Carcinoma Of Unknown Primary Site Research Articles

Epirubicin, cisplatin, and prolonged or brief infusional 5-fluorouracil in the treatment of carcinoma of unknown primary site.

The cytotoxic regimen of epirubicin, cisplatin, and continuous infusional 5-fluorouracil (ECF) has demonstrated activity in a range of malignancies, including gastroesophageal, breast, and pancreatic cancers. Prolonged infusional central venous catheter (CVC) mediated therapy is not always feasible and modifications of the 5-fluorouracil (5FU) schedule have been reported. We reviewed our experience of both the standard and a modified ECF regimen in patients diagnosed with carcinoma of unknown primary site (CUPS). A retrospective analysis of all patients diagnosed with CUPS (31 adenocarcinoma and 5 poorly differentiated carcinoma) and treated with ECF between June 1994 and June 1998 was undertaken. Thirty-six patients, median age 56 (range: 24-74), were treated thrice-weekly with 50 mg/m2 epirubicin, 60 mg/m2 cisplatin, and 5-FU administered either by continuous infusion 200 mg/m2/d via a CVC (standard ECF) or as a 6-h infusion 600 mg/m2 through a peripheral venous catheter (modified ECF). Thirteen patients were treated with standard ECF and 23 received modified ECF. The median number of cycles administered was 4 (range: 1-10). Thirty-two patients had evaluable disease, seven (22%; 95% confidence interval: 8-36%) demonstrated a partial response, including three patients that received standard ECF and four treated with modified ECF. There were no complete responses. The median survival for all 36 patients was 9.0 mo. Median survival for patients treated with standard ECF was 11.7 mo as compared to 5.1 mo for the modified ECF schedule (p = 0.052). Liver involvement and elevation of serum CA19.9 were identified as possible adverse prognostic factors. Both regimens were well tolerated, with the only grade 3/4 toxicity recorded being leukopenia (four patients), nausea/vomiting (seven patients), and diarrhea (one patient). CVC complications in the standard ECF group were thrombosis (one patient) and infection (three patients). There were no treatment-related deaths. We conclude that ECF, whether modified or standard, has modest activity in the setting of CUPS. Patient survival is comparable to survival documented in previous reports of CUPS treatment. The apparent survival difference between the two ECF schedules may be the result of patient selection factors. The optimal treatment of CUPS remains unknown and can only be determined through randomized controlled trials.

Gemcitabine in the Second-Line Therapy of Patients with Carcinoma of Unknown Primary Site: A Phase II Trial of the Minnie Pearl Cancer Research Network

The purpose of this study was to evaluate the activity ofsingle-agent gemcitabine in previously treated patients with carcinoma ofunknown primary site. Between January 1997 and October 1998, 39 patients wereenrolled in this multicenter Phase II trial performed in the Minnie PearlCancer Research Network. Twenty-seven patients (69%) had adenocarcinoma orpoorly differentiated adenocarcinoma; 35 patients (90%) had previously receivedtreatment with chemotherapy regimens containing both a platinum agent anda taxane. Only 21% of patients had ever responded to previous therapy. Gemcitabine1000 mg/m2 was administered intravenously on days1, 8, and 15 of each 28-day course. Three of 36 evaluable patients (8%) hadpartial responses, and 9 patients (25%) had minor responses or stable diseasewith improved symptoms. The median time to progression for patients with partialresponses or stable disease/improved symptoms was 5 months. Treatment waswell tolerated, with uncommon grade 3 or 4 toxicity. Gemcitabine produceda low objective response rate in this refractory patient population, althoughapproximately one-third of patients experienced symptomatic improvement. Treatmentwith gemcitabine was well tolerated. Because gemcitabine has activity againsta variety of adenocarcinomas, further evaluation of this agent as part offirst-line therapy for patients with carcinoma of unknown primary site isappropriate.

Carcinoma of unknown primary site

Carcinoma of an unknown primary site is a common clinical syndrome, accounting for approximately 3% of all oncologic diagnoses. Patients in this group are heterogeneous, having a wide variety of clinical presentations and pathologic findings.

