今日の臨床サポート

原発不明癌

著者: 米盛勧 国立がん研究センター中央病院

監修: 田村研治 国立がん研究センター中央病院

著者校正/監修レビュー済:2021/04/07
参考ガイドライン:
患者向け説明資料

概要・推奨   

  1. 原発不明癌における精査目的でのFDG-PET(またはPET/CT)は、部原発不明、あるいは単一転移病と考えられた症例で検討する。それ以外では、かの画像診断で原発巣を特定できない場合には検討する(推奨度2)
  1. 原発不明癌の原発巣精査において組織診断は推奨される(推奨度1)
  1. 原発不明癌の原発巣の同定に免疫組織化学染色を用いた病理学的診断は推奨される(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必 要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
  1. 閲覧にはご契約が必 要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必 要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必 要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご
  1. 閲覧にはご契約が必 要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご
  1. 閲覧にはご契約が必 要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
米盛勧 : 未申告[2021年]
監修:田村研治 : 未申告[2021年]

改訂のポイント:
  1. 原発不明がん診療ガイドライン改訂第2版に基づき、主に診断についての改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 原発不明癌とは、転移巣が先に発見され、転移のもととなった臓器が不明である癌のことである。
  1. 臨床的に十分な全身検索を行っても原発巣が特定されず、かつ悪性腫瘍が確定診断されている病態と定義される。
  1. 原発巣が自然に消退しているか微小で特定できない、疾患が進行し特定できないなどの状況が推測されている。実際は、さまざまな悪性腫瘍が混在している不均一な疾患グループと考えられている。
  1. 全悪性腫瘍のうち約1~5%を占めるとされる。原因やリスクファクターは特定されていない。転移性腫瘍のため、多くは転移性病変による症状を呈する。
  1. 原発不明癌において特定の治療を行うべきサブグループ(favorable subset)のなかには、再発なく長期生存する例もあり、治癒していると考えられる経過もある。それ以外のグループ(unfavorable subset)は、生存期間中央値は5~13カ月程度で予後不良な病態である。
  1. 治療方針は、以下の二つで大きく異なる。
  1. 1:病態において特定の治療を行うべきサブグループ
  1. 2:それ以外のグループ
  1. 最終的に解剖で原発巣が特定される患者は30~50%と報告されている。診療医は、原発不明癌とは多くが全経過で原発巣の特定できない病態であることを理解し、「原発巣探し」にこだわらず迅速に診断し、治療につなげていくべきである。
  1. まれな病態であり、診療には臨床腫瘍学の総合的な知識や経験を要することが多い。腫瘍内科のある専門医療機関への紹介を推奨する。
問診・診察のポイント  
  1. 「原発不明」との先入観を持たずに、原発を探す意識を持ち問診・診察をする。

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文献 

著者: Roberto C Delgado-Bolton, Cristina Fernández-Pérez, Alfredo González-Maté, José L Carreras
雑誌名: J Nucl Med. 2003 Aug;44(8):1301-14.
Abstract/Text UNLABELLED: Detection of the primary tumor has a key role in the management of patients with unknown primary tumors (UPT). The aim of this study was to perform a meta-analysis of the literature to evaluate the accuracy of (18)F-FDG PET in primary tumor detection in patients with UPT.
METHODS: Systematic methods were used to identify, select, and evaluate the methodologic quality of the studies as well as to summarize the overall findings of sensitivity, specificity, and detection capacity of the primary tumor. The search strategy consisted of identifying studies published between January 1994 and May 2001 indexed in MEDLINE and CANCERLIT. Studies identified by manually searching reference lists of retrieved studies or by reviewing abstracts from recent conference proceedings were also included. Inclusion criteria were studies that evaluated primary tumor detection with (18)F-FDG PET in patients with UPT. Exclusion criteria were duplicated studies or those outdated by subsequent ones. The statistical analysis included 95% confidence intervals (CI) of sensitivity and specificity, both in the pooled data and in the types of studies found. Variation in accuracy between studies was analyzed calculating the natural logarithm of the odds ratio (ln OR) due to study characteristics. Funnel plots of sensitivity and specificity and the summary receiver-operating-characteristic (ROC) curve were also represented.
RESULTS: Fifteen studies met the inclusion criteria and were analyzed. Although sample sizes were small, compliance with the methodologic quality criteria was adequate. Heterogeneity analysis showed that differences in the study quality did not correlate with differences in study results. The 95% CI of sensitivity and specificity presented global homogeneity, estimating the sensitivity at 0.87 (95% CI, 0.81-0.92) and the specificity at 0.71 (95% CI, 0.64-0.78). The summary ROC curve showed a good relationship between sensitivity and specificity. The ln OR presented significant values in >75% of the studies.
CONCLUSION: (18)F-FDG PET could be useful in patients with UPT for the detection of the primary tumor. (18)F-FDG PET has intermediate specificity and high sensitivity, indicating the existence of few false-negative results, an important feature in the management of oncologic patients that could suggest its utility in the initial stages of the management process.

PMID 12902422  J Nucl Med. 2003 Aug;44(8):1301-14.
著者: Kyle E Rusthoven, Mary Koshy, Arnold C Paulino
雑誌名: Cancer. 2004 Dec 1;101(11):2641-9. doi: 10.1002/cncr.20687.
Abstract/Text BACKGROUND: The authors performed a comprehensive review of the efficacy of fluorodeoxyglucose positron emission tomography (FDG-PET) in the detection of primary tumors in patients with cervical metastases from unknown primary tumors.
METHODS: Sixteen studies (involving a total of 302 patients) published between 1994 and 2003 were reviewed. These studies evaluated the role of FDG-PET in the detection of unknown primary tumors after conventional workup. In all studies, conventional workup included either panendoscopy or computed tomographic/magnetic resonance imaging, and in 10 of 16 studies, both of these diagnostic techniques were performed before diagnosis.
RESULTS: The overall sensitivity, specificity, and accuracy rates of FDG-PET in detecting unknown primary tumors were 88.3%, 74.9%, and 78.8%, respectively. Furthermore, FDG-PET detected 24.5% of tumors that were not apparent after conventional workup. FDG-PET imaging also led to the detection of previously unrecognized metastases in 27.1% of patients (regional, 15.9%; distant, 11.2%). FDG-PET had notably low specificity and a high false-positive rate (39.3%) in the tonsils. In contrast, the false-positive rates for FDG-PET of the base of tongue and hypopharynx were only 21.4% and 8.3%, respectively. FDG-PET exhibited decreased sensitivity to tumors in the base of tongue (81.5%). The sensitivity of this technique at other sites was 90.5%.
CONCLUSIONS: FDG-PET detected primary tumors that went undetected by other modalities in approximately 25% of cases and was sensitive in the detection of previously unrecognized regional or distant metastases in 27% of cases. FDG-PET had low specificity for tonsillar tumors and low sensitivity for base-of-tongue malignancies.

(c) 2004 American Cancer Society
PMID 15517576  Cancer. 2004 Dec 1;101(11):2641-9. doi: 10.1002/cncr.20・・・
著者: Pascal Sève, Claire Billotey, Christiane Broussolle, Charles Dumontet, John R Mackey
雑誌名: Cancer. 2007 Jan 15;109(2):292-9. doi: 10.1002/cncr.22410.
Abstract/Text BACKGROUND: The authors conducted a comprehensive review of the efficacy of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG-PET) in the detection of primary tumors in patients with disseminated carcinoma of unknown primary site.
METHODS: Ten studies (involving a total of 221 patients) tat were published between 1998 and 2006 were reviewed. Each study evaluated the role of FDG-PET in the detection of unknown primary tumors after a conventional diagnostic workup. Although 94% of patients had a single site of metastases, the studies otherwise were very heterogeneous in the studied population, study design, and additional diagnostic workup.
RESULTS: In 41% of patients, FDG-PET detected primary tumors that were not apparent after conventional workup. In this group of patients, the overall sensitivity, specificity, and accuracy rates of FDG-PET in detecting unknown primary tumors were 91.9%, 81.9%, and 80.5%, respectively. FDG-PET imaging also led to the detection of previously unrecognized metastases in 37% of patients. Lung cancers represented 59% of the detected tumors. FDG-PET had a notably high false-positive rate (58.3%) in tumors of the lower digestive tract. FDG-PET altered the clinical management in 34.7% of patients. Most of those patients (53%) received specific chemotherapy for lung and pancreatic cancers; whereas 12% received specific therapy for breast, ovarian, and prostate cancers; and 14% underwent surgery with curative intent.
CONCLUSIONS: FDG-PET was an efficient method for detecting primary tumors that were undetected by other modalities and was sensitive for the detection of previously unrecognized metastases. FDG-PET significantly changed clinical management in approximately one-third of the patients studied.

