clinical recommendations
Annals of Oncology 20 (Supplement 4): iv154–iv155, 2009 doi:10.1093/annonc/mdp159
Cancers of unknown primary site: ESMO Clinical Recommendations for diagnosis, treatment and follow-up E. Briasoulis1, N. Pavlidis1 & E. Felip2 On behalf of the ESMO Guidelines Working Group* 1
Department of Medical Oncology, University of Ioannina, Ioannina Ipiros, Greece; 2Medical Oncology Service, Vall d’Hebron University Hospital, Barcelona, Spain
incidence Cancers of unknown primary site (CUPs) represent a heterogeneous group of metastatic tumors for which a workup as listed below fails to identify the site of origin at the time of diagnosis. CUPs accounts for 3–5% of all malignancies.
diagnosis
from directed therapy. The following recommendations epitomize standard and optional assessments suggested.
CUPs require pathology evaluation and are categorized by pathology into:
well- and moderately differentiated adenocarcinomas; poorly differentiated carcinomas; squamous cell carcinomas; undifferentiated neoplasms; carcinomas with neuroendocrine differentiation.
Immunohistochemistry should be applied in poorly differentiated cases to exclude chemosensitive and potentially curable tumors (i.e. lymphomas and germ cell tumors). If diagnosis is adenocarcinoma, immunostaining for prostate-specific antigen (PSA) in male patients and for estrogen and progesterone receptors in females with axillary node metastases is advisable to rule out hormone-sensitive tumors amenable to specific therapy. Staining for keratins CK7 and CK20 may provide indications towards a possible primary site.
staging and risk assessment Appropriate staging and diagnostic work-up can help to identify a minority of CUP patients who can expect to benefit
Thorough physical examination (including head and neck, rectal, pelvic and breast examination), basic blood and biochemistry survey, urinalysis, fecal occult blood test and CT scan of thorax, abdomen and pelvis constitute a minimal basic work-up. Endoscopies should be sign- or symptom-guided. Serum assessment of a-fetoprotein (aFP), b-human chorionic gonadotropin (bHCG) and PSA is suggested in male patients to exclude potentially curable extragonadal germ cell tumor and amenable to hormone treatment prostate cancer. A mammogram should be performed in women with an adenocarcinoma. Whole body 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (CT/FDG-PET) may contribute to the management of patients with CUP tumors and especially those with cervical adenopathies and single metastasis. Subsets of chemosensitive and potentially curable tumors, such as patients with predominantly nodal metastases of poorly differentiated carcinomas and females with peritoneal carcinomatosis of a serous histologic type adenocarcinoma must not be missed.
Diagnostic and staging guidelines for patients with an anticipatory CUP diagnosis are summarized in Table 1.
treatment Therapy should be tailored on an individual basis by recognition of well-defined clinicopathologic subsets that differ in prognosis as described in Table 2 [III, B].
response evaluation *Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail:
[email protected]
Response evaluation is recommended after two or three chemotherapy cycles by individually adequate tests.
Approved by the ESMO Guidelines Working Group: April 2002, last update June 2008. This publication supercedes the previously published version—Ann Oncol 2008; 19 (Suppl 2): ii106–ii107.
follow-up
Conflict of interest: the authors have reported no conflicts of interest.
There is no evidence that follow-up of asymptomatic patients is needed. Specific examinations as clinically indicated.
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected]
Annals of Oncology
clinical recommendations
Table 1. Diagnostic and staging guidelines for cancers of unknown primary site Assessment suggested
Target patient population
Minimal standard work-up Thorough medical history and physical examination Basic blood and biochemistry survey CT scans of thorax, abdomen and pelvis Work-up for clinicopathological subsets Mammography or breast MRI (optional) Serum a-fetoprotein and b-human chorionic gonadotropin Serum prostate-specific antigen Head and neck CT scan or CT/PET scan (optional) Endoscopies
All patients All patients All patients Female with axillary adenopathy Patients with midline metastastatic disease Male with adenocarcinoma bone metastases Cervical adenopathies with squamous cell carcinoma Must be sign or symptom oriented
Table 2. Therapy of cancer of unkown primary site CUP subtype
Proposed treatment
Poorly differentiated carcinoma, predominantly nodal disease Poorly differentiated neuroendocrine carcinomas Peritoneal carcinomatosis of a serous histologic type adenocarcinoma in female Isolated axillary nodal metastases in female Squamous carcinoma involving cervical lymph nodes
Platinum-based combination chemotherapy Platinum plus etoposide combination chemotherapy Similar to FIGO III ovarian cancer: optimal surgical debulking followed by platinum chemotherapy Identical to patients with breast cancer and similar nodal involvement Irradiation for N1–2 disease. For advanced stages induction chemotherapy with platinum-based combination or chemoradiation is indicated Hormonal therapy as for prostate cancer
Adenocarcinoma with bone metastases and elevated prostate-specific antigen in males Liver, bone or multiple-site metastases of adenocarcinoma
note Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the expert authors and the ESMO faculty.
literature 1. Pavlidis N, Briasoulis E, Hainsworth J, Greco FA. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer 2003; 39: 1990–2005.
Volume 20 | Supplement 4 | May 2009
Low toxicity chemotherapy of palliative orientation or best supportive care
2. Abbruzzese JL, Abbruzzese MC, Lenzi R et al. Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol 1995; 13: 2094–2103. 3. Culine S, Kramar A, Saghatchian M 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; 20: 4679–4683. 4. Seve P, Billotey C, Broussolle C et al. The role of 2-deoxy-2-[F-18]fluoro-Dglucose positron emission tomography in disseminated carcinoma of unknown primary site. Cancer 2007; 109: 292–299. 5. Bugat R, Bataillard A, Lesimple T et al. Summary of the standards, options and recommendations for the management of patients with carcinoma of unknown primary site. Br J Cancer 2003; 89 (Suppl 1): S59–S66. 6. Pavlidis N. Forty years experience of treating cancer of unknown primary. Acta Oncol 2007; 46: 592–601.
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