The role of cytokeratins 20 and 7 and estrogen receptor analysis in separation of metastatic lobular carcinoma of the breast and metastatic signet ring cell carcinoma of the gastrointestinal tract

Metastatic signet ring cell carcinomas of unknown primary site can represent a clinical problem. Gastrointestinal signet ring cell carcinomas and invasive lobular carcinomas of the breast are the most common sources of these metastases. Immunohistochemical algorithms have been successfully used in the search for the unknown primary adenocarcinomas. In the present study a series of primary invasive lobular breast carcinomas (79 cases) and their metastases and a series of gastrointestinal signet ring cell carcinomas (22 primary and 13 metastases) were stained with monoclonal antibodies for cytokeratin (CK) 20 and CK7 and for estrogen receptors (ER). The staining was evaluated as negative (no staining), focally (less than 10% of the tumor cells stained) or diffusely positive. All the primary and metastatic gastrointestinal signet ring cell carcinomas proved to be CK20 positive, while only 2/79 (3%) of the primary and 1/21 metastatic lobulr carcinomas (5%) stained positively for this CK. None of the gastrointestinal carcinomas and the majority of the lobular carcinomas expressed ER. The majority of the tumors were CK7+. Using CK20 alone, 33 of 34 metastases could be properly classified as gastrointestinal (CK20+) or mammary (CK20‐). ER identified 31/34 of breast cancer metastases. By combining the results of CK20 and ER staining all the metastases could be properly classified as the CK20+/ER‐ pattern identified all the gastrointestinal tumors.

Phase II study of epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) for carcinoma of unknown primary site

Patients with carcinoma of unknown primary site account for up to 15% of cancer diagnoses but chemotherapy has disappointing response rates and little impact on overall survival [1,2]. Cisplatin-based regimens are the mainstay of treatment [3]. The combination of epirubicin, cisplatin and continuous infusion 5-fluorouracil (5-FU) has been shown to be very active and reasonably well tolerated in the treatment of metastatic breast cancer, esophagogastric and pancreatic adenocarcinomas [4, 5]. There has been a report of this combination for cancer of unknown primary that suggests further evaluation [6].

Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites.

The thyroid transcription factor-1 (TTF-1) is a highly specific immunohistochemical marker for the identification of pulmonary adenocarcinomas and non-neuroendocrine large cell carcinomas, especially in patients presenting with metastatic carcinomas of unknown primary site. In this study we tested if anti-TTF-1 can also be used to verify a pulmonary origin of neuroendocrine carcinomas, placing emphasis on the discrimination of pulmonary small cell carcinomas (SCCs) from extrapulmonary SCCs and the distinction of SCCs from Merkel cell carcinomas of the skin. We studied 37 pulmonary SCCs, 15 SCCs of extrapulmonary origin, 4 pulmonary large cell neuroendocrine carcinomas (LCNECs), four extrapulmonary LCNECs, six medullary thyroid carcinomas, 16 Merkel cell carcinomas, and a total of 32 carcinoids/low-grade neuroendocrine carcinomas of pulmonary (12 cases) and extrapulmonary (20 cases) origin. Using the commercially available monoclonal antibody 8G7G3/1, TTF-1 was immunohistochemically detectable in 81% of pulmonary SCCs but also in 80% of extrapulmonary SCCs. Furthermore, anti-TTF-1 showed a positive staining in 50% of all pulmonary carcinoids, in one gastric carcinoid, in 2/4 of pulmonary, and 1/4 of extrapulmonary LCNECs. All medullary thyroid carcinomas were also TTF-1-positive. Merkel cell carcinomas were consistently TTF-1-negative. Our results suggest that in contrast to non-neuroendocrine carcinomas, anti-TTF-1 cannot be used to prove or to exclude a pulmonary origin of SCCs or LCNECs of unknown or uncertain primary site. Therefore, before using anti-TTF-1 as a marker for pulmonary carcinomas one should be sure to have excluded SCC and LCNEC. On the other hand, anti-TTF-1 might be used to specifically discriminate SCCs of various origin from Merkel cell carcinomas.