PMID 17167760  Cancer. 2007 Jan 15;109(2):292-9. doi: 10.1002/cncr.224・・・
著者: Thomas C Kwee, Robert M Kwee
雑誌名: Eur Radiol. 2009 Mar;19(3):731-44. doi: 10.1007/s00330-008-1194-4. Epub 2008 Oct 17.
Abstract/Text The aim of this study was to systematically review and meta-analyze published data on the diagnostic performance of combined 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the detection of primary tumors in patients with cancer of unknown primary (CUP). A systematic search for relevant studies was performed of the PubMed/MEDLINE and Embase databases. Methodological quality of the included studies was assessed. Reported detection rates, sensitivities and specificities were meta-analyzed. Subgroup analyses were performed if results of individual studies were heterogeneous. The 11 included studies, comprising a total sample size of 433 patients with CUP, had moderate methodological quality. Overall primary tumor detection rate, pooled sensitivity and specificity of FDG-PET/CT were 37%, 84% (95% CI 78-88%) and 84% (95% CI 78-89%), respectively. Sensitivity was heterogeneous across studies (P = 0.0001), whereas specificity was homogeneous across studies (P = 0.2114). Completeness of diagnostic workup before FDG-PET/CT, location of metastases of unknown primary, administration of CT contrast agents, type of FDG-PET/CT images evaluated and way of FDG-PET/CT review did not significantly influence diagnostic performance. In conclusion, FDG-PET/CT can be a useful method for unknown primary tumor detection. Future studies are required to prove the assumed advantage of FDG-PET/CT over FDG-PET alone and to further explore causes of heterogeneity.

PMID 18925401  Eur Radiol. 2009 Mar;19(3):731-44. doi: 10.1007/s00330-・・・
著者: D Rades, G Kühnel, I Wildfang, A R Börner, H J Schmoll, W Knapp
雑誌名: Ann Oncol. 2001 Nov;12(11):1605-9. doi: 10.1023/a:1013107732572.
Abstract/Text BACKGROUND: Two to four percent of cancer patients present with CUP syndrome. Median survival for localised disease is 20 and for disseminated disease, seven months. For localised disease, curative treatment is more likely and individual therapeutic strategies become more important. After conservative diagnostic procedures including MRI, the primary is detected in less than 25%. The diagnostic value of PET and its influence on therapeutic strategies was evaluated.
PATIENTS AND METHODS: Forty-two patients with localised CUP were investigated from 5 of 98 to 10 of 2000. The presenting site was lymph node metastasis in 34 and visceral metastasis in 8 patients. After a median of 7 (3-11) diagnostic procedures without detection of the primary, but evidence of localised disease, PET was performed with fluorine-18-fluorodeoxyglucose.
RESULTS: In 26 of 42 patients (62%), a primary was suggested by PET and confirmed in 18 (43%). In 5 of 18 patients beyond localised disease, additional dissemination, not detected by previous diagnostic measures, was diagnosed by PET. Overall, dissemination was only detected only by PET in 16 of 42 patients (38%). In29 of 42 patients (69%), the PET result influenced selection of the definitive treatment.
CONCLUSION: In CUP patients, PET has a certain impact on detection of the primary as well as of the disseminated disease. and may also have a certain impact on therapeutic management.

PMID 11822762  Ann Oncol. 2001 Nov;12(11):1605-9. doi: 10.1023/a:10131・・・
著者: Nicholas Pavlidis, George Pentheroudakis
雑誌名: Lancet. 2012 Apr 14;379(9824):1428-35. doi: 10.1016/S0140-6736(11)61178-1. Epub 2012 Mar 12.
Abstract/Text Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 3-5% of all malignant epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. Diagnostic approaches to identify the primary site include detailed histopathological examination with specific immunohistochemistry and radiological assessment. Gene-profiling microarray diagnosis has high sensitivity, but further prospective study is necessary to establish whether patients' outcomes are improved by its clinical use. Metastatic adenocarcinoma is the most common CUP histopathology (80%). CUP patients are divided into subsets of favourable (20%) and unfavourable (80%) prognosis. Favourable subsets are mostly given locoregional treatment or systemic platinum-based chemotherapy. Responses and survival are similar to those of patients with relevant known primary tumours. Patients in unfavourable subsets are treated with empirical chemotherapy based on combination regimens of platinum or taxane, but responses and survival are generally poor.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22414598  Lancet. 2012 Apr 14;379(9824):1428-35. doi: 10.1016/S01・・・
著者: M J Hewitt, K Anderson, G D Hall, M Weston, R Hutson, N Wilkinson, T J Perren, G Lane, J A Spencer
雑誌名: BJOG. 2007 Jan;114(1):46-50. doi: 10.1111/j.1471-0528.2006.01176.x.
Abstract/Text OBJECTIVES: To evaluate the use of image-guided biopsy (IGB) in routine clinical practice to obtain site-specific diagnoses in women presenting with peritoneal carcinomatosis (PC).
STUDY DESIGN: Retrospective case study.
SETTING: Tertiary referral centre.
POPULATION: A total of 149 consecutive women with PC who underwent IGB.
METHODS: Biopsy was performed in women considered unsuitable for primary surgery because of poor performance status or disease unlikely to be optimally debulked, with a prior history of malignancy or where there was clinicoradiological uncertainty about primary tumour site. Standard haematoxylin-eosin histological analysis was supplemented with immunohistochemistry.
MAIN OUTCOME MEASURES: The rate of site-specific diagnosis.
RESULTS: A total of 149 women underwent IGB using computed tomography or ultrasound over a 6-year period. The only complication was one rectus sheath haematoma. In 138 (93%) women, a site-specific cancer diagnosis was made on the IGB (including 111 müllerian tract, 8 gastrointestinal tract, 4 breast and 3 lymphoma); in ten women, a repeat biopsy was necessary, giving an overall failure rate of 7%. In a further six women, malignancy was confirmed but a site-specific diagnosis could not be made, and in four women, biopsy showed benign tissue. A site-specific diagnosis was obtained in 29 of the 32 women (94%) with previous malignancy, of which 18/32 (56%) showed a new primary cancer.
CONCLUSIONS: IGB is a safe and accurate technique for providing site-specific diagnoses in women with PC in routine clinical practice, including those with a previous relevant malignancy. IGB can replace laparoscopic or open biopsy in defining primary therapeutic options. The data would suggest that the biopsy should be performed with ultrasound where feasible.

