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• W2045984627 abstract "Two percent to 5% of patients with cancer present with metastatic disease from an undiagnosed primary tumor.1Hainsworth JD Greco FA. Treatment of patients with cancer of unknown primary site.Important Adv Oncol. 1991; : 173-190PubMed Google Scholar, 2Hainsworth JD Greco FA. Management of patients with cancer of unknown primary site.Oncology (Huntington). 2000; 14: 563-574PubMed Google Scholar Although this is indicative of advanced malignancy, a proportion of these patients will respond to therapy. This may not be curative, but treatment may inhibit tumor growth, improve quality of life, and prolong survival.3Hainsworth JD Erland JB Kalman LA Schreeder MT Greco FA. Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide.J Clin Oncol. 1997; 15: 2385-2393PubMed Google Scholar, 4Briasoulis E Kalofonos H Bafaloukos D Samantas E Fountzilas G Xiros N et al.Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study.J Clin Oncol. 2000; 18: 3101-3107PubMed Google Scholar, 5Fong Y Fortner J Sun RL Brennan MF Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.Ann Surg. 1999; 230: 309-318Crossref PubMed Scopus (3038) Google Scholar In some instances patients may survive indefinitely. Therefore, in patients with metastatic cancer of unknown origin, the goal is to diagnose those tumors likely to respond to specific therapies while minimizing the use of time-consuming, costly, invasive tests in a search for tumors that are likely to be poorly responsive.A number of new agents have been shown to be potentially beneficial in the treatment of GI cancers.6Bleiberg H. CPT-11 in gastrointestinal cancer.Eur J Cancer. 1999; 35: 371-379Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 7Rosenberg L. Pancreatic cancer: a review of emerging therapies.Drugs. 2000; 59: 1071-1089Crossref PubMed Scopus (82) Google Scholar, 8Hainsworth JD Meluch AA Greco PA. Paclitaxel, carboplatin, and long-term continuous 5-fluorouracil infusion in the treatment of upper aerodigestive malignancies: preliminary results of phase II trial.Semin Oncol. 1997; 24 ([abstract]): S19Google Scholar In parallel, the armamentarium of tests for the diagnosis of cancer has expanded. In light of these developments, it is important to reappraise current practice with respect to the evaluation of patients with occult primary cancers. This is illustrated by metastatic colon cancer, a disease in which a significant survival benefit can be obtained in selected patients by surgical resection of liver metastasis and the use of combinations of chemotherapeutic agents. Thus, colonoscopy can have an important role in the evaluation of patients with metastatic colon cancer.5Fong Y Fortner J Sun RL Brennan MF Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.Ann Surg. 1999; 230: 309-318Crossref PubMed Scopus (3038) Google Scholar, 9Saltz LB Cox JV Blanke C Rosen LS Fehrenbacher L Moore MJ et al.Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group.N Engl J Med. 2000; 343 ([see comments]): 905-914Crossref PubMed Scopus (2847) Google ScholarApproximately 80% of patients with metastases from an undiagnosed primary tumor will have adenocarcinoma.2Hainsworth JD Greco FA. Management of patients with cancer of unknown primary site.Oncology (Huntington). 2000; 14: 563-574PubMed Google Scholar In the majority, the neoplasm will have originated in the pancreas, GI tract, or lung. Pancreatic cancer generally carries a poor prognosis because the disease is frequently advanced at presentation.10Staley CA Lee JE Cleary KR Abbruzzese JL Fenoglio CJ Rich TA et al.Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head.Am J Surg. 1996; 171: 118-124Abstract Full Text PDF PubMed Scopus (221) Google Scholar Surgical resection offers the best chance of survival.11Nitecki SS San MG Colby TV van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving?.Ann Surg. 1995; 221: 59-66Crossref PubMed Scopus (600) Google Scholar, 12Yeo CJ Cameron JL Lillemoe KD Sitzmann JV Hruban RH Goodman SN et al.Pancreaticoduodenectomy for cancer of the head of the pancreas: 201 patients.Ann Surg. 1995; 221: 721-731Crossref PubMed Scopus (963) Google Scholar However, this is technically possible in less than 20% of patients because of locally advanced or metastatic disease.13Geer RJ Brennan ME. Prognostic indicators for survival after resection of pancreatic adenocarcinoma.Am J Surg. 1993; 165: 68-72Abstract Full Text PDF PubMed Scopus (755) Google Scholar, 14Michelassi F Erroi F Dawson PJ Pietrabissa A Noda S Handcock M et al.Experience with 647 consecutive tumors of the duodenum, ampulla, head of the pancreas, and distal common bile duct.Ann Surg. 1989; 210: 544-554Crossref PubMed Scopus (230) Google Scholar Median survival for patients with untreated advanced disease is 4 months.15Flanders TY Foulkes WD. Pancreatic adenocarcinoma: epidemiology and genetics [review].J Med Genetics. 