Carcinoma of unknown primary site: Phase II trials with docetaxel plus cisplatin or carboplatin

To evaluate the toxicity, response rate and short-term survival associated with the chemotherapy combinations of docetaxel plus cisplatin or carboplatin when used for the treatment of patients with metastatic carcinoma of unknown primary site. Twenty-six patients were treated with docetaxel 75 mg/m2 i.v. and cisplatin 75 mg/m2 i.v. given every three weeks (study A) and subsequently, 47 patients were treated with docetaxel 65 mg/m2 and carboplatin (AUC dose = 6) every three weeks (study B). Stable or responding patients received a maximum of eight courses of therapy. Patients who were known to be in treatable subset groups were excluded from these trials. The majority of patients had two or more sites of metastasis; about 45% had adenocarcinoma and 50% poorly differentiated carcinoma. In study A, 6 of 23 (26%) assessable patients had a major response to therapy. The median survival was eight months and one-year survival 42%. Seven patients were removed from the study early for grade 3 or 4 nausea and vomiting. In study B, 9 of 40 assessable patients (22%) had a major response to therapy. Median survival was eight months and one-year survival 29%. Toxicity associated with this regimen was predominantly myelosuppression. Comparisons of the two sequential trials showed no differences in response rates or survivals (P = 0.75). Docetaxel and cisplatin (study A) is an active combination in carcinoma of unknown primary site, but associated with substantial gastrointestinal toxicity. A combination of docetaxel plus carboplatin (study B) is better tolerated and produced a similar response rate, median survival and one-year survival. Comparative phase III trials will be necessary to unequivically prove a survival advantage for any form of therapy in these patients. However, the survival for patients with carcinoma of unknown primary site receiving docetaxel-based chemotherapy is comparable to the survivals for several other groups of advanced cancer patients, such as non-small cell lung cancer, receiving various types of chemotherapy.

Carcinoma of unknown primary site

The long term survival and toxicity associated with the chemotherapy combination of paclitaxel, carboplatin, and extended-schedule etoposide used for the treatment of patients with metastatic carcinoma of unknown primary site were evaluated. Seventy-one patients were treated between March 1995 and November 1996 with paclitaxel, carboplatin, and oral etoposide every 21 days. Stable or responding patients received four to eight courses of therapy. The following histologies were represented: well differentiated adenocarcinoma (34 patients); poorly differentiated adenocarcinoma or poorly differentiated carcinoma (30 patients); poorly differentiated neuroendocrine carcinoma (6 patients); and squamous cell carcinoma (1 patient). Forty-eight percent of assessable patients had major responses to therapy (95% confidence interval, 39%-55%), and 10 patients (15%) had complete responses. There were no response differences among the major histologic types. The median survival for all 71 patients was 11 months, and the 1-year, 2-year, and 3-year survival rates were 48%, 20%, and 14%, respectively. The minimum follow-up period was 34 months (range, 34-50 mos). The regimen was tolerated well with no treatment-related deaths and only 12 hospitalizations for neutropenia and fever. There was no serious long term toxicity. In this large Phase II trial, the combination of paclitaxel, carboplatin, and oral etoposide produced major responses or stable disease status in nearly 80% of patients who had carcinoma of unknown primary site. The median survival and 1-year, 2-year, and 3-year survival rates were noteworthy. The current study obtained similar or superior results to those seen with chemotherapy for many other groups of patients, such as those who had well defined advanced malignancies, those who were considered to have responsive tumors, and those who had obtained substantial benefits from cytotoxic therapy. Although the regimen reported in the current study can become an attractive option for many patients with carcinoma of unknown primary site, there remains a need for further clinical trials.

The role of cytokeratins 20 and 7 and estrogen receptor analysis in separation of metastatic lobular carcinoma of the breast and metastatic signet ring cell carcinoma of the gastrointestinal tract.