PMID 17233859  BJOG. 2007 Jan;114(1):46-50. doi: 10.1111/j.1471-0528.2・・・
著者: Shabnam Jaffer, Ira J Bleiweiss
雑誌名: Cancer Invest. 2004;22(3):445-65.
Abstract/Text Immunohistochemistry, a technique that microscopically detects cellular constituents via specific antibodies, has revolutionized the field of surgical pathology by tremendously empowering the hematoxylin and eosin (H&E) slide. In the investigation of the unknown primary, it enables detecting the origin of the tumor by use of tissue- or organ-specific antibodies as well as antibodies associated with minimal histogenetic differentiation. It has almost perfected the pathologist's ability to make specific diagnoses such as those of mesothelioma, melanoma, and neuroendocrine tumors. These diagnoses should be reached by interpreting the immunohistochemical results in the context of a detailed morphological analysis and differential diagnosis based on the H&E. Other important uses include detection of microinvasive and micrometastatic disease. Through the use of prognostic markers, immunohistochemistry can provide valuable information regarding tumor behavior and therapy. Lastly, immunohistochemistry serves a small but valuable role in highlighting microorganisms, particularly viruses.

PMID 15493365  Cancer Invest. 2004;22(3):445-65.
著者: Gauri R Varadhachary, Dmitri Talantov, Martin N Raber, Christina Meng, Kenneth R Hess, Tim Jatkoe, Renato Lenzi, David R Spigel, Yixin Wang, F Anthony Greco, James L Abbruzzese, John D Hainsworth
雑誌名: J Clin Oncol. 2008 Sep 20;26(27):4442-8. doi: 10.1200/JCO.2007.14.4378.
Abstract/Text PURPOSE: To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site.
PATIENTS AND METHODS: Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy.
RESULTS: The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer-specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement.
CONCLUSION: This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated.

PMID 18802157  J Clin Oncol. 2008 Sep 20;26(27):4442-8. doi: 10.1200/J・・・
著者: Hugo M Horlings, Ryan K van Laar, Jan-Martijn Kerst, Helgi H Helgason, Jelle Wesseling, Jacobus J M van der Hoeven, Marc O Warmoes, Arno Floore, Anke Witteveen, Jaana Lahti-Domenici, Annuska M Glas, Laura J Van't Veer, Daphne de Jong
雑誌名: J Clin Oncol. 2008 Sep 20;26(27):4435-41. doi: 10.1200/JCO.2007.14.6969.
Abstract/Text PURPOSE: Patients with adenocarcinoma of unknown primary origin (ACUP) constitute approximately 4% of all malignancies. For effective treatment of these patients, it is considered optimal to identify the primary tumor origins. Currently, the success rate of the diagnostic work-up is only 20% to 30%. Our goal was to evaluate the contribution of gene expression profiling for routine clinical practice in patients with ACUP.
PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded (FFPE) samples were obtained from 84 patients with a known primary adenocarcinoma and from 38 patients with ACUP. An extensive immunohistochemical panel classified 16 of the patients with ACUP, whereas 22 patients remained unclassified for their histogenetic origin. Information about staging procedures and clinical follow-up were available in all patient cases. The expression data were analyzed in relation to clinicopathologic variables and immunohistochemical results.
RESULTS: The gene expression-based assay classified the primary site correctly in 70 (83%) of 84 patient cases of primary and metastatic tumors of known origin, with good sensitivity for the majority of the tumor classes and relatively poor sensitivity for primary lung adenocarcinoma. Gene expression profiling identified 15 (94%) of 16 patients with initial ACUP who were classified by immunohistochemistry, and it made a valuable contribution to a potential site of origin in 14 of the 22 patients with ACUP.
CONCLUSION: The gene expression platform can classify correctly from FFPE samples the majority of tumors classes both in patients with known primary and in patients with ACUP. Therefore, gene expression profiling represents an additional analytic approach to assist with the histogenetic diagnosis of patients with ACUP.

PMID 18802156  J Clin Oncol. 2008 Sep 20;26(27):4435-41. doi: 10.1200/・・・
著者: K R Hess, M C Abbruzzese, R Lenzi, M N Raber, J L Abbruzzese
雑誌名: Clin Cancer Res. 1999 Nov;5(11):3403-10.
Abstract/Text The clinical features and survival times of patients with unknown primary carcinoma (UPC) are heterogeneous. Therefore, the goals of this study were to apply a novel analytical method to UPC patients to: (a) identify novel prognostic factors; (b) explore the interactions between clinical variables and their impact on survival; and (c) illustrate explicitly how the covariates interact. The 1000 patients analyzed were referred to the University of Texas M. D. Anderson Cancer Center from January 1, 1987 through November 30, 1994. Clinical data from these patients were entered into a computerized database for storage, retrieval, and analysis. Multivariate analyses of survival were performed using recursive partitioning referred to as classification and regression tree (CART) analysis. The median survival for all 1000 consecutive UPC patients was 11 months. CART was performed with an initial split on liver involvement, and 10 terminal subgroups were formed. Median survival of the 10 subgroups ranged from 40 months (95% confidence interval, 22-66 months) for UPC patients with one or two metastatic organ sites, with nonadenocarcinoma histology, and without liver, bone, adrenal, or pleural metastases to 5 months (95% confidence interval, 4-7 months) in UPC patients with liver metastases, tumor histologies other than neuroendocrine carcinoma, age >61.5 years, and a small subgroup of patients with adrenal metastases. Two additional trees were also explored. These analyses demonstrated that important prognostic variables were consistently applied by the CART program and effectively segregated patients into groups with similar clinical features and survival. CART also identified previously unappreciated patient subsets and is a useful method for dissecting complex clinical situations and identifying homogeneous patient populations for future clinical trials.

PMID 10589751  Clin Cancer Res. 1999 Nov;5(11):3403-10.
著者: A van der Gaast, J Verweij, A S Planting, W C Hop, G Stoter
雑誌名: J Clin Oncol. 1995 Jul;13(7):1720-5.
Abstract/Text PURPOSE: We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy.
PATIENTS AND METHODS: Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted.
RESULTS: In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors.
CONCLUSION: Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status < or = 1 or an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status > or = 1 and an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.

PMID 7541451  J Clin Oncol. 1995 Jul;13(7):1720-5.
著者: Stéphane Culine, Andrew Kramar, Mahasti Saghatchian, Roland Bugat, Thierry Lesimple, Alain Lortholary, Yacine Merrouche, Agnès Laplanche, Karim Fizazi, French Study Group on Carcinomas of Unknown Primary
雑誌名: J Clin Oncol. 2002 Dec 15;20(24):4679-83.
Abstract/Text PURPOSE: To identify clinical and biologic variables with significant impact on survival in patients with carcinomas of an unknown primary site and to develop a simple prognostic model for the selection of patients in prospective clinical trials.
PATIENTS AND METHODS: Univariate and multivariate prognostic factor analyses were conducted in a population of 150 unselected patients and led to the construction of two successive classification schemes. An external data set of 116 patients enrolled onto two prospective trials was used for validation.
RESULTS: When studying clinical variables only, poor performance status (2 or 3) and presence of liver metastases were retained in the multivariate analysis. The first classification scheme consisted of three subgroups of patients with median survivals of 10.8, 6.0, and 2.4 months, according to the number of adverse prognostic factors. With the introduction of serum lactate dehydrogenase (LDH) levels in a further step, liver metastases were no longer significant. The second classification scheme therefore included poor performance status (relative risk [RR], 2.1) and elevated serum LDH level (RR, 2.1). Good-risk and poor-risk patients were identified, with median survivals of 11.7 months and 3.9 months, respectively (P <.0001). The 1-year survival rates were 45% and 11%, respectively. This second classification scheme was validated in an external data set: the median survival rates of patients assigned to the good-risk group and the poor-risk group were 12 months and 7 months, respectively (P =.0089). The 1-year survival rates were 53% and 23%, respectively.
CONCLUSION: A simple prognostic model using performance status and serum LDH levels was developed and validated. It allows the assignment of patients into two subgroups with divergent outcome. Further prospective trials will be designed using this prognostic model.