1996; 33: 889-898Crossref PubMed Scopus (73) Google Scholar, 16Bakkevold KE Pettersen A Amesjo B Espehaug B. Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and the papilla of Vater.Br J Surg. 1990; 77: 725-730Crossref PubMed Scopus (77) Google ScholarPromising results have been obtained with the use of several new chemotherapeutic agents in the treatment of locally invasive and metastatic pancreatic cancer in phase II and III clinical trials.17Carmichael J. Clinical response benefit in patients with advanced pancreatic cancer. Role of gemcitabine.Digestion. 1997; 58: 503-507Crossref PubMed Scopus (34) Google Scholar, 18Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer.Oncology. 2001; 60: 8-18Crossref PubMed Scopus (126) Google Scholar One such agent, gemcitabine, is structurally similar to cytarabine and has relatively low toxicity. When compared with 5-fluorouracil (5-FU), gemcitabine has produced significant clinical benefits and prolonged survival (beyond 12 months in some patients).19Bruckner HW Crown J McKenna A Hart R. Leucovorin and 5-fluorouracil as a treatment for disseminated cancer of the pancreas and unknown primary tumors.Cancer Research. 1988; 48: 5570-5572PubMed Google Scholar Irinotecan is another agent for which efficacy has been demonstrated in the treatment of GI tumors. Interim results from a phase II trial of irinotecan-gemcitabine combination chemotherapy in advanced pancreatic cancer are encouraging, as are the results from a phase II trial in which 5-FU was combined with gemcitabine.20Rocha Lima C Savarese D Bruckner H Dudeck A Echardt J Hainsworth J et al.Multicenter phase II trial of first-line irinotecan and gemcitabine (irinogem) in patients with locally advanced or metastatic pancreatic cancer.Proceedings of American Society of Clinical Oncology. 2000; 19 ([abstract]): 263aGoogle Scholar, 21Cascinu S Frontini L Comella G Barni S Labianca R Battelli N et al.Intensive weekly chemotherapy is not effective in advanced pancreatic cancer patients: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).Br J Cancer. 1999; 79: 491-494Crossref PubMed Scopus (4) Google Scholar Thus, specific therapies are emerging that offer clinical benefits, including lengthened survival, to patients with advanced pancreatic cancer. Other therapies with enhanced results will likely evolve in the future.EUS is being used increasingly for the diagnosis of pancreatic cancer.22Rösch T Lorenz R Braig C Classen M. Endoscopic ultrasonography in diagnosis and staging of pancreatic and biliary tumors.Endoscopy. 1992; 24: 304-308Crossref PubMed Scopus (63) Google Scholar, 23Palazzo L Roseau G Gayet B Vilgrain V Belghiti J Fekete F et al.Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma. Results of a prospective study with comparison to ultrasonography and CT scan.Endoscopy. 1993; 25: 143-150Crossref PubMed Scopus (404) Google Scholar, 24Tio TL Sie LH Kallimanis G Luiken GJ Kimmings AN Huibregtse K et al.Staging of ampullary and pancreatic carcinoma: comparison between endosonography and surgery.Gastrointest Endosc. 1996; 44: 706-713Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 25Yasuda K Mukai H Nakajima M Kawai K. Staging of pancreatic carcinoma by endoscopic ultrasonography.Endoscopy. 1993; 25: 151-155Crossref PubMed Scopus (143) Google Scholar, 26Rösch T Braig C Gain T Feuerbach S Siewert JR Schusdziarra V et al.Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography. Comparison with conventional sonography, computed tomography, and angiography.Gastroenterology. 1992; 102: 188-199PubMed Google Scholar It is both sensitive and specific with respect to this cancer, particularly when combined with fine needle aspiration.27Chang KJ Katz KD Durbin TB Erickson RA Butler JA Lin F et al.Endoscopic ultrasound-guided fine-needle aspiration.Gastrointest Endosc. 