Management of “unfavourable” carcinoma of unknown primary site: Synthesis of recent literature

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Abstract

Carcinomas of unknown primary (CUP) approximately represent 2–3% of all adult cancers. Various clinicopathological subsets of CUP have been identified, which may be treated with tailored approaches. Nevertheless, 80% of CUP do not fall into these subsets. Even when at least 4 prognostic models have been developed and validated in independent patient cohorts, there is no consensus or reliable guidance for estimating the prognosis of these “unfavourable” CUP. Consequently, targeting patients who benefit from palliative chemotherapy is difficult. Thirty-eight phase II trials were published between 1997 and 2011; a systematic analysis of these trials did not allow the recommendation of any of the tested regimens as a standard of care. Currently, there is only one published phase III clinical trial (Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan); without significant difference between both regimens. Thus, with the promise of molecular profiling, we are waiting for a large collaborative clinical trial that validates the concept of targeted treatment in this population of patients with “unfavourable” CUP.

Introduction

Carcinomas of unknown primary site (CUP) represent a group of heterogeneous tumours that share the unique characteristic of revealing metastases with no identifiable origin at the time of treatment [1], [2], [3]. There are histologically heterogeneous CUP subtypes, with adenocarcinoma (40–50%) and poorly differentiated carcinomas (30–40%) constituting the vast majority of cases. In the mid-1990s, approximately 50,000 cases of CUP were diagnosed in the United States of America, accounting for 5% of all adult cancers in Western countries. According to an epidemiological study, the incidence of CUP remains stable from 2002 to 2007 [4]. On the contrary, Greco et al. found that that number has been reduced by half due to the improvement of initial patient workup [6]. Currently, autopsy procedures of patients with CUP are able to identify the primary in approximately 60–80% of the cases, with the most common identified primaries being the following: lung, pancreas (both accounting for approximately 40% of identified primaries), other gastro-intestinal sites (colon, liver, biliary tree, etc.) and ovarian [6]. Nevertheless, despite recent improvements of modern imaging, functional imaging and immunohistochemistry, CUP still account for 2–3% of adult cancers [7], [8], [9]. Thus, the management of CUP patients remains a daily problem for clinical practice. In recent phase II trials, the median overall survival is approximately 8–12 months [7], [8], [9], [10], [11], but this figure could be partly due to the selection bias, so the respective roles of chemotherapy and best supportive care are still debated.

Recent guidelines based on the recently available data describe the ideal diagnostic management of revealing metastases and identifying specific subgroups of CUP requiring targeted approaches [3] (Table 1). Unfortunately, the vast majority (>80%) of CUP do not fit into these subsets. Based on a literature review, most physicians propose wide-spectrum empiric chemotherapy to these patients who do not fit the specific subsets. However, complete response or long-lasting stable disease in these patients is rare. Thus, the aim of the present review was to systematically analyse the clinical relevance of published prognostic scores and the results of phase II trials published in the last 15 years focusing on “unfavourable” CUP. This review updates two reviews published in Critical Reviews in Oncology/Hematology in 2005 [10] and 2009 [11].

Section snippets

Prognostic scores

Using Medline, we have systematically reviewed all articles related to the prognostic factors of CUP patients. We have compiled the data from the reprints of the studies, which account for at least 200 patients for whom the prognostic scores were validated on an independent cohort of patients. Four studies fulfilled these criteria and have been summarised in the present review.

Phase II clinical trials

Using Medline, we have reviewed all phase II clinical trials fulfilling the following criteria: (i) trials specifically

Prognostic scores

From the previous studies, four prognostic scores were developed [12], [13], [14], [15] and evaluated in independent cohorts [16] (Table 2). Three of these identified prognostic factors for overall survival [12], [13], [14] using Log-rank tests and then Cox models, whereas one identified the prognostic factors for early death (90-day mortality) using logistic regression analysis [13]. The prognostic models are different, but the scores are the combinations of up to 6 of the following prognostic

Discussion

Reviewing the recent literature on CUP management is a frustrating exercise. Currently, there are at least 4 formally validated prognostic models; however, none of the models is currently in practice or being used for the design of new clinical trials.

