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Introduction: Unknown Primary Cancer
Introduction: Unknown Primary Cancer
U
nknown primary cancer (UPC) is a common, well-recognized clinical syndrome, accounting for 4% to 5% of all invasive cancers. Patients with UPC present with neoplasm in sites usually associated with metastasis, and despite further clinical evaluation, a primary site is not identified. Although the clinical syndrome is easy to recognize, this entity does not represent one clearly defined cancer but encompasses a multitude of clinical presentations and pathologies. At present, many basic questions regarding the pathobiology and pathophysiology of these tumors remain unanswered. It is likely there is no single explanation for all of these tumors. In a sizable portion of unknown primary adenocarcinomas, clinically undetectable primaries are at play (as proven by autopsy series). However, we have no clear understanding of how or why these tumors differ from known, easily detectable primary adenocarcinomas. Occasionally, a patient with the initial diagnosis of UPC has a primary site subsequently identified. Although the metastatic pattern in these patients is often atypical,1 there is no direct evidence that molecular genetic abnormalities in these tumors differ from those seen in metastatic cancers of known primary site. Other theories have been postulated to explain the genesis of some UPCs, including the embryologic migration error theory and the cancer stem cell theory, each of which seems probable for some tumors in some patients.2 With this acknowledged level of ignorance, it is reasonable to ask why an entire issue of Seminars in Oncology is devoted to UPCs. In planning this issue, our primary intent was to provide an up-to-date clinical guide to medical oncologists and other physicians who frequently manage UPC patients. The stakes have been raised: with improved systemic treatment for most types of advanced cancer the potential for selecting suboptimal therapy for the patient with UPC increases. When treatment was relatively poor for most solid tumors, the use of a “broad-spectrum” regimen, such as paclitaxel/carboplatin, seemed to cover the bases pretty well. Today, no oncologist would select paclitaxel/carboplatin as treatment for a patient with known metastatic colon cancer. To aid in treatment decisions for patients with UPC, three broad areas are addressed in this publication: (1) recognition and treatment of Supported in part by the Minnie Pearl Cancer Foundation. 0270-9295/08/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2008.10.007
6
specific favorable patient subsets; (2) optimum diagnosis (with emphasis on improvements in pathologic evaluation); and (3) empiric treatment. In addition, considerable attention is focused on molecular profiling, a new technology that may facilitate identification of the tissue of origin and decrease the need for empiric treatment in future patients.
RECOGNITION OF TREATABLE OR FAVORABLE SUBSETS In the last three decades the outer surface of the complex puzzle of UPC has been partially chipped away. Characteristic clinical and/or pathologic features have helped us to recognize several subsets of patients with favorable prognostic factors (see Hainsworth and Fizazi and Spigel et al in this issue). At least five of these subsets have clinical features (minus the primary site) similar to specific cancer types: women with isolated axillary adenocarcinoma— breast; women with papillary serous peritoneal adenocarcinoma—primary peritoneal carcinoma or ovary; young men with the extragonadal germ cell syndrome— germ cell tumor; men with blastic bone metastasis and tumor staining or elevated serum levels of prostate specific antigen—prostate; isolated neck nodes involved with squamous cell carcinoma— head and neck primary. Therapy directed at the presumed primary benefits these patients and supports the idea that at least some UPCs retain similar sensitivity to therapies useful in known primaries. Other favorable UPC subsets are less well understood, including poorly differentiated neuroendocrine carcinomas and UPC presenting at a single site. Patients with poorly differentiated neuroendocrine carcinomas benefit from therapy known to be useful for another well-known neuroendocrine tumor, small cell lung cancer. Patients with a single detectable site form a heterogeneous group, with various sites of involvement (eg, lymph node, brain, liver, bone, soft tissue). Their survival is often prolonged after definitive local therapy, and is likely further improved with the addition of systemic therapies. Some of these patients’ tumors may have arisen in these isolated sites as a result of an error in utero during the embryologic migration of cells.2 If this theory is correct, some of these patients may in essence have a “primary” arising from the isolated site discovered, and obviously should be treated with curative intent. Although these favorable subsets of patients comprise only about 20% of all UPCs, specific treatments Seminars in Oncology, Vol 36, No 1, February 2009, pp 6-7
Introduction
result in greatly improved outcomes when compared to other UPC patients.
EMPIRIC CHEMOTHERAPY IN THE LAST DECADE The treatment for patients with UPC with unfavorable prognostic factors (about 80% of all UPC patients) has improved in the last decade (see Greco and Pavlidis in this issue). The majority of these patients have carcinomas, usually adenocarcinomas. The use of empiric combination chemotherapy often with broad spectrum antineoplastic agents has improved the overall survival of these patients, and a minority are surviving for more than 2 years. These data are derived from phase II trials reported in the last decade with long-term follow-up. Phase III studies are lacking. The heterogeneity of these patients and their tumors, as well as variable recently appreciated prognostic factors, makes single small noncomparative studies difficult to interpret (see Culine in this issue). However, when considering all of the trials (N ⫽ 13) reporting long-term follow-up (2 years and beyond) in the past decade, it is apparent that these therapies are an improvement compared to historical controls and older therapies reported from 1964 to 1997. The newer combinations are the state of the art therapies for these patients, but recent biologic insight regarding some of these tumors may make a less empiric and more site-specific therapeutic approach superior.