1994; 40: 694-699PubMed Google Scholar The evaluation of patients with metastatic cancer and an undiagnosed primary tumor usually includes CT of the abdomen. However, in terms of sensitivity and specificity for the diagnosis of pancreatic cancer, EUS is superior to CT.23Palazzo L Roseau G Gayet B Vilgrain V Belghiti J Fekete F et al.Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma. Results of a prospective study with comparison to ultrasonography and CT scan.Endoscopy. 1993; 25: 143-150Crossref PubMed Scopus (404) Google Scholar, 26Rösch T Braig C Gain T Feuerbach S Siewert JR Schusdziarra V et al.Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography. Comparison with conventional sonography, computed tomography, and angiography.Gastroenterology. 1992; 102: 188-199PubMed Google Scholar It is therefore likely that in some cases of occult primary cancer EUS could detect pancreatic primary tumors not evident on CT. EUS might be particularly useful when CT suggests the presence of nonspecific abnormalities in the pancreas or in cases in which colonoscopy has been negative. EUS can also provide an endoscopic survey of the upper GI tract with the potential to identify an unsuspected gastric or esophageal primary neoplasm, tumors for which specific chemotherapeutic regimens are also emerging.6Bleiberg H. CPT-11 in gastrointestinal cancer.Eur J Cancer. 1999; 35: 371-379Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 28Beaujard AC Glehen O Caillot JL Francois Y Bienvenu J Panteix G et al.Intraperitoneal chemohyperthermia with mitomycin C for digestive tract cancer patients with peritoneal carcinomatosis.Cancer. 2000; 88: 2512-2519Crossref PubMed Scopus (139) Google Scholar, 29Bjarnason GA Cripps C Goel R Fine S Oza AM Skillings JR et al.Phase I-II study of 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and long-term oral etoposide (FLAME) in unresectable or metastatic gastric cancer.Am J Clin Oncol. 1998; 21: 537-542Crossref PubMed Google Scholar, 30Kollmannsberger C Quietzsch D Haag C Lingenfelser T Schroeder M Hartmann JT et al.A phase II study of paclitaxel, weekly, 24-hour continuous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer.Br J Cancer. 2000; 83: 458-462Crossref PubMed Scopus (116) Google ScholarAt present EUS is not routinely performed in the clinical setting of metastatic cancer of unknown primary source. Erickson and Garza31Erickson RA Garza AA. Impact of endoscopic ultrasound on the management and outcome of pancreatic carcinoma.Am J Gastroenterol. 2000; 95: 2248-2254Crossref PubMed Google Scholar reported an increase in the number of pancreatic cancer diagnoses at a large referral center after the introduction of EUS. These investigators suggested that the increase may be attributable to the endosonographic identification of pancreatic primary tumors in patients who would otherwise have been given a diagnosis of adenocarcinoma of unknown source. In a recent survey, respondents indicated that EUS-guided fine needle analysis of liver metastases identified a pancreatic primary tumor in 17 of 18 cases in which CT of the pancreas had been negative.32Ten Berge J Hawes RH Hoffmann BJ van Enekevort C Erickson RA Catalano M et al.EUS guided fine needle aspiration of the liver. Indications, yield, and safety from an international survey of 167 cases.Gastrointest Endosc. 2001; 53 ([abstract]): AB176Google Scholar Although the possibility of recall bias cannot be excluded, this observation suggests that EUS may have a role in the evaluation of patients with metastatic adenocarcinoma and an occult primary, particularly if colonoscopy does not disclose the origin of cancer. A prospective study would be required to confirm this suggestion.Other types of evidence may point to a pancreatic primary tumor in patients with metastatic disease of uncertain origin. An elevated CA 19-9 or cytokeratin immunostaining patterns in metastatic deposits may prompt closer examination of the pancreas.33Andriulli A Gindro T Piantino P Farini R Cavallini G Piazzi L et al.Prospective evaluation of the diagnostic efficacy of CA 19-9 assay as a marker for gastrointestinal cancers.Digestion. 1986; 33: 26-33Crossref PubMed Scopus (44) Google Scholar, 34Tot T. Adenocarcinomas metastatic to the liver: the value of cytokeratins 20 and 7 in the search for unknown primary tumors.Cancer. 