Metastatic signet ring cell carcinomas of unknown primary site can represent a clinical problem. Gastrointestinal signet ring cell carcinomas and invasive lobular carcinomas of the breast are the most common sources of these metastases. Immunohistochemical algorithms have been successfully used in the search for the unknown primary adenocarcinomas. In the present study a series of primary invasive lobular breast carcinomas (79 cases) and their metastases and a series of gastrointestinal signet ring cell carcinomas (22 primary and 13 metastases) were stained with monoclonal antibodies for cytokeratin (CK) 20 and CK7 and for estrogen receptors (ER). The staining was evaluated as negative (no staining), focally (less than 10% of the tumor cells stained) or diffusely positive. All the primary and metastatic gastrointestinal signet ring cell carcinomas proved to be CK20 positive, while only 2/79 (3%) of the primary and 1/21 metastatic lobular carcinomas (5%) stained positively for this CK. None of the gastrointestinal carcinomas and the majority of the lobular carcinomas expressed ER. The majority of the tumors were CK7+. Using CK20 alone, 33 of 34 metastases could be properly classified as gastrointestinal (CK20+) or mammary (CK20-). ER identified 31/34 of breast cancer metastases. By combining the results of CK20 and ER staining all the metastases could be properly classified as the CK20+/ER- pattern identified all the gastrointestinal tumors.

Immunohistochemical Analysis of Carcinomas of Unknown Primary Site

With increasing frequency, the pathologist is confronted with biopsy specimens of lymph node, liver, lung, bone, or brain in which the diagnosis of carcinoma is certain but the determination of primary site is not. Owing to the availability of sophisticated screening technologies such as CT and MRI, biopsies can be performed on even small tumor nodules with a high degree of precision, resulting in needle core or fine needle aspirate specimens containing well-preserved carcinoma. The focus of this review will be carcinomas presenting as metastases, and the principal antibodies and panels of antibodies that can be used effectively in this clinical setting to determine the most likely primary sites.

Chemotherapy in carcinomas of unknown primary site: A high-dose intensity policy

Unknown primary tumors are highly malignant diseases which portend a dire prognosis. We designed a prospective high dose-intensity policy with the aim of improving the results obtained with conventional chemotherapy. Chemotherapy regimens were determined according to clinical features. In patients younger than 61 years with an ECOG performance status of 0 or 1, poorly differentiated adenocarcinoma or poorly differentiated carcinoma, and no evidence of brain or bone marrow involvement (group A), the treatment plan included four sequential high-dose courses with hematopoietic progenitor cell and growth factor support. Peripheral blood progenitor cells were collected by apheresis as the leukocyte counts recovered from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m2, cyclophosphamide 6000 mg/m2). Patients then received two cycles of etoposide (800 mg/m2) and carboplatin (900 mg/m2) separated by one cycle of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2). G-CSF (5 micrograms/kg/d) was given until engraftment. It was planned that cycles would be delivered every three weeks. The remaining patients (group B) received alternative cycles of AC (doxorubicin 50 mg/m2, cyclophosphamide 1000 mg/m2) and EP (etoposide 300 mg/m2, cisplatin 100 mg/m2). Cycles were given at two-week intervals with GM-CSF support (5 micrograms/kg/d) from day 4 to day 10. Patients without measurable lesions were included, since the major endpoint was survival. Sixty patients entered the study. Twenty patients were assigned to group A and 40 patients to group B. In group A, 5 of 12 patients with measurable lesions (42%; 95% confidence interval (95% CI): 22%-62%) achieved major responses to chemotherapy, including one complete response. The duration of the overall median survival was 11 months. In group B, a major response was observed in 12 (39%; 95% CI: 28%-50%) of 31 patients with measurable lesions, including three complete responses. The overall median survival was 8 months. Hematological toxicities were noteworthy in both groups. Two toxic deaths occurred in group B. Using these doses and schedules of chemotherapy, a high-dose intensity policy does not appear to improve the outcome of patients with carcinoma of unknown primary site. Alternative studies dealing with new drugs are required.

Adénocarcinomes d'origine inconnue à manifestation thoracique et VIH : à propos de quatre cas

Adenocarcinomas of unknown primary site with thoracic localization and HIV : four case reports. Introduction. — Non AIDS-defining cancer would have increased in HIV-patients as suggested by numerous studies. Four cases of adenocarcinoma of unknown primary site with thoracic localization that occurred in HIV-infected patients are described. Exegesis. — To date, there have been no published data about carcinomas of unknown primary site relating to HIV-infected patients; however, immunodepression could promote them. Carcinomas of unknown primary site account for 0.5 to 10% of all cancers in general population. Primary carcinoma is identified in approximately one third of the cases and often corresponds to lung cancer in case of sus-diaphragmatic metastasis, particularly in case of pleural metastasis. Lung cancer in HIV-infected patients affects mostly youg men who smoke and are often intravenous drug addicts. Adenocarcinoma is the most common histological type of cancer. Conclusion. — Further studies of lung cancer in HIV-infected patients will help evaluate their frequency. In case of increasing frequency, lung cancer should then be included in AIDS-defining cancers.