Due to the lack of sufficiently powered phase III trials, there are no definitive answers to questions related to CUP patient management. We have accumulated the results of decades of successive phase II trials. Most of these trials included both

Eric Yaovi Amela is a young physician born on May 1977 in the Togo and having studied Medicine at the Lille University. Graduate as general practitioner, he is physician at the Oscar Lambret Cancer Center. He currently acquires additional education and education to subspecialise in Oncology. His fields of expertise are testis and bladder cancers and carcinoma of unknown primary site.

References (56)

  • H.M. Horlings et al.

    Gene expression profiling to identify the histogenetic origin of metasatic adenocarcinomas of unknown primary

    J Clin Oncol

    (2008)
  • G.R. Varadahachary et al.

    Carcinoma of unknown primary wit a colon-cancer profile-changing paradigm and emerging definitions

    Lancet Oncol

    (2008)
  • G.R. Varadhachary et al.

    Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation

    J Clin Oncol

    (2008)
  • A. Van der Gaast et al.

    Simple prognostic model to predict survival in patients with undifferentiated carcinoma of unknown primary site

    J Clin Oncol

    (1995)
  • S. Culine et al.

    Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site

    J Clin Oncol

    (2002)
  • P. Seve et al.

    Low serum albumin levels and liver metastasis are powerful prognostic markers for survival in patients with unknown primary site

    Cancer

    (2006)
  • N. Penel et al.

    Development and validation of a bedside score to predict early death in cancer of unknown primary patients

    PLOS One

    (2009)
  • C. Ferté et al.

    Individual life-expectancy estimation using validated prognostic score for patients with cancer of unknown primary

    Oncology

    (2010)
  • M. Gross-Goupil et al.

    A randomized trial of cisplatin with or without gemcitabine in patients with carcinoma of an unknown primary and without poor prognostic factors: results of the GEFCAPI02 trial

    Ann Oncol

    (2008)
  • S. Culine et al.

    Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site:results of a randomized phase II study-trial for the French study group on carcinomas of unknown primary (GEFCAPI 01)

    J Clin Oncol

    (2003)
  • S. Palmeri et al.

    Cisplatin and gemcitabine with either vinorelebine or paclitaxel in the treatment of carcinomas of unknown primary

    Cancer

    (2006)
  • L. Asserhorn et al.

    A randomised study of protracted venous infusion of 5-fluorourcil (5-FU) with or without bolus mitomycin C (MMC) in patients with carcinoma of unknown primary

    Eur J Cancer

    (2003)
  • J.E. Dowell et al.

    A randomized phase II trial in patients with carcinoma of an unknown primary site

    Cancer

    (2001)
  • C.I. Falkson et al.

    Epirubicin and cisplatin versus mitomycin C alone as therapy for carcinoma of unknown primary origin

    Oncology

    (1998)
  • G. Huebner et al.

    Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with andeo- or undifferentiated carcinoma of unknown primary: a randomized prospective phase II trial

    Br J Cancer

    (2008)
  • S. Culine et al.

    Chemotherapy in carcinoma of unknown primary site: a high-dose intensity policy

    Ann Oncol

    (1999)
  • J.D. Hainsworth et al.

    Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: a phase II trial of the Minnie Pearl cancer research network

    Cancer Invest

    (2001)
  • J.D. Hainsworth et al.

    Combination chemotherapy with gemcitabine in patients with previously treated carcinoma of unknown primary site

    Cancer

    (2005)
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    Eric Yaovi Amela is a young physician born on May 1977 in the Togo and having studied Medicine at the Lille University. Graduate as general practitioner, he is physician at the Oscar Lambret Cancer Center. He currently acquires additional education and education to subspecialise in Oncology. His fields of expertise are testis and bladder cancers and carcinoma of unknown primary site.

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