PMID 12488413  J Clin Oncol. 2002 Dec 15;20(24):4679-83.
著者: Kan Yonemori, Masashi Ando, Taro Shibata, Noriyuki Katsumata, Koji Matsumoto, Yasuhiro Yamanaka, Tsutomu Kouno, Chikako Shimizu, Yasuhiro Fujiwara
雑誌名: J Cancer Res Clin Oncol. 2006 Oct;132(10):635-42. doi: 10.1007/s00432-006-0110-z. Epub 2006 Jun 22.
Abstract/Text OBJECTIVES: To evaluate the usefulness of tumor-marker measurements and to identify prognostic factors in patients with cancer of unknown primary (CUP), receiving platinum-based combination chemotherapy and to verify the adjustment of previously reported prognostic models in this population.
METHODS: We conducted univariate and multivariate analyses in consecutive patients with CUP receiving platinum-based combination chemotherapy. Previously reported prognostic models were then validated in this population.
RESULTS: A total of 93 patients were analyzed and the response rate to platinum-based chemotherapeutic regimens among the 93 patients was 39.8%. The median time to progression and overall survival period were 4.1 and 12.4 months, respectively. The ST-439 level was significantly higher in patients with histologically confirmed adenocarcinoma than in patients with poorly differentiated adenocarcinoma or poorly differentiated carcinoma. A multivariate analysis indicated that performance status, the number of involved organs, and the serum lactate dehydrogenase level were the prognostic factors of the outcome. Both the previously reported prognostic models for predicting the duration of survival in this population were shown to be valid.
CONCLUSION: Tumor-marker measurements are not helpful in the management of patients with CUP. Previously reported prognostic models may be useful for selecting indication for chemotherapy or for stratifying the patients in clinical trial.

PMID 16791594  J Cancer Res Clin Oncol. 2006 Oct;132(10):635-42. doi: ・・・
著者: E Briasoulis, G Fountzilas, A Bamias, M A Dimopoulos, N Xiros, G Aravantinos, E Samantas, H Kalofonos, T Makatsoris, N Mylonakis, P Papakostas, D Skarlos, I Varthalitis, N Pavlidis
雑誌名: Cancer Chemother Pharmacol. 2008 Jul;62(2):277-84. doi: 10.1007/s00280-007-0604-7. Epub 2007 Sep 28.
Abstract/Text BACKGROUND: Cancer of unknown primary (CUP) lacks established therapy although it affects 3% of cancer patients. We evaluated the irinotecan-oxaliplatin combination (IROX regimen) in previously untreated patients with non-favorable subsets of unknown primary carcinomas.
METHODS: This was a multicenter phase-II trial. Protocol treatment consisted of oxaliplatin 80 mg/m(2) followed by irinotecan 160 mg/m(2) administered every 3 weeks. The primary end points were response rate and toxicity, and secondary end points were time to progression and survival.
RESULTS: Forty-seven patients with liver, bone or multiple visceral metastases entered into the trial and received a median 6 chemotherapy cycles (1-11). The regimen was very well tolerated with one febrile neutropenia case and six cases with diarrhea grade 3 (16%). In intent-to-treat analysis the tumor response rate was 13% (95% CI = 4.8-25.7%) and 12 patients (27%, 95%CI 13.9-40.4%) had at least 4 months' duration of disease stabilization. The median time to progression was 2.7 months and the median survival was 9.5 months, with 40% of patients alive at 1 year.
CONCLUSIONS: The IROX regimen demonstrated similar efficacy and a favorable toxicity profile compared to other more toxic chemotherapy combinations in patients with poor-prognosis CUP.

PMID 17901952  Cancer Chemother Pharmacol. 2008 Jul;62(2):277-84. doi:・・・
著者: Katharina Schuette, Gunnar Folprecht, Albrecht Kretzschmar, Hartmut Link, Claus-Henning Koehne, Viktor Gruenwald, Michael Stahl, Gerdt Huebner
雑誌名: Onkologie. 2009 Apr;32(4):162-6. doi: 10.1159/000201125. Epub 2009 Mar 13.
Abstract/Text BACKGROUND: Carcinomas of unknown primary (CUP) account for approximately 2-5% of all cancer diagnoses. Except for some subsets with favorable prognosis, for most of these patients treatment options are limited, and no standard first-line regimen has been identified. We performed a phase II study with oxaliplatin (OX) and capecitabine (CAP) as first-line treatment for patients with histo-or cytologically proven adeno- or undifferentiated CUP.
PATIENTS AND METHODS: Protocol treatment in this multicenter trial consisted of CAP 1,000 mg/m(2) twice daily orally (days 1-14) and OX 130 mg/m(2) intravenously (day 1), repeated every 21 days at a maximum of 6 cycles. The primary endpoint was the response rate (RR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: 51 patients with CUP (71% with poorly differentiated adenocarcinoma; 41% ECOG performance status (PS) 0, 39% PS 1, 10% PS 2, 55% with elevated lactate dehydrogenase (LDH), and 39% with liver metastases) were enrolled in this study. We observed an objective RR of 11.7% and a median PFS of 2.5 months as well as an OS of 7.5 months with a good toxicity profile.
CONCLUSION: CAP/OX did not reach higher RR compared to a standard regimen with paclitaxel/carboplatin, which discourages further investigation of this schedule in CUP.

Copyright 2009 S. Karger AG, Basel.
PMID 19372710  Onkologie. 2009 Apr;32(4):162-6. doi: 10.1159/000201125・・・
著者: G Huebner, H Link, C H Kohne, M Stahl, A Kretzschmar, S Steinbach, G Folprecht, H Bernhard, S E Al-Batran, P Schoffski, C Burkart, F Kullmann, B Otremba, M Menges, M Hoffmann, U Kaiser, A Aldaoud, A Jahn, German CUP Study Group
雑誌名: Br J Cancer. 2009 Jan 13;100(1):44-9. doi: 10.1038/sj.bjc.6604818. Epub 2008 Dec 9.
Abstract/Text Platinum/taxane combinations are widely used in patients with carcinoma of unknown primary (CUP), yielding response rates of 30% and median overall survival of 9-11 months in selected patients. Yet these combinations have not been subject to a randomised trial to overcome selection bias, a major problem in CUP. We randomised 92 patients to either paclitaxel/carboplatin (arm A) or the non-platinum non-taxane regimen gemcitabine/vinorelbine (arm B). The primary endpoint was rate of practicability as defined: application of >or=2 cycles of therapy (1) with a maximal delay of 1 week (2) and survival of >or=8 months (3). Practicability was shown in 52.4% (95% CI 36-68%) in arm A and in 42.2% (95% CI 28-58%) in arm B, respectively. The median overall survival, 1-year survival -rate and response rate of patients treated in arm A was 11.0 months, 38, and 23.8%, arm B 7.0 months, 29, and 20%. In conclusion, the paclitaxel/carboplatin regimen showed clinically meaningful activity in this randomised trial (Clinical trial registration number 219, 'Deutsches KrebsStudienRegister', German Cancer Society.)

PMID 19066607  Br J Cancer. 2009 Jan 13;100(1):44-9. doi: 10.1038/sj.b・・・
著者: J E Dowell, A M Garrett, Y Shyr, D H Johnson, K R Hande
雑誌名: Cancer. 2001 Feb 1;91(3):592-7.
Abstract/Text BACKGROUND: Current therapy for patients with carcinoma of an unknown primary site (CUP) is inadequate. To develop less toxic and more effective therapies for patients with CUP, a multicenter, randomized, Phase II study was conducted. Patients with CUP received either carboplatin and etoposide (CE) or a combination of paclitaxel, 5-fluorouracil, and leucovorin (TFL).
METHODS: Patients randomized to Arm A received paclitaxel, 175 mg/m(2), intravenously over 3 hours on Day 1 followed by leucovorin, 300 mg, over 30-60 minutes and 5-fluorouracil, 350 mg/m(2), both intravenously on Days 1-3. Patients randomized to Arm B received etoposide, 100 mg/m(2), intravenously on Days 1-3 and carboplatin at an area under the curve of 6 on Day 1 only. The cycles in both treatment arms were repeated every 28 days. Patients were followed for tumor response, survival, and toxicity.
RESULTS: Thirty-four patients were enrolled, 32 of whom were evaluable for response. An identical overall response rate of 19% (95% confidence interval, 4-45%) was noted in each treatment arm. The median survival for the entire study population was 194 days. The median survivals observed in Arm A and Arm B were 251 days and 194 days, respectively (P = 0.91 [difference not significant]). Hematologic toxicity on Arm B was considerable with 29% of the patients developing neutropenia and fever. Toxicity on Arm A was modest.
CONCLUSIONS: In this randomized Phase II trial, CE and TFL appeared to have modest activity in CUP patients, with response rates similar to those reported with previously described chemotherapy regimens. Toxicity with CE was more severe than expected, although TFL was found to be well tolerated.