1999; 85: 171-177Crossref PubMed Scopus (160) Google Scholar Positron emission tomography (PET) scanning, which identifies the preferential uptake of 18-fluorodeoxyglucose by malignant cells, is another alternative investigation in this setting. PET provides whole-body scanning in the search for cancerous deposits and has a proven role in the diagnosis of pancreatic cancer.35Rose DM Delbeke D Beauchamp RD Chapman WC Sandler MP Sharp KW et al.18-Fluorodeoxyglucose-positron emission tomography in the management of patients with suspected pancreatic cancer.Ann Surg. 1999; 229: 729-737Crossref PubMed Scopus (171) Google Scholar Several small studies have evaluated the diagnostic potential of PET in the setting of an occult primary cancer.36Bohuslavizki KH Klutmann S Kroger S Sonnemann U Buchert R Werner JA et al.FDG PET detection of unknown primary tumors.J Nucl Med. 2000; 41: 816-822PubMed Google Scholar, 37Dragoiescu C Comans BE Van Riel A Hoekstra OS. F-18 fluorodeoxyglucose positron emission tomographic imaging: in search of an unknown primary tumor.Clin Nucl Med. 2000; 25: 308-309Crossref PubMed Google Scholar Primary lesions, including pancreatic cancer, have been identified in 25% to 75% of cases. However, false-positive results are relatively frequent.38Lonneux M Reffad A. Metastases from unknown primary tumor. PET-FDG as initial diagnostic procedure?.Clin Positron Imaging. 2000; 3: 137-141Crossref PubMed Scopus (35) Google Scholar Nevertheless, PET scanning is minimally invasive and surveys the entire body for the presence of tumors.Every decision to include additional diagnostic tests in the search for an occult primary tumor must balance the benefits of specific therapy for a given metastatic tumor against the disadvantages of a prolonged, potentially fruitless search in a patient who will likely have additional priorities. The patient must be provided with the diagnostic options, therapeutic choices, and likely outcomes, and must be assisted in reaching a decision as to which short-to-medium-term benefits, whether survival or quality of life, are meaningful.Untreated, patients with metastatic carcinoma from an undiagnosed primary source have a median survival of 4 to 6 months.1Hainsworth JD Greco FA. Treatment of patients with cancer of unknown primary site.Important Adv Oncol. 1991; : 173-190PubMed Google Scholar In those in whom the diagnosis remains elusive, best-guess therapy based on tests already performed, or regimens of proven efficacy in the treatment of undiagnosed primary cancer, may be offered. The goal(s) of treatment may comprise palliation, cytotoxic chemotherapy, or both. For example, carboplatin-paclitaxel-based regimens improve median survival to 10 to 15 months.4Briasoulis E Kalofonos H Bafaloukos D Samantas E Fountzilas G Xiros N et al.Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study.J Clin Oncol. 2000; 18: 3101-3107PubMed Google Scholar Unfortunately, patients with visceral metastasis appear to fall into the group that responds poorly to this therapeutic regimen.Newer therapies for metastatic cancer of the pancreas prolong survival and improve quality of life. EUS can potentially diagnose such tumors when the primary tumor is not identified by CT. However, the PET scan, by its ability to survey the whole body, appears to offer the best chance of finding the primary cancer. Therefore, EUS should be reserved for cases in which the index of suspicion for pancreatic cancer is high and common primary tumors in other organs such as the colon, breast, and lung have been excluded. Among the various tests available, the choice will be also be dictated by local availability and expertise. If a search for an occult primary tumor is undertaken, each test used should be minimally invasive, have a high yield, and lead to meaningful therapeutic gains for the patient. Unfortunately, even with specific treatment, metastatic cancer of the pancreas carries a poor prognosis. In the event that the primary tumor remains undiagnosed, combination therapy with carboplatin/paclitaxel affords the best outcome at present. However, ongoing advances in cancer treatment necessitate continuous reevaluation of the approach to patients with metastatic cancer and an unidentified primary tumor. Two percent to 5% of patients with cancer present with metastatic disease from an undiagnosed primary tumor.1Hainsworth JD Greco FA. Treatment of patients with cancer of unknown primary site.Important Adv Oncol. 