Extended-schedule oral etoposide in selected neoplasms and overview of administration and scheduling issues.

Extended schedules of oral etoposide have been evaluated in many types of advanced cancer. In addition to their use in the common solid tumours, extended schedules have been employed in Kaposi's sarcoma (both AIDS-related and endemic types), medulloblastoma, glioma, and hepatocellular carcinoma. Single agent activity was demonstrated in all of these tumour subtypes. For patients with carcinoma of unknown primary site, we have recently incorporated a 10-day oral etoposide schedule into a combination regimen that also includes paclitaxel and carboplatin. With this regimen we achieved a 47% response rate in a group of 53 evaluable patients, with a median survival of 13.4 months. Patients with adenocarcinoma and poorly differentiated carcinoma of unknown primary site had comparable response rates and survival. According to a large number of clinical trials and pharmacokinetic data, a daily oral etoposide dose of 50 mg/m2 consistently produces serum concentrations >1 mg/L for several hours each day. Lower doses fail to consistently produce this serum concentration, which is considered necessary for optimum tumoricidal activity. Optimal dose duration is 10 to 14 days, particularly when combination regimens are being employed. Oral etoposide has an established role as a single agent in patients with low grade non-Hodgkin's lymphoma, Kaposi's sarcoma, and testicular cancer (if residual carcinoma is resected after first-line treatment). The optimal use of extended-schedule etoposide in combination regimens is not defined but is being evaluated in a number of etoposide-sensitive malignancies.

Les carcinomes de primitif inconnu. À propos de 100 patients traités au centre régional de lutte contre le cancer de Montpellier

Carcinomas of unknown primary site. A study based on 100 patients treated at the Montpellier Cancer Center. Purpose. — Carcinomas of unknown primary site are frequent neoplasms which raise diagnostic and therapeutic problems in clinical practice. Methods. — Clinical records of 100 patients with carcinoma of unknown primary site whose clinical management took place at the Centre Régional de Lutte Contre le Cancer de Montpellier were retrospectively reviewed. Initial clinical and biological characteristics, pre-treatment evaluation, therapies and outcome were recorded. Results. — Three main histological types were observed: adenocarcinoma (66 patients), poorly differentiated carcinoma (19 patients), epidermoid carcinoma (11 patients). Bone, lung, lymph nodes and liver were the most frequently involved metastatic sites. Analysis of the investigations aimed at identifying the primary site (none of which being positive) showed 68 different combinations in 100 patients. Anemia (< 100 g/L) was observed in 10 patients, while serum alkaline phosphatase was increased in 42 patients. Seven patients died before any therapy. Chemotherapy or radiotherapy was advocated in 70 and 59 patients, respectively. Thirty-six patients had concomitant chemoradiotherapy. Chemotherapy included a platinum derivative in 53 patients. The median number of cycles was four. Nine objective responses were observed, six of which occurred in patients who were receiving platinum-based chemotherapy. Ninety-six deaths were encountered, 95 due to the disease progress and one due to an intercurrent cause. The median survival was 9 months. Univariate analysis identified two prognostic factors: the number of metastatic sites and the serum alkaline phosphatase. Conclusions. — This retrospective study confirms the difficulties in the management of patients with carcinomas of unknown primary site. A literature review suggests limited diagnostic investigations in clinical practice with the aim of identifying tumors of potential prognostic (breast and ovary) or therapeutic (prostate) value. Apart from specific subgroups of patients for whom specific therapy is recommended, there is no current standard chemotherapy.