Copyright 2001 American Cancer Society.
PMID 11169943  Cancer. 2001 Feb 1;91(3):592-7.
著者: John D Hainsworth, David R Spigel, Bobby L Clark, Dianna Shipley, Dana S Thompson, Cynthia Farley, Kimberly West-Osterfield, Cassie M Lane, Terrence Cescon, Martin J Bury, F Anthony Greco
雑誌名: Cancer J. 2010 Jan-Feb;16(1):70-5. doi: 10.1097/PPO.0b013e3181c6aa89.
Abstract/Text PURPOSE: To compare the results of empiric first-line therapy with paclitaxel/carboplatin/etoposide (PCE) versus gemcitabine/irinotecan, both followed by single-agent gefitinib, in patients with carcinoma of unknown primary site.
PATIENTS AND METHODS: Patients with previously untreated carcinoma of unknown primary site were randomized to receive either PCE or gemcitabine/irinotecan. Responding and stable patients continued treatment for 4 to 6 cycles. Patients with no evidence of tumor progression at that time received single-agent gefitinib until tumor progression. The trial was designed to detect an improvement in the 2-year survival rate from 20% to 30%.
RESULTS: Between September 2003 and July 2008, 198 patients entered this multicenter, community-based trial. Because of slow accrual, the trial was stopped short of its target accrual of 320 patients. Clinical characteristics were comparable for patients receiving PCE (N = 93) and gemcitabine/irinotecan (N = 105). PCE and gemcitabine/irinotecan produced similar 2-year survival (15% vs. 18%), median survival (7.4 months vs. 8.5 months), median progression-free survival (3.3 months vs. 5.3 months), and response rate (18% vs. 18%). Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, and red blood cells transfusions were more common with PCE; diarrhea was more common with gemcitabine/irinotecan. The median duration of gefitinib maintenance was 3 months, suggesting no role as a maintenance therapy in this setting.
DISCUSSION: The PCE and gemcitabine/irinotecan regimens have comparable efficacy in the first-line treatment of patients with carcinoma of unknown primary site. Gemcitabine/irinotecan is the preferable regimen, due to its favorable toxicity profile. However, the moderate efficacy of both regimens underscores the need for novel treatment approaches in this patient population.

PMID 20164695  Cancer J. 2010 Jan-Feb;16(1):70-5. doi: 10.1097/PPO.0b0・・・
著者: F Anthony Greco, Howard A Burris, Sharlene Litchy, John H Barton, James E Bradof, Paul Richards, Daniel C Scullin, Joan B Erland, Lisa H Morrissey, John D Hainsworth
雑誌名: J Clin Oncol. 2002 Mar 15;20(6):1651-6.
Abstract/Text PURPOSE: To evaluate the efficacy and toxicity of the novel chemotherapy combination that includes gemcitabine, carboplatin, and paclitaxel in the treatment of patients with carcinoma of unknown primary site.
PATIENTS AND METHODS: One hundred twenty patients were treated with the following regimen, administered every 21 days for a planned four courses: gemcitabine 1,000 mg/m(2) intravenously (i.v.) on days 1 and 8, carboplatin at an estimated area under the concentration-time curve of 5 mg min/mL i.v. on day 1, and paclitaxel 200 mg/m(2) i.v. on day 1. After four courses, stable and responding patients were given weekly paclitaxel 70 mg/m(2) i.v. for 6 weeks for three 8-week courses. All patients had relatively poor prognostic features. Sixty-three patients had well-differentiated adenocarcinoma, 56 patients had poorly differentiated carcinoma, and 104 patients had performance status of 0 or 1.
RESULTS: Twenty-eight (25%) of 113 assessable patients (95% confidence interval, 22% to 30%) had major objective responses to treatment. Response rates were similar in the two major histologic types. Response rate did not seem to be improved by continued therapy with weekly paclitaxel. The median progression-free survival time was 6 months. Median survival for the entire group was 9 months, and the actuarial survival at 1 and 2 years was 42% and 23%, respectively.
CONCLUSION: Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel is an active and tolerable treatment for patients with carcinoma of unknown primary site. The survival seen in this poor-prognosis group of patients in this multicenter community-based trial is notable and similar to other taxane-based regimens for these patients. Study of additional combinations or sequences of newer drugs, as well as the exploration of targeted biologic agents for patients with an identified target in their tumors, is warranted.

PMID 11896116  J Clin Oncol. 2002 Mar 15;20(6):1651-6.
著者: Bryan J Schneider, Basil El-Rayes, Jeffery H Muler, Philip A Philip, Gregory P Kalemkerian, Kent A Griffith, Mark M Zalupski
雑誌名: Cancer. 2007 Aug 15;110(4):770-5. doi: 10.1002/cncr.22857.
Abstract/Text BACKGROUND: The purposes of this study were to evaluate efficacy and toxicity of the combination of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site (CUP).
METHODS: Patients with CUP received carboplatin AUC 5 mg/mL a minute intravenously Day 1, gemcitabine 1000 mg/m(2) intravenously Days 1 and 8, and capecitabine 1600 mg/m(2) orally in divided doses, Days 1-14 of a 21-day cycle for up to 8 cycles. The primary endpoint of the study was objective response rate by intent-to-treat analysis.
RESULTS: Thirty-three patients were treated (median age, 58 years; men:women ratio, 19:14). Most patients had a baseline performance status of 1. The objective response rate was 39.4% (95% CI, 22.9%-57.9%) in all patients, 36.4% in 22 patients with well to moderately differentiated adenocarcinoma, and 40.0% in 20 patients with liver metastases. Median progression-free survival time was 6.2 months (95% CI, 5.4%-8.0%), and median survival time was 7.6 months (95% CI, 6.3-14.1). One and 2-year survival rates were 35.6% and 14.2%, respectively. The most frequent grade > or =3 adverse events were neutropenia (67%), thrombocytopenia (48%), and anemia (33%).
CONCLUSIONS: The combination of carboplatin, gemcitabine, and capecitabine is active in CUP, especially in patients with liver metastases. This regimen may be a potential therapy for CUP patients with good performance status, particularly those with a suspected origin below the diaphragm.