1991; : 173-190PubMed Google Scholar, 2Hainsworth JD Greco FA. Management of patients with cancer of unknown primary site.Oncology (Huntington). 2000; 14: 563-574PubMed Google Scholar Although this is indicative of advanced malignancy, a proportion of these patients will respond to therapy. This may not be curative, but treatment may inhibit tumor growth, improve quality of life, and prolong survival.3Hainsworth JD Erland JB Kalman LA Schreeder MT Greco FA. Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide.J Clin Oncol. 1997; 15: 2385-2393PubMed Google Scholar, 4Briasoulis E Kalofonos H Bafaloukos D Samantas E Fountzilas G Xiros N et al.Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study.J Clin Oncol. 2000; 18: 3101-3107PubMed Google Scholar, 5Fong Y Fortner J Sun RL Brennan MF Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.Ann Surg. 1999; 230: 309-318Crossref PubMed Scopus (3038) Google Scholar In some instances patients may survive indefinitely. Therefore, in patients with metastatic cancer of unknown origin, the goal is to diagnose those tumors likely to respond to specific therapies while minimizing the use of time-consuming, costly, invasive tests in a search for tumors that are likely to be poorly responsive. A number of new agents have been shown to be potentially beneficial in the treatment of GI cancers.6Bleiberg H. CPT-11 in gastrointestinal cancer.Eur J Cancer. 1999; 35: 371-379Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 7Rosenberg L. Pancreatic cancer: a review of emerging therapies.Drugs. 2000; 59: 1071-1089Crossref PubMed Scopus (82) Google Scholar, 8Hainsworth JD Meluch AA Greco PA. Paclitaxel, carboplatin, and long-term continuous 5-fluorouracil infusion in the treatment of upper aerodigestive malignancies: preliminary results of phase II trial.Semin Oncol. 1997; 24 ([abstract]): S19Google Scholar In parallel, the armamentarium of tests for the diagnosis of cancer has expanded. In light of these developments, it is important to reappraise current practice with respect to the evaluation of patients with occult primary cancers. This is illustrated by metastatic colon cancer, a disease in which a significant survival benefit can be obtained in selected patients by surgical resection of liver metastasis and the use of combinations of chemotherapeutic agents. Thus, colonoscopy can have an important role in the evaluation of patients with metastatic colon cancer.5Fong Y Fortner J Sun RL Brennan MF Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.Ann Surg. 1999; 230: 309-318Crossref PubMed Scopus (3038) Google Scholar, 9Saltz LB Cox JV Blanke C Rosen LS Fehrenbacher L Moore MJ et al.Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group.N Engl J Med. 2000; 343 ([see comments]): 905-914Crossref PubMed Scopus (2847) Google Scholar Approximately 80% of patients with metastases from an undiagnosed primary tumor will have adenocarcinoma.2Hainsworth JD Greco FA. Management of patients with cancer of unknown primary site.Oncology (Huntington). 2000; 14: 563-574PubMed Google Scholar In the majority, the neoplasm will have originated in the pancreas, GI tract, or lung. Pancreatic cancer generally carries a poor prognosis because the disease is frequently advanced at presentation.10Staley CA Lee JE Cleary KR Abbruzzese JL Fenoglio CJ Rich TA et al.Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head.Am J Surg. 1996; 171: 118-124Abstract Full Text PDF PubMed Scopus (221) Google Scholar Surgical resection offers the best chance of survival.11Nitecki SS San MG Colby TV van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving?.Ann Surg. 1995; 221: 59-66Crossref PubMed Scopus (600) Google Scholar, 12Yeo CJ Cameron JL Lillemoe KD Sitzmann JV Hruban RH Goodman SN et al.Pancreaticoduodenectomy for cancer of the head of the pancreas: 201 patients.Ann Surg. 1995; 221: 721-731Crossref PubMed Scopus (963) Google Scholar However, this is technically possible in less than 20% of patients because of locally advanced or metastatic disease.13Geer RJ Brennan ME. Prognostic indicators for survival after resection of pancreatic adenocarcinoma.Am J Surg. 1993; 165: 68-72Abstract Full Text PDF PubMed Scopus (755) Google Scholar, 14Michelassi F Erroi F Dawson PJ Pietrabissa A Noda S Handcock M et al.Experience with 647 consecutive tumors of the duodenum, ampulla, head of the pancreas, and distal common bile duct.Ann Surg. 1989; 210: 544-554Crossref PubMed Scopus (230) Google Scholar Median survival for patients with untreated advanced disease is 4 months.15Flanders TY Foulkes WD. Pancreatic adenocarcinoma: epidemiology and genetics [review].J Med Genetics. 