7
chary and Greco in this issue). Molecular profiling can correctly identify a high percentage (80%–90%) of primary sites, when applied to tissue from metastatic lesions in patients with known primaries. Until recently, experience with molecular profiling assays in UPC was very limited. However, recent data suggest that a UPC colon cancer profile can be identified, and these patients appear to respond well to current regimens for metastatic colorectal cancer.3 Further clinical validation of therapy directed by the results of immunohistochemical panels and/or molecular tumor profiles is an important area of current clinical research. Basic understanding of the molecular mechanisms responsible for the genesis, growth and metastasis of neoplastic cells will eventually lead to more effective therapy for many cancer patients, including those with UPC. Knowledge of the genetic lesions or potential therapeutic targets in an individual patient’s tumor, regardless of the primary site, will aid in the identification of a drug regimen likely to benefit the individual patient. Prior to that time, improved identification of the tissue of origin, as well as the incorporation of new targeted agents into therapy, will continue to improve the treatment for patients with UPC.
F. Anthony Greco, MD Director, Sarah Cannon Cancer Center John D. Hainsworth, MD Chief Scientific Officer, Sarah Cannon Research Institute Nashville, TN Guest Editors
IMPROVEMENTS IN IMMUNOHISTOCHEMICAL DIAGNOSIS, MOLECULAR PROFILING AND TAILORED THERAPIES Diagnostic cellular pathology has improved remarkably in the last decade (see Oien in this issue). Immunohistochemistry is now able to reliably pinpoint the general lineage of most neoplasms that are difficult to diagnose by routine heamtoxylin and eosin light microscopy. Various staining patterns can support, at times with a high confidence level, the origin of some UPCs. More recently the field of molecular profiling of human neoplasms is exploding, and this testing has important potential diagnostic and therapeutic implications in UPC (see Bender and Erlander and Varadha-
REFERENCES 1. Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer. 2007;43:2026-36. 2. Greco FA, Hainsworth JD. Cancer of unknown primary site. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice oncology. 8th ed. Philadelphia: Lippincott; 2008. p. 2363-87. 3. Varadhachary G, Talantov D, Raber M, Meng C, Hess KR, Jatkoe T, et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol. 2008;26:4442-8.
U
nknown primary cancer (UPC) is a common, well-recognized clinical syndrome, accounting for 4% to 5% of all invasive cancers. Patients with UPC present with neoplasm in sites usually associated with metastasis, and despite further clinical evaluation, a primary site is not identified. Although the clinical syndrome is easy to recognize, this entity does not represent one clearly defined cancer but encompasses a multitude of clinical presentations and pathologies. At present, many basic questions regarding the pathobiology and pathophysiology of these tumors remain unanswered. It is likely there is no single explanation for all of these tumors. In a sizable portion of unknown primary adenocarcinomas, clinically undetectable primaries are at play (as proven by autopsy series). However, we have no clear understanding of how or why these tumors differ from known, easily detectable primary adenocarcinomas. Occasionally, a patient with the initial diagnosis of UPC has a primary site subsequently identified. Although the metastatic pattern in these patients is often atypical,1 there is no direct evidence that molecular genetic abnormalities in these tumors differ from those seen in metastatic cancers of known primary site. Other theories have been postulated to explain the genesis of some UPCs, including the embryologic migration error theory and the cancer stem cell theory, each of which seems probable for some tumors in some patients.2 With this acknowledged level of ignorance, it is reasonable to ask why an entire issue of Seminars in Oncology is devoted to UPCs. In planning this issue, our primary intent was to provide an up-to-date clinical guide to medical oncologists and other physicians who frequently manage UPC patients. The stakes have been raised: with improved systemic treatment for most types of advanced cancer the potential for selecting suboptimal therapy for the patient with UPC increases. When treatment was relatively poor for most solid tumors, the use of a “broad-spectrum” regimen, such as paclitaxel/carboplatin, seemed to cover the bases pretty well. Today, no oncologist would select paclitaxel/carboplatin as treatment for a patient with known metastatic colon cancer. To aid in treatment decisions for patients with UPC, three broad areas are addressed in this publication: (1) recognition and treatment of Supported in part by the Minnie Pearl Cancer Foundation. 0270-9295/08/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2008.10.007
6
specific favorable patient subsets; (2) optimum diagnosis (with emphasis on improvements in pathologic evaluation); and (3) empiric treatment. In addition, considerable attention is focused on molecular profiling, a new technology that may facilitate identification of the tissue of origin and decrease the need for empiric treatment in future patients.