PMID 17594717  Cancer. 2007 Aug 15;110(4):770-5. doi: 10.1002/cncr.228・・・
著者: John D Hainsworth, David R Spigel, Sharlene Litchy, F Anthony Greco
雑誌名: J Clin Oncol. 2006 Aug 1;24(22):3548-54. doi: 10.1200/JCO.2005.05.0575.
Abstract/Text PURPOSE: To evaluate the efficacy of chemotherapy with paclitaxel, carboplatin, and etoposide in advanced adult poorly differentiated neuroendocrine carcinomas.
PATIENTS AND METHODS: Patients eligible for this multicenter, phase II trial had metastatic poorly differentiated neuroendocrine carcinoma and had received no previous treatment. Patients with a variety of known primary sites (excepting small-cell lung cancer) and patients with unknown primary site were eligible. Patients received four courses of chemotherapy with paclitaxel, carboplatin, and etoposide, administered at 3-week intervals. After completing four courses of treatment, patients with objective response or stable disease received three courses (24 weeks) of weekly paclitaxel.
RESULTS: Seventy-eight patients were treated; 62% had unknown primary site. Forty-one patients (53%) had major responses (complete response rate, 15%), and five patients remain disease free from 18 to 66 months after therapy. Response rates were similar regardless of histology (small-cell v poorly differentiated carcinoma) or primary site. The median, 2-year, and 3-year survivals for the entire group were 14.5 months, 33%, and 24%, respectively. Myelosuppression was the major toxicity, as has been reported previously with this regimen.
CONCLUSION: This prospective phase II trial provides additional evidence that this family of relatively uncommon carcinomas is initially chemosensitive, with a high overall response rate to combination chemotherapy and a minority of complete responses. The three-drug regimen evaluated in this trial is moderately toxic, and has no obvious efficacy advantages when compared with standard platinum/etoposide regimens. Treatment for advanced poorly differentiated neuroendocrine carcinoma should parallel treatments used for small-cell lung cancer.

PMID 16877720  J Clin Oncol. 2006 Aug 1;24(22):3548-54. doi: 10.1200/J・・・
著者: Sergio Palmeri, Vito Lorusso, Laura Palmeri, Marina Vaglica, Camillo Porta, Rolando Nortilli, Francesco Ferraú, Giuseppe Comella, Bruno Massidda, Marco Danova, Carcinomas of Unknown Primary Italian Study Group
雑誌名: Cancer. 2006 Dec 15;107(12):2898-905. doi: 10.1002/cncr.22379.
Abstract/Text BACKGROUND: : To date, the standard treatment for patients who have carcinoma of unknown primary site has not been established.
METHODS: : In this randomized Phase II study, 66 previously untreated patients (33 patients per arm) with carcinomas of unknown primary site received cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) with either paclitaxel (70 mg/m2) or vinorelbine (25 mg/m2), and all drugs were administered intravenously on Days 1 and 8 of a 21-day cycle. Twenty-nine patients (44%) presented with > or =2 involved sites. The pathologic diagnosis was mainly adenocarcinoma (48 patients; 72.7%) and squamous carcinoma (7 patients; 10.6%).
RESULTS: : In the first arm, 16 patients (48.5%) experienced an objective response, and 9 patients (27.2%) had disease stabilization. In the vinorelbine-containing arm, 14 patients (42.3%) experienced an objective response, and 8 patients (24.2%) had disease stabilization. The median response duration and the median time to progression were similar in both treatment arms; the median overall survival was 9.6 months (95% confidence interval, 7.11-12.09 months) for patients who received the cisplatin/gemcitabine/paclitaxel regimen and 13.6 months (95% confidence interval, 6.61-20.59 months) for patients who received the vinorelbine combination. Grade 3 and 4 toxicities were more frequent in the paclitaxel-containing arm.
CONCLUSIONS: : Both combinations satisfied the 2-step design, demonstrating antitumor activity without relevant differences in response rates or response duration; however, the vinorelbine-containing regimen yielded superior results both in terms of overall survival (13.6 months vs 9.6 months) and in terms of treatment tolerability. Therefore, according to a pick the winner attitude, the combination of cisplatin/gemcitabine/vinorelbine may be considered in the design of future randomized, Phase III trials for patients with carcinomas of unknown primary site.

Copyright 2006 American Cancer Society.
PMID 17109447  Cancer. 2006 Dec 15;107(12):2898-905. doi: 10.1002/cncr・・・
著者: John D Hainsworth, David R Spigel, Dana S Thompson, Patrick B Murphy, Cassie M Lane, David M Waterhouse, Yuval Naot, F Anthony Greco
雑誌名: Oncologist. 2009 Dec;14(12):1189-97. doi: 10.1634/theoncologist.2009-0112. Epub 2009 Dec 4.
Abstract/Text INTRODUCTION: This phase II trial evaluated the efficacy and toxicity of the combination of paclitaxel, carboplatin, bevacizumab, and erlotinib in the first-line treatment of patients with carcinoma of unknown primary site (CUP).
METHODS: Patients with previously untreated CUP (adenocarcinoma, poorly differentiated carcinoma, poorly differentiated squamous carcinoma) without clinical or pathologic characteristics of a well-defined treatable subset were eligible. All patients received paclitaxel, carboplatin, bevacizumab, and erlotinib. Treatment cycles were repeated at 21-day intervals. After four cycles, paclitaxel and carboplatin were discontinued; bevacizumab-erlotinib treatment was continued until tumor progression. Patients were initially evaluated for response after completion of two treatment cycles; re-evaluations occurred every 6 weeks thereafter.
RESULTS: Forty-nine of 60 patients (82%) completed four cycles of therapy, and 44 patients (73%) subsequently received maintenance bevacizumab and erlotinib. Thirty-two patients (53%) had major responses to treatment; an additional 18 patients had stable disease. After a median follow-up of 19 months, the median progression-free survival time was 8 months, with 38% of patients progression free at 1 year. The median survival time and 2-year overall survival rate were 12.6 months and 27%, respectively. Treatment was generally well tolerated, with a toxicity profile as predicted based on the known toxicities of each treatment component.
CONCLUSIONS: Empiric treatment with paclitaxel, carboplatin, bevacizumab, and erlotinib is effective and well tolerated as first-line treatment for patients with CUP. Further development of this regimen is warranted.

PMID 19965914  Oncologist. 2009 Dec;14(12):1189-97. doi: 10.1634/theon・・・
著者: John D Hainsworth, David R Spigel, Cindy Farley, Dana S Thompson, Dianna L Shipley, F Anthony Greco, Minnie Pearl Cancer Research Network
雑誌名: J Clin Oncol. 2007 May 1;25(13):1747-52. doi: 10.1200/JCO.2006.09.3047.
Abstract/Text PURPOSE: Treatment remains poor for many patients with carcinoma of unknown primary site (CUP), and no effective second-line treatment has been identified. Combination inhibition of vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) with bevacizumab and erlotinib has proved efficacious and well tolerated in other solid tumors. We therefore have evaluated the efficacy and toxicity of this combination in patients with CUP.
PATIENTS AND METHODS: Patients with CUP who either had received previous chemotherapy or were previously untreated with poor-prognosis clinical features were eligible for this study. All patients received bevacizumab 10 mg/kg IV every 2 weeks, along with erlotinib 150 mg orally daily. Patients were re-evaluated after 8 weeks of treatment; those with objective response or stable disease continued treatment until disease progression.
RESULTS: Forty-seven (92%) of 51 patients received at least 8 weeks of treatment. Five patients (10%) had partial responses, and 29 patients (61%) had stable disease as the best response. The median survival for the entire group was 7.4 months, with 33% of patients alive at 1 year. This regimen was well tolerated by most patients.
CONCLUSION: The combination of bevacizumab and erlotinib has substantial activity in the treatment of patients with CUP. The median survival is superior to survival previously reported with second-line chemotherapy, and is similar to the results of many first-line chemotherapy trials in this setting. This regimen merits further evaluation in patients with CUP.