1996; 33: 889-898Crossref PubMed Scopus (73) Google Scholar, 16Bakkevold KE Pettersen A Amesjo B Espehaug B. Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and the papilla of Vater.Br J Surg. 1990; 77: 725-730Crossref PubMed Scopus (77) Google Scholar Promising results have been obtained with the use of several new chemotherapeutic agents in the treatment of locally invasive and metastatic pancreatic cancer in phase II and III clinical trials.17Carmichael J. Clinical response benefit in patients with advanced pancreatic cancer. Role of gemcitabine.Digestion. 1997; 58: 503-507Crossref PubMed Scopus (34) Google Scholar, 18Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer.Oncology. 2001; 60: 8-18Crossref PubMed Scopus (126) Google Scholar One such agent, gemcitabine, is structurally similar to cytarabine and has relatively low toxicity. When compared with 5-fluorouracil (5-FU), gemcitabine has produced significant clinical benefits and prolonged survival (beyond 12 months in some patients).19Bruckner HW Crown J McKenna A Hart R. Leucovorin and 5-fluorouracil as a treatment for disseminated cancer of the pancreas and unknown primary tumors.Cancer Research. 1988; 48: 5570-5572PubMed Google Scholar Irinotecan is another agent for which efficacy has been demonstrated in the treatment of GI tumors. Interim results from a phase II trial of irinotecan-gemcitabine combination chemotherapy in advanced pancreatic cancer are encouraging, as are the results from a phase II trial in which 5-FU was combined with gemcitabine.20Rocha Lima C Savarese D Bruckner H Dudeck A Echardt J Hainsworth J et al.Multicenter phase II trial of first-line irinotecan and gemcitabine (irinogem) in patients with locally advanced or metastatic pancreatic cancer.Proceedings of American Society of Clinical Oncology. 2000; 19 ([abstract]): 263aGoogle Scholar, 21Cascinu S Frontini L Comella G Barni S Labianca R Battelli N et al.Intensive weekly chemotherapy is not effective in advanced pancreatic cancer patients: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).Br J Cancer. 1999; 79: 491-494Crossref PubMed Scopus (4) Google Scholar Thus, specific therapies are emerging that offer clinical benefits, including lengthened survival, to patients with advanced pancreatic cancer. Other therapies with enhanced results will likely evolve in the future. EUS is being used increasingly for the diagnosis of pancreatic cancer.22Rösch T Lorenz R Braig C Classen M. Endoscopic ultrasonography in diagnosis and staging of pancreatic and biliary tumors.Endoscopy. 1992; 24: 304-308Crossref PubMed Scopus (63) Google Scholar, 23Palazzo L Roseau G Gayet B Vilgrain V Belghiti J Fekete F et al.Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma. Results of a prospective study with comparison to ultrasonography and CT scan.Endoscopy. 1993; 25: 143-150Crossref PubMed Scopus (404) Google Scholar, 24Tio TL Sie LH Kallimanis G Luiken GJ Kimmings AN Huibregtse K et al.Staging of ampullary and pancreatic carcinoma: comparison between endosonography and surgery.Gastrointest Endosc. 1996; 44: 706-713Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 25Yasuda K Mukai H Nakajima M Kawai K. Staging of pancreatic carcinoma by endoscopic ultrasonography.Endoscopy. 1993; 25: 151-155Crossref PubMed Scopus (143) Google Scholar, 26Rösch T Braig C Gain T Feuerbach S Siewert JR Schusdziarra V et al.Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography. Comparison with conventional sonography, computed tomography, and angiography.Gastroenterology. 1992; 102: 188-199PubMed Google Scholar It is both sensitive and specific with respect to this cancer, particularly when combined with fine needle aspiration.27Chang KJ Katz KD Durbin TB Erickson RA Butler JA Lin F et al.Endoscopic ultrasound-guided fine-needle aspiration.Gastrointest Endosc. 