RECOGNITION OF TREATABLE OR FAVORABLE SUBSETS In the last three decades the outer surface of the complex puzzle of UPC has been partially chipped away. Characteristic clinical and/or pathologic features have helped us to recognize several subsets of patients with favorable prognostic factors (see Hainsworth and Fizazi and Spigel et al in this issue). At least five of these subsets have clinical features (minus the primary site) similar to specific cancer types: women with isolated axillary adenocarcinoma— breast; women with papillary serous peritoneal adenocarcinoma—primary peritoneal carcinoma or ovary; young men with the extragonadal germ cell syndrome— germ cell tumor; men with blastic bone metastasis and tumor staining or elevated serum levels of prostate specific antigen—prostate; isolated neck nodes involved with squamous cell carcinoma— head and neck primary. Therapy directed at the presumed primary benefits these patients and supports the idea that at least some UPCs retain similar sensitivity to therapies useful in known primaries. Other favorable UPC subsets are less well understood, including poorly differentiated neuroendocrine carcinomas and UPC presenting at a single site. Patients with poorly differentiated neuroendocrine carcinomas benefit from therapy known to be useful for another well-known neuroendocrine tumor, small cell lung cancer. Patients with a single detectable site form a heterogeneous group, with various sites of involvement (eg, lymph node, brain, liver, bone, soft tissue). Their survival is often prolonged after definitive local therapy, and is likely further improved with the addition of systemic therapies. Some of these patients’ tumors may have arisen in these isolated sites as a result of an error in utero during the embryologic migration of cells.2 If this theory is correct, some of these patients may in essence have a “primary” arising from the isolated site discovered, and obviously should be treated with curative intent. Although these favorable subsets of patients comprise only about 20% of all UPCs, specific treatments Seminars in Oncology, Vol 36, No 1, February 2009, pp 6-7
Introduction
result in greatly improved outcomes when compared to other UPC patients.
EMPIRIC CHEMOTHERAPY IN THE LAST DECADE The treatment for patients with UPC with unfavorable prognostic factors (about 80% of all UPC patients) has improved in the last decade (see Greco and Pavlidis in this issue). The majority of these patients have carcinomas, usually adenocarcinomas. The use of empiric combination chemotherapy often with broad spectrum antineoplastic agents has improved the overall survival of these patients, and a minority are surviving for more than 2 years. These data are derived from phase II trials reported in the last decade with long-term follow-up. Phase III studies are lacking. The heterogeneity of these patients and their tumors, as well as variable recently appreciated prognostic factors, makes single small noncomparative studies difficult to interpret (see Culine in this issue). However, when considering all of the trials (N ⫽ 13) reporting long-term follow-up (2 years and beyond) in the past decade, it is apparent that these therapies are an improvement compared to historical controls and older therapies reported from 1964 to 1997. The newer combinations are the state of the art therapies for these patients, but recent biologic insight regarding some of these tumors may make a less empiric and more site-specific therapeutic approach superior.
7
chary and Greco in this issue). Molecular profiling can correctly identify a high percentage (80%–90%) of primary sites, when applied to tissue from metastatic lesions in patients with known primaries. Until recently, experience with molecular profiling assays in UPC was very limited. However, recent data suggest that a UPC colon cancer profile can be identified, and these patients appear to respond well to current regimens for metastatic colorectal cancer.3 Further clinical validation of therapy directed by the results of immunohistochemical panels and/or molecular tumor profiles is an important area of current clinical research. Basic understanding of the molecular mechanisms responsible for the genesis, growth and metastasis of neoplastic cells will eventually lead to more effective therapy for many cancer patients, including those with UPC. Knowledge of the genetic lesions or potential therapeutic targets in an individual patient’s tumor, regardless of the primary site, will aid in the identification of a drug regimen likely to benefit the individual patient. Prior to that time, improved identification of the tissue of origin, as well as the incorporation of new targeted agents into therapy, will continue to improve the treatment for patients with UPC.
F. Anthony Greco, MD Director, Sarah Cannon Cancer Center John D. Hainsworth, MD Chief Scientific Officer, Sarah Cannon Research Institute Nashville, TN Guest Editors
IMPROVEMENTS IN IMMUNOHISTOCHEMICAL DIAGNOSIS, MOLECULAR PROFILING AND TAILORED THERAPIES Diagnostic cellular pathology has improved remarkably in the last decade (see Oien in this issue). Immunohistochemistry is now able to reliably pinpoint the general lineage of most neoplasms that are difficult to diagnose by routine heamtoxylin and eosin light microscopy. Various staining patterns can support, at times with a high confidence level, the origin of some UPCs. More recently the field of molecular profiling of human neoplasms is exploding, and this testing has important potential diagnostic and therapeutic implications in UPC (see Bender and Erlander and Varadha-
REFERENCES 1. Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer. 2007;43:2026-36. 2. Greco FA, Hainsworth JD. Cancer of unknown primary site. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice oncology. 8th ed. Philadelphia: Lippincott; 2008. p. 2363-87. 3. Varadhachary G, Talantov D, Raber M, Meng C, Hess KR, Jatkoe T, et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol. 2008;26:4442-8.