Combination Regimen with Carboplatin, Epirubicin and Etoposide in Metastatic Carcinomas of Unknown Primary Site: A Hellenic Co-Operative Oncology Group Phase II Study

The encouraging results that have been reported for cisplatin combination chemotherapy in a minority of patients with cancer of unknown primary (CUP) together with the previously shown equal activity of carboplatin in this setting, prompted us to investigate the effectiveness of a carboplatin-containing regimen in a phase II clinical trial.Sixty-two evaluable CUP patients entered the protocol. The chemotherapy regimen consisted of carboplatin 300 mg/m² IV D₁, epirubicin 45 mg/m² IV D₁ and etoposide 120 mg/m² IV D_1–3 (CEE regimen) administered every 3 weeks. The median age of the patients was 61 years and 36 were male. Thirty-one diagnosed as poorly differentiated carcinomas (pdc) and the rest as adenocarcinomas. By clinicopathological criteria, 14 patients had a predominately nodal disease with pdc or poorly differentiated adenocarcinomas (pda), 3 women peritoneal carcinomatosis, and the remaining 46 patients had a predominately splanchnic involvement (24 pdc, 22 pda). Twenty-three patients responded to chemotherapy with 4 (6.5%) complete and 19 (30.5%) partial responders (RR 37%, 95% CI 25–49%). An equal activity of the regimen was observed between the two major histopathological types, the pdc and the adenocarcinomas. Nevertheless, significant differences were seen when the CEE regimen was assessed for its activity in the distinct clinicopathological subsets of CUP. Patients with predominately nodal disease of midline distribution with pdc or pda, and women with peritoneal carcinomatosis, achieved a response rate of 64 and 62% respectively, as compared with a 26% response rate for those with predominately splanchnic involvement. Overall median survival was 10 months and for patients with midline distribution 15 months. The regimen was well tolerated. It is concluded that CEE is a relatively nontoxic chemotherapy regimen and easily administered on an outpatient basis. This prospective phase II study confirmed the activity of carboplatin in the chemosensitive subsets of the predominately nodal disease of midline distribution and peritoneal carcinomatosis in women in the CUP syndrome.

Four-step high-dose sequential chemotherapy with hematopoietic progenitor-cell support as induction treatment for patients with solid tumors

Despite recent progress in modern chemotherapy, metastatic solid tumors still have a poor outcome. The delivery of increased dose intensities of cytotoxic agents could improve response rates. We assessed the feasibility and safety of a high-dose sequential chemotherapy program in chemotherapy-naive patients with solid tumors. Thirty patients (14 with carcinoma of unknown primary site, seven with metastatic breast cancer, six with small-cell lung cancer, and three with other diseases) were treated by an induction therapy regimen consisting of four cycles of high-dose chemotherapy with hematopoietic progenitor cell and growth factor support. Peripheral blood progenitor cells were collected by apheresis as the leukocyte counts recovered from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m2, cyclophosphamide 6000 mg/m2). Patients then received two cycles of etoposide (800 mg/m2) and carboplatin (900 mg/m2) separated by one cycle of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2). G-CSF (5 microg/kg/d) was given until engraftment. Cycles were scheduled to be delivered every three weeks. A total of 108 cycles of chemotherapy were administered. Six patients went off study before the end of the program (three because of progressive disease, three because of toxicity). After the first cycle, a median number of 10 x 10(6)/kg CD34+ cells (range 8-30) were collected. The median number of apheresis procedures was 1 (range 1-3). From cycle 2 to cycle 4, the median number of days when there was an absolute neutrophil count of less than 500/microl increased from three to five, and the median number of days when the platelet count was less than 25,000/microl increased from three to six. Episodes of febrile neutropenia occurred in 36%, 50% and 46% of cycles during cycles 2, 3 and 4, respectively. The median numbers of days between cycle 1 and cycle 2, cycle 2 and cycle 3, cycle 3 and cycle 4 were 24 (range 20-30), 22 (range 20-36) and 22 (range 18-35), respectively. There were no treatment-related deaths. Non-hematologic toxicity included severe (WHO grades 3 or 4) nausea/vomiting in 19 (18%) cycles, mucositis in 8 (7%) cycles and diarrhea in 7 (6%) cycles. Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high-dose chemotherapy in chemotherapy-naive patients, resulting in a significant increase in dose intensity. Toxicity is noteworthy but manageable and does not compromise further therapy.

Triple therapy helpful in carcinoma of unknown primary site

Triple therapy helpful in carcinoma of unknown primary site

Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide.