1994; 40: 694-699PubMed Google Scholar The evaluation of patients with metastatic cancer and an undiagnosed primary tumor usually includes CT of the abdomen. However, in terms of sensitivity and specificity for the diagnosis of pancreatic cancer, EUS is superior to CT.23Palazzo L Roseau G Gayet B Vilgrain V Belghiti J Fekete F et al.Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma. Results of a prospective study with comparison to ultrasonography and CT scan.Endoscopy. 1993; 25: 143-150Crossref PubMed Scopus (404) Google Scholar, 26Rösch T Braig C Gain T Feuerbach S Siewert JR Schusdziarra V et al.Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography. Comparison with conventional sonography, computed tomography, and angiography.Gastroenterology. 1992; 102: 188-199PubMed Google Scholar It is therefore likely that in some cases of occult primary cancer EUS could detect pancreatic primary tumors not evident on CT. EUS might be particularly useful when CT suggests the presence of nonspecific abnormalities in the pancreas or in cases in which colonoscopy has been negative. EUS can also provide an endoscopic survey of the upper GI tract with the potential to identify an unsuspected gastric or esophageal primary neoplasm, tumors for which specific chemotherapeutic regimens are also emerging.6Bleiberg H. CPT-11 in gastrointestinal cancer.Eur J Cancer. 1999; 35: 371-379Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 28Beaujard AC Glehen O Caillot JL Francois Y Bienvenu J Panteix G et al.Intraperitoneal chemohyperthermia with mitomycin C for digestive tract cancer patients with peritoneal carcinomatosis.Cancer. 2000; 88: 2512-2519Crossref PubMed Scopus (139) Google Scholar, 29Bjarnason GA Cripps C Goel R Fine S Oza AM Skillings JR et al.Phase I-II study of 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and long-term oral etoposide (FLAME) in unresectable or metastatic gastric cancer.Am J Clin Oncol. 1998; 21: 537-542Crossref PubMed Google Scholar, 30Kollmannsberger C Quietzsch D Haag C Lingenfelser T Schroeder M Hartmann JT et al.A phase II study of paclitaxel, weekly, 24-hour continuous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer.Br J Cancer. 2000; 83: 458-462Crossref PubMed Scopus (116) Google Scholar At present EUS is not routinely performed in the clinical setting of metastatic cancer of unknown primary source. Erickson and Garza31Erickson RA Garza AA. Impact of endoscopic ultrasound on the management and outcome of pancreatic carcinoma.Am J Gastroenterol. 2000; 95: 2248-2254Crossref PubMed Google Scholar reported an increase in the number of pancreatic cancer diagnoses at a large referral center after the introduction of EUS. These investigators suggested that the increase may be attributable to the endosonographic identification of pancreatic primary tumors in patients who would otherwise have been given a diagnosis of adenocarcinoma of unknown source. In a recent survey, respondents indicated that EUS-guided fine needle analysis of liver metastases identified a pancreatic primary tumor in 17 of 18 cases in which CT of the pancreas had been negative.32Ten Berge J Hawes RH Hoffmann BJ van Enekevort C Erickson RA Catalano M et al.EUS guided fine needle aspiration of the liver. Indications, yield, and safety from an international survey of 167 cases.Gastrointest Endosc. 2001; 53 ([abstract]): AB176Google Scholar Although the possibility of recall bias cannot be excluded, this observation suggests that EUS may have a role in the evaluation of patients with metastatic adenocarcinoma and an occult primary, particularly if colonoscopy does not disclose the origin of cancer. A prospective study would be required to confirm this suggestion. Other types of evidence may point to a pancreatic primary tumor in patients with metastatic disease of uncertain origin. An elevated CA 19-9 or cytokeratin immunostaining patterns in metastatic deposits may prompt closer examination of the pancreas.33Andriulli A Gindro T Piantino P Farini R Cavallini G Piazzi L et al.Prospective evaluation of the diagnostic efficacy of CA 19-9 assay as a marker for gastrointestinal cancers.Digestion. 1986; 33: 26-33Crossref PubMed Scopus (44) Google Scholar, 34Tot T. Adenocarcinomas metastatic to the liver: the value of cytokeratins 20 and 7 in the search for unknown primary tumors.Cancer. 