information thus gathered may prompt the retrieval, reexamination, and comparison of histologic material obtained as part of the evaluation of a prior neoplastic condition.

The physical examination is an essential component of the clinical evaluation. Sometimes overlooked but necessary components of the physical examination include a digital rectal examination with testing for occult blood, a pelvic examination in women, and careful testis and prostate examination in men.

A “complete” initial laboratory and imaging evaluation should include a complete blood count, chemistry profile, serum prostate-specific antigen (PSA) level in men, chest radiography, computed tomography (CT) of the abdomen, and CT or ultrasound examination of the pelvis. We also routinely perform a mammogram in all women referred with a diagnosis of cancer of unknown primary.[4]

Abnormal results noted upon completion of the above evaluation should be pursued with additional diagnostic tests as appropriate. As Drs. Hainsworth and Greco emphasize, additional testing that does not focus on a specific symptom or abnormal finding from the initial work-up has a very small chance of contributing to the detection of a primary.

Clinicopathologic Subsets

Through astute clinical observations and definition of specific pathologic and molecular characteristics, subgroups of patients have been identified who share similar clinical characteristics and for whom specific treatment strategies have been defined. These subgroups include: women with adenocarcinoma in axillary lymph nodes, women with peritoneal carcinomatosis, patients with a single metastatic lesion, patients with squamous cell cancer involving cervical or inguinal lymph nodes, patients with poorly differentiated neuroendocrine carcinoma, patients with differentiated neuroendocrine carcinoma, and patients with poorly differentiated carcinoma. The diagnostic features of these subgroups of patients are clearly outlined in the article, and the respective treatment strategies and prognostic features are comprehensively described.

Patients Who Do Not Fall Into Specific Subgroups

The majority of patients with carcinoma of unknown primary do not fall into specific clinical subgroups. A number of clinical trials have attempted to determine the most effective treatment regimen for these patients. Historically, such trials have been built around the most active drugs available for the treatment of the metastatic stage of common primary malignancies. The article includes a review of such trials.

Although, overall, progress in the treatment of patients who do not belong in specific subgroups has paralleled progress in the discovery of new active chemotherapeutic agents, the most successful advances clearly have been made through the identification of specific patient subsets.[5-7]. For these patients, subset identification has translated into specific diagnostic and therapeutic strategies, higher treatment response rates, and increased duration of survival.

Treatment of patients not belonging to a specific subgroup has remained relatively nontargeted, and overall survival duration has shown limited improvement. In a recent report on the use of a combination of paclitaxel (Taxol), carboplatin (Paraplatin), and etoposide in the treatment of these patients,[8] survival was 11 months and response rate, 47%. Clearly, further research is needed to improve the outcome of treatment in these patients.

The authors provide an interesting review of several agents effective against a broad spectrum of common primary malignancies that are presently being investigated for the treatment of cancer of unknown primary site. Of particular interest is the exploration of the role of regimens containing gemcitabine (Gemzar). A well tolerated drug effective against several common tumor types, gemcitabine may prove to be a significant addition to the armamentarium of drugs used in the treatment of cancer of unknown primary.

In the setting of cancer of unknown primary, the authors report that, in a trial that they conducted, single-agent gemcitabine produced responses in 8% of patients with refractory or resistant disease, as well as stable disease in 25% of patients. These results provide an encouraging starting point for the exploitation of this drug’s known synergy with platinum compounds.

Future Directions

Several areas of investigation hold promise for achieving progress in the diagnosis and treatment of patients with cancer of unknown primary. Certain imaging modalities, such as positron emission tomography (PET)[9] and indium-111 pentetreotide scanning,[10] need to be evaluated further with regard to their specific roles in the diagnostic work-up of these patients.

New strategies to enhance the identification of additional clinical/biological patient subgroups need to be developed. Classification and regression tree (CART) analysis[11] has shown promise in identifying subsets of patients with a similar prognosis. This analytic method may contribute to the definition of variables useful for the formulation of a more accurate prognosis and, possibly, for a more precise tailoring of treatment strategies.

Perhaps the most promising developments are recent advances in the study of gene expression. The ability to study the expression of hundreds of genes at a time in a single sample by DNA microarray technology, and to evaluate hundreds of biopsy samples for one gene of interest using tissue microarrays,[12] has opened the door to the molecular classification of tumors, the identification of novel tumor subgroups,[13] and, perhaps, the molecular identification of the primary site.

References:

1. Abbruzzese JL, Abruzzese MC, Lenzi R, et al: Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol 13:2094-2103, 1995.

2. Mackay B, Ordonez N: Pathological evaluation of neoplasms with unknown primary tumor site. Semin Oncol 20:206-228, 1993.

3. 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

4. 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.

5. 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.

6. 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.

7. Moertel CG, Kvols LK, O’Connell MJ, et al: Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin: Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227-232, 1991.

8. Hainsworth JD, Erland JB, Kalman L, et al: Carcinoma of unknown primary site: Treatment with one-hour paclitaxel, carboplatin, and extended schedule etoposide. J Clin Oncol 15:2385-2393, 1997.

9. Lassen U, Daugaard G , Eigtved A, et al: 18F-FDG whole body positron emission tomography (PET) in patients with unknown primary tumours (UPT). Eur J Cancer 35:1076-1082, 1999.

10. Lenzi R, Kim EE, Raber MN, et al: Detection of primary breast cancer presenting as metastatic carcinoma of unknown primary origin by 111In-pentetreotide scan. Ann Oncol 9:213-216, 1998.

11. Hess KR, Abbruzzese MC, Lenzi R, et al: Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 5:3403-3410, 1999.

12. Kononen J, Bubendorf L, Kallioniemi A, et al: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844-847, 1998.

13. Golub TR, Slonim DK, Tamayo P, et al: Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring. Science 286(5439):531-537, 1999.