To evaluate the efficacy and toxicity of a novel chemotherapy combination that includes paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of patients with carcinoma of unknown primary tumor site. Fifty-five patients with carcinoma of unknown primary tumor site were treated with the following regimen, administered every 21 days: paclitaxel 200 mg/m2 by 1-hour intravenous (I.V.) infusion on day 1, carboplatin at an estimated area under the concentration-time curve (AUC) of 6.0 on day 1, and etoposide 50 mg alternated with 100 mg orally on days 1 through 10. Responding patients received a total of four courses of treatment. The following histologies were included: adenocarcinoma, 30 patients; poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA), 21; poorly differentiated neuroendocrine carcinoma, three; and squamous carcinoma, one. Twenty-five of 53 assessable patients (47%; 95% confidence interval [CI], 33% to 61%) had major objective responses to treatment (seven complete responses). Response rates were similar in patients with adenocarcinoma versus PDC (45% and 48%, respectively). The actuarial median survival time for the entire group was 13.4 months. The regimen was well tolerated, with only seven hospitalizations for treatment of neutropenia and fever (4% of courses) and no treatment-related deaths. The combination of paclitaxel, carboplatin, and extended-schedule etoposide is highly active and well tolerated in patients with carcinoma of unknown primary tumor site. Response rates and survival in this multicenter community-based trial compare favorably with all previously studied empiric regimens. In addition, this regimen is substantially less toxic and easier to administer than the cisplatin-based regimens previously used in this setting. If this level of efficacy is confirmed, this treatment should be considered standard first-line therapy in patients with carcinoma of unknown primary tumor site.

Treating Advanced Cancer in an Era of Increasing Cost Consciousness

IN THIS ISSUEof theARCHIVES, Schapira and Jarrett 1 critically examine the cost vs the benefit of various diagnostic procedures in the evaluation of patients with carcinoma of unknown primary site. In an era with an increasing focus on the cost-effectiveness of therapy, this article is one of a burgeoning number of analyses aimed at optimizing the use of the American health care dollar. It is likely that diseases considered to be poorly treated, both malignant and nonmalignant, will be frequent targets for such analysis. For most patients with carcinoma of unknown primary site, treatment remains relatively ineffective. It has been well documented that once the diagnosis of metastatic cancer is established, the yield of extensive radiologic and endoscopic procedures in identifying a primary site is low. All current textbooks of internal medicine and medical oncology recommend a limited diagnostic evaluation, including only a routine chemistry profile, hemogram, chest

Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site.

A minority of patients with poorly differentiated carcinoma achieve a complete response to cisplatin therapy. Recently, specific chromosomal abnormalities have been described for several solid tumor malignancies. Molecular and cytogenetic techniques were used to study tumors of patients with midline carcinoma of unknown primary site. Forty patients with poorly differentiated carcinoma of unknown primary site had fresh tumor samples studied by cytogenetic analysis, Southern blot analysis for 12p copy number, and fluorescence in situ hybridization (FISH) for the identification of i(12p) and chromosome 12 aneuploidy. The response to cisplatin therapy was correlated to the diagnosis provided by the genetic studies. In 17 (42%) patients, a diagnosis was suggested by the genetic studies. This included a germ cell tumor in 12 (30%) patients by the finding of i(12p), increased 12p copy number, or a deletion of the long arm of chromosome 12. In five patients, a specific diagnosis other than germ cell tumor was suggested by tumor karyotype. These were neuroepithelioma, lymphoma, desmoplastic small-cell tumor, melanoma, and clear-cell sarcoma. The 75% response proportion to cisplatin therapy in patients with tumors showing chromosome structural abnormalities of germ cell tumor was greater than the 18% response proportion in patients for whom no diagnosis was provided (P = .002). Molecular and cytogenetic studies are useful in establishing specific diagnoses in patients with poorly differentiated carcinomas of unknown primary site. This group of tumors is heterogeneous and is composed of germ cell tumors, melanoma, lymphoma, neuroepithelioma, and desmoplastic small-round-cell tumor in addition to some that are not yet classifiable. Response to cisplatin therapy correlates with the finding of i(12p) in tumor by either molecular or cytogenetic studies.