PMID 17470864  J Clin Oncol. 2007 May 1;25(13):1747-52. doi: 10.1200/J・・・
著者: J D Hainsworth, H A Burris, S W Calvert, N T Willcutt, D C Scullin, J Bramham, F A Greco
雑誌名: Cancer Invest. 2001;19(4):335-9.
Abstract/Text The purpose of this study was to evaluate the activity of single-agent gemcitabine in previously treated patients with carcinoma of unknown primary site. Between January 1997 and October 1998, 39 patients were enrolled in this multicenter Phase II trial performed in the Minnie Pearl Cancer Research Network. Twenty-seven patients (69%) had adenocarcinoma or poorly differentiated adenocarcinoma; 35 patients (90%) had previously received treatment with chemotherapy regimens containing both a platinum agent and a taxane. Only 21% of patients had ever responded to previous therapy. Gemcitabine 1000 mg/m2 was administered intravenously on days 1, 8, and 15 of each 28-day course. Three of 36 evaluable patients (8%) had partial responses, and 9 patients (25%) had minor responses or stable disease with improved symptoms. The median time to progression for patients with partial responses or stable disease/improved symptoms was 5 months. Treatment was well tolerated, with uncommon grade 3 or 4 toxicity. Gemcitabine produced a low objective response rate in this refractory patient population, although approximately one-third of patients experienced symptomatic improvement. Treatment with gemcitabine was well tolerated. Because gemcitabine has activity against a variety of adenocarcinomas, further evaluation of this agent as part of first-line therapy for patients with carcinoma of unknown primary site is appropriate.

PMID 11405172  Cancer Invest. 2001;19(4):335-9.
著者: John D Hainsworth, David R Spigel, Eric L Raefsky, Michel E Kuzur, Kathleen Yost, Michael Kommor, Sharlene Litchy, F Anthony Greco
雑誌名: Cancer. 2005 Nov 1;104(9):1992-7. doi: 10.1002/cncr.21416.
Abstract/Text BACKGROUND: The current study was performed to evaluate the activity of combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site.
METHODS: Patients with carcinoma of an unknown primary site who had received one previous chemotherapy regimen were eligible for this study. All patients received gemcitabine at a dose of 1000 mg/m2 intravenously (i.v.) and irinotecan at a dose of 100 mg/m2 i.v. on Days 1 and 8; treatment courses were repeated every 21 days. Patients were evaluated for response after completing two courses of treatment; responders/stable patients continued treatment for a recommended six courses.
RESULTS: Forty patients entered this multicenter, community-based Phase II trial between September 2000 and July 2003. Four of these 40 patients (10%) achieved objective responses (a partial response in 3 patients and a complete response in 1 patient). An additional 17 patients (43%) had stable disease/minor response at first reevaluation; 7 of these patients (18%) remained stable for longer than 6 months. The median survival for the entire group was 4.5 months, with 1-year and 2-year survival rates of 25% and 13%, respectively. The treatment was well tolerated by most patients. Neutropenia was the most common Grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria, version 3.0) (occurring in 36% of patients). Myelosuppression-related complications were uncommon, as were severe nonhematologic toxicities.
CONCLUSIONS: The combination of gemcitabine and irinotecan has modest activity and is well tolerated in patients with recurrent/refractory carcinoma of an unknown primary site. Treatment-related toxicity, particularly myelosuppression, appears to be less severe than toxicity produced by the taxane and platinum regimens frequently used in the first-line therapy of these patients. Evaluation of the gemcitabine and irinotecan combination as first-line therapy is indicated.

(c) 2005 American Cancer Society.
PMID 16130138  Cancer. 2005 Nov 1;104(9):1992-7. doi: 10.1002/cncr.214・・・
著者: Anne Kirstine Hundahl Møller, Karen Damgaard Pedersen, Julie Abildgaard, Bodil Laub Petersen, Gedske Daugaard
雑誌名: Acta Oncol. 2010 May;49(4):431-5. doi: 10.3109/02841861003649240.
Abstract/Text BACKGROUND: Treatment of patients with carcinoma of unknown primary site (CUP) remains a challenge, and no effective second-line treatment has been identified. In CUP patients who are non-responsive or relapse early after first-line platinum/taxane-based regimens, it is likely that gastrointestinal (GI) tract tumours may be overrepresented. These patients could be candidates for GI tract-directed therapy. We here report the results obtained with oxaliplatin and capecitabine as second-line therapy in 25 recurrent/refractory CUP patients following first-line treatment with paclitaxel, cisplatin and gemcitabine.
PATIENTS AND METHODS: Patients received capecitabine orally (1000 mg/m(2)) twice daily, days 1-14, and oxaliplatin (130 mg/m(2)) intravenously on day 1 in a three-week schedule.
RESULTS: Twenty-five CUP patients received a median of three cycles of capecitabine and oxaliplatin as second-line treatment. Histopathological assessments suggested the primary site to be of GI tract origin in the majority of the patients (76%). We found an objective response rate of 13%, a median progression-free survival and overall survival rate of 2.3 and 3.9 months, respectively, and 32% of patients alive at one year after initiation of second-line therapy. The regimen was well tolerated by most patients.
CONCLUSIONS: This study, demonstrates that there is still a significant need for improved second-line therapy in CUP patients.

PMID 20235750  Acta Oncol. 2010 May;49(4):431-5. doi: 10.3109/02841861・・・
著者: Makiko Ono, Masashi Ando, Kan Yonemori, Harukaze Yamamoto, Taizo Hirata, Chikako Shimizu, Kenji Tamura, Noriyuki Katsumata, Yasuhiro Fujiwara
雑誌名: J Cancer Res Clin Oncol. 2011 Aug;137(8):1185-91. doi: 10.1007/s00432-011-0983-3. Epub 2011 May 11.
Abstract/Text PURPOSE: There are few existing reports on the efficacy of second-line chemotherapy in patients with cancer of unknown primary site (CUP). The aim of this study was to identify characteristics of CUP patients linked to a positive response to chemotherapy.
METHODS: We retrospectively studied the clinical outcomes of second-line chemotherapy in patients with CUP who had previously been treated with platinum-based first-line chemotherapy.
RESULTS: A total of 27 patients received second-line chemotherapy. Of these patients, 5 (19%) showed an objective response to second-line chemotherapy; 4 of these patients had shown a favorable response to first-line chemotherapy and had a chemotherapy-free interval (CFI) of more than 4.5 months. Among the 8 patients in whom the CFI was more than 4.5 months, 4 (50%) showed an objective response to platinum-based second-line chemotherapy, whereas among the 16 patients with a CFI of less than 4.5 months, only 1 (6%) showed a response to any chemotherapeutic regimen.
CONCLUSIONS: The response to second-line chemotherapy in CUP patients who had received platinum-based first-line treatment seemed to be associated with the response to first-line chemotherapy and the CFI. Although it remains unclear whether second-line chemotherapy might contribute to a survival benefit in patients with CUP, patients who show a favorable response to first-line chemotherapy and also a relatively prolonged CFI appear to be likely to benefit from second-line chemotherapy.

PMID 21559815  J Cancer Res Clin Oncol. 2011 Aug;137(8):1185-91. doi: ・・・
著者: E Briasoulis, H Kalofonos, D Bafaloukos, E Samantas, G Fountzilas, N Xiros, D Skarlos, C Christodoulou, P Kosmidis, N Pavlidis
雑誌名: J Clin Oncol. 2000 Sep;18(17):3101-7.
Abstract/Text PURPOSE: To evaluate the efficacy of the carboplatin/paclitaxel combination in patients with carcinoma of unknown primary site (CUP).
PATIENTS AND METHODS: Seventy-seven consecutive CUP patients (45 women and 32 men; median age, 60 years) were treated with carboplatin at target area under the curve 6 mg/mL/min followed by paclitaxel 200 mg/m(2) as a 3-hour infusion and granulocyte colony-stimulating factor from days 5 to 12. Treatment courses were repeated every 3 weeks to a maximum of eight cycles. Forty-seven patients had adenocarcinomas, 27 had undifferentiated carcinomas, and three had squamous cell carcinomas. Thirty-three patients presented with liver, bone, or multiple organ metastases, 23 with predominantly nodal/pleural disease, and 19 (16 women) with peritoneal carcinomatosis.
RESULTS: The overall response rate by intent-to-treat analysis was 38.7% (95% confidence interval, 27.5% to 49.9%). There were no differences in response between adenocarcinomas and undifferentiated carcinomas, but efficacy varied among clinical subsets. The response rates and median survival times in the three clinically defined subsets were 47.8% and 13 months, respectively, for patients with predominantly nodal/pleural disease, 68.4% and 15 months, respectively, in women with peritoneal carcinomatosis, and 15.1% and 10 months, respectively, in patients with visceral or disseminated metastases. Chemotherapy was well-tolerated.
CONCLUSION: Carboplatin plus paclitaxel combination chemotherapy is effective in patients with predominantly nodal/pleural metastases of unknown primary carcinoma and in women with peritoneal carcinomatosis. However, in patients with liver, bone, or multiple organ involvement, the combination offers limited benefit. The investigation of novel treatment approaches is highly warranted for this group of patients.

