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]
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. 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. 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. 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. 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.
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.
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