1999; 85: 171-177Crossref PubMed Scopus (160) Google Scholar Positron emission tomography (PET) scanning, which identifies the preferential uptake of 18-fluorodeoxyglucose by malignant cells, is another alternative investigation in this setting. PET provides whole-body scanning in the search for cancerous deposits and has a proven role in the diagnosis of pancreatic cancer.35Rose DM Delbeke D Beauchamp RD Chapman WC Sandler MP Sharp KW et al.18-Fluorodeoxyglucose-positron emission tomography in the management of patients with suspected pancreatic cancer.Ann Surg. 1999; 229: 729-737Crossref PubMed Scopus (171) Google Scholar Several small studies have evaluated the diagnostic potential of PET in the setting of an occult primary cancer.36Bohuslavizki KH Klutmann S Kroger S Sonnemann U Buchert R Werner JA et al.FDG PET detection of unknown primary tumors.J Nucl Med. 2000; 41: 816-822PubMed Google Scholar, 37Dragoiescu C Comans BE Van Riel A Hoekstra OS. F-18 fluorodeoxyglucose positron emission tomographic imaging: in search of an unknown primary tumor.Clin Nucl Med. 2000; 25: 308-309Crossref PubMed Google Scholar Primary lesions, including pancreatic cancer, have been identified in 25% to 75% of cases. However, false-positive results are relatively frequent.38Lonneux M Reffad A. Metastases from unknown primary tumor. PET-FDG as initial diagnostic procedure?.Clin Positron Imaging. 2000; 3: 137-141Crossref PubMed Scopus (35) Google Scholar Nevertheless, PET scanning is minimally invasive and surveys the entire body for the presence of tumors. Every decision to include additional diagnostic tests in the search for an occult primary tumor must balance the benefits of specific therapy for a given metastatic tumor against the disadvantages of a prolonged, potentially fruitless search in a patient who will likely have additional priorities. The patient must be provided with the diagnostic options, therapeutic choices, and likely outcomes, and must be assisted in reaching a decision as to which short-to-medium-term benefits, whether survival or quality of life, are meaningful. Untreated, patients with metastatic carcinoma from an undiagnosed primary source have a median survival of 4 to 6 months.1Hainsworth JD Greco FA. Treatment of patients with cancer of unknown primary site.Important Adv Oncol. 1991; : 173-190PubMed Google Scholar In those in whom the diagnosis remains elusive, best-guess therapy based on tests already performed, or regimens of proven efficacy in the treatment of undiagnosed primary cancer, may be offered. The goal(s) of treatment may comprise palliation, cytotoxic chemotherapy, or both. For example, carboplatin-paclitaxel-based regimens improve median survival to 10 to 15 months.4Briasoulis E Kalofonos H Bafaloukos D Samantas E Fountzilas G Xiros N et al.Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study.J Clin Oncol. 2000; 18: 3101-3107PubMed Google Scholar Unfortunately, patients with visceral metastasis appear to fall into the group that responds poorly to this therapeutic regimen. Newer therapies for metastatic cancer of the pancreas prolong survival and improve quality of life. EUS can potentially diagnose such tumors when the primary tumor is not identified by CT. However, the PET scan, by its ability to survey the whole body, appears to offer the best chance of finding the primary cancer. Therefore, EUS should be reserved for cases in which the index of suspicion for pancreatic cancer is high and common primary tumors in other organs such as the colon, breast, and lung have been excluded. Among the various tests available, the choice will be also be dictated by local availability and expertise. If a search for an occult primary tumor is undertaken, each test used should be minimally invasive, have a high yield, and lead to meaningful therapeutic gains for the patient. Unfortunately, even with specific treatment, metastatic cancer of the pancreas carries a poor prognosis. In the event that the primary tumor remains undiagnosed, combination therapy with carboplatin/paclitaxel affords the best outcome at present. However, ongoing advances in cancer treatment necessitate continuous reevaluation of the approach to patients with metastatic cancer and an unidentified primary tumor." @default.
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