PMID 10963638  J Clin Oncol. 2000 Sep;18(17):3101-7.
著者: F A Greco, J B Erland, L H Morrissey, H A Burris, R C Hermann, R Steis, D Thompson, J Gray, J D Hainsworth
雑誌名: Ann Oncol. 2000 Feb;11(2):211-5.
Abstract/Text PURPOSE: 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.
PATIENTS AND METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.

PMID 10761758  Ann Oncol. 2000 Feb;11(2):211-5.
著者: K Yonemori, M Ando, M Yunokawa, T Hirata, T Kouno, C Shimizu, K Tamura, N Katsumata, A Hirakawa, K Matsumoto, Y Yamanaka, H Arioka, Y Fujiwara
雑誌名: Br J Cancer. 2009 Jan 13;100(1):50-5. doi: 10.1038/sj.bjc.6604829. Epub 2008 Dec 16.
Abstract/Text Carcinoma of unknown primary site (CUP) is rarely encountered in clinical practice and optimal chemotherapy has not yet been established. This phase II study was conducted to evaluate the efficacy and toxicity of combined irinotecan+carboplatin therapy in chemotherapy-naive patients with CUP. Irinotecan was administered at 60 mg m(-2) as a 90-min intravenous infusion on days 1, 8 and 15. Carboplatin was administered at an area-under-the curve of 5 mg ml(-1) min as a 60-min intravenous infusion on day 1. This cycle was repeated every 28 days for up to six cycles. Forty-five patients were enrolled in the study. An intent-to-treat analysis revealed an objective response rate to the treatment of 41.9% (95% confidence interval, 27.0-57.9%). The median time to progression was 4.8 months and the median survival was 12.2 months. The 1- and 2-year survival rates were 44 and 27%, respectively. The most frequent grade 3 or more severe adverse events were leukopaenia (21%), neutropaenia (33%), anaemia (25%) and thrombocytopaenia (20%). Thus, the combination of irinotecan plus carboplatin was found to be active in patients with CUP. Therefore, the regimen may be one of the potentially available chemotherapeutic options for community standard of care in patients with a good performance status.

PMID 19088717  Br J Cancer. 2009 Jan 13;100(1):50-5. doi: 10.1038/sj.b・・・
著者: K B Pittman, I N Olver, B Koczwara, D Kotasek, W K Patterson, D M Keefe, C S Karapetis, F X Parnis, S Moldovan, S J Yeend, T J Price, Adelaide Cancer Trials and Education Collaborative (ACTEC)
雑誌名: Br J Cancer. 2006 Nov 20;95(10):1309-13. doi: 10.1038/sj.bjc.6603440. Epub 2006 Oct 31.
Abstract/Text Cancer of unknown primary site (CUP) represents up to 5% of all cancer diagnoses and is associated with poor survival. We have performed a prospective multicentre phase 2 trial to evaluate efficacy and toxicity of the combination of gemcitabine (G) and carboplatin (C) for patients with CUP. Patients with histologically confirmed metastatic carcinoma in which the primary site of cancer was not evident after prospectively designated investigation and who had ECOG performance status 0-2 were treated with G 1000 mg m(-2) intravenously (i.v.) days 1 and 8, and C AUC 5 i.v. on day 8 every 3 weeks to a maximum of nine cycles. The primary end points were response rate, and toxicity, with secondary end points of progression-free survival and overall survival. Fifty-one (23 male, 27 female) patients were enrolled (one patient ineligible), with a median age of 69 years (range 41-83 years). Fifty patients were evaluable for toxicity and 46 patients were evaluable for efficacy. The overall response rate to the GC regimen was 30.5%. With a median follow-up of 24 months, the median progression-free survival was 18 weeks (4.2 months) and the median overall survival was 34 weeks (7.8 months). The frequency of grade 3 or 4 toxicity was low. Nausea/vomiting was the most common side effect, but was usually only mild in severity. Uncomplicated neutropenia (14%), thrombocytopenia (10%) and anaemia (8%) were the most common causes of grade 3-4 toxicity. The regimen was very well tolerated, particularly in the elderly. The GC regimen is an active regimen in CUP with excellent tolerability and should be considered particularly for elderly patients with CUP.

PMID 17088914  Br J Cancer. 2006 Nov 20;95(10):1309-13. doi: 10.1038/s・・・
著者: Yeon Hee Park, Baek-Yeol Ryoo, Seong-Jun Choi, Sung Hyun Yang, Heung-Tae Kim
雑誌名: Jpn J Clin Oncol. 2004 Nov;34(11):681-5. doi: 10.1093/jjco/hyh124.
Abstract/Text OBJECTIVE: We evaluated the efficacy and toxicity of combined paclitaxel and cisplatin chemotherapy in patients with cancer of unknown primary site (CUP). Efficacy was evaluated in terms of response rate, progression-free survival and overall survival.
METHODS: Thirty-seven patients with CUP were enrolled between January 2001 and September 2003 at Korea Cancer Center Hospital. The patients received 21-day cycles of paclitaxel (175 mg/m(2) i.v.) with cisplatin (60 mg/m(2) i.v.) given on the first day.
RESULTS: Of the 37 patients, 31 had adenocarcinoma subtypes. The overall response rate of 26 patients with measurable lesions was 42% [95% confidence interval (CI) 23-61%]. Stable disease was seen in six patients and progressive disease in nine. Median time to progression was 4 months (95% CI 1.3-6.8). Median overall survival was 11 months (95% CI 8.3-13.5). The major toxicities were neuropathy and neutropenia. Grade 4 neutropenia occurred in 10 patients, but febrile neutropenia was seen in four.
CONCLUSIONS: This combined paclitaxel and cisplatin regimen was well tolerated with an encouraging level of effectiveness for patients with CUP.

PMID 15613558  Jpn J Clin Oncol. 2004 Nov;34(11):681-5. doi: 10.1093/j・・・
著者: Stéphane Culine, Alain Lortholary, Jean-Jacques Voigt, Roland Bugat, Christine Théodore, Frank Priou, Marie-Christine Kaminsky, Thierry Lesimple, Xavier Pivot, Bruno Coudert, Jean-Yves Douillard, Yacine Merrouche, Jelila Allouache, Alain Goupil, Sylvie Négrier, Juliette Viala, Peter Petrow, Jeannine Bouzy, Agnès Laplanche, Karim Fizazi, Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01)
雑誌名: J Clin Oncol. 2003 Sep 15;21(18):3479-82. doi: 10.1200/JCO.2003.12.104.
Abstract/Text PURPOSE: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site.
PATIENTS AND METHODS: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done.
RESULTS: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively.
CONCLUSION: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.

PMID 12972523  J Clin Oncol. 2003 Sep 15;21(18):3479-82. doi: 10.1200/・・・
著者: F A Greco, H A Burris, J B Erland, J R Gray, L A Kalman, M T Schreeder, J D Hainsworth
雑誌名: Cancer. 2000 Dec 15;89(12):2655-60.
Abstract/Text BACKGROUND: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.

Copyright 2000 American Cancer Society.
PMID 11135228  Cancer. 2000 Dec 15;89(12):2655-60.

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