Here's a recent article that gives survival stats after using local procedures:
http://www.nature.com/nrclinonc/jour...011.44.html#t1
If it can't be accessed, I cut and pasted the article, which appeared in Nature Reviews, Clinical Oncology 8, 378-382 (June 2011)
Joan
FOCUS ON: metastasis
Oligometastases revisited
Ralph R. Weichselbaum & Samuel Hellman
Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago Medical Center, 5758 South Maryland Avenue, Chicago, IL 60637, USA
Abstract
We previously proposed a clinical state of metastasis termed 'oligometastases' that refers to restricted tumor metastatic capacity. The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases. Here we review clinical and laboratory data that support the hypothesis that oligometastasis is a distinct clinical entity. Investigations of the prevalence, mechanism of occurrence, and position in the metastatic cascade, as well as the determination of molecular markers to distinguish oligometastatic from polymetastatic disease, are ongoing.
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Introduction
Current methods of cancer staging and treatment frequently separate patients into groups with tumors confined to the primary site or regional spread (lymph-node metastases).1 These patients are usually treated with curative intent in contrast to patients with distant metastasis who are not usually considered curable by current regional treatment methods. In most adult solid cancers, the treatment for metastasis is systemic cytotoxic chemotherapy and/or hormonal manipulation. In general, distant metastases are the primary cause of cancer mortality and have led to a 'leukemia-like' consideration of solid tumor metastases whereby metastases are frequently, if not always, considered extensive in number and organ site. We proposed an intermediate state of metastases termed 'oligometastases'.2 In this concept, the number and site of metastatic tumors are limited. We suggested that the evolution of metastatic capacity has intermediate states in which spread may be limited to specific organs and metastases might be present in limited numbers. The clinical implication of this hypothesis is that localized forms of cancer treatment may be effective in patients with oligometastases. This is clearly the case since curative surgical resection of liver metastases from colon cancer,3, 4, 5, 6 lung metastases from a variety of primary sites,7 and adrenal metastases from lung cancer,8 result in cure in some patients. A major question is the prevalence of oligometastasis. Since current research indicates that tumors evolve in their malignant capacity, the improving imaging methods (for example, MRI and PET), as well as blood-based tests (such as prostate-specific antigen levels), might identify a significant population of patients with oligometastases and afford opportunities for detecting primary tumors early in their progression as well as permitting early diagnosis of oligometastases amenable to curative local treatment. More recently, the use of stereotactic radiotherapy, radiofrequency ablation, and MRI-guided focused ultrasound offer less invasive methods of regional treatment than surgical resection, and could offer curative potential in the treatment of oligometastases.9, 10, 11, 12, 13, 14 However, longer follow-up and larger patient numbers are required to assess the curative potential of stereotactic radiotherapy and other ablative techniques for oligometastases. We review the surgical treatment of liver and lung metastases as support for the oligometastatic concept as well as novel laboratory investigations pertinent to the selection of appropriate candidates for localized treatment of oligometastases.
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Treatment of oligometastases
Liver metastases
Liver metastases have a role in the mortality of many patients with cancer, in particular those of the gastrointestinal (GI) tract.3, 4, 5, 6 This association is partially explained by the venous drainage of the GI tract travelling through the portal vein, although tumor and host genetic factors also have a role in the tropism of GI metastases to the liver. Support for the oligometastatic state of some GI-associated liver metastases comes from data regarding the outcome of patients with colorectal cancer who underwent partial liver resection for metastasis to the liver (Table 1).3, 4, 5, 6 The curative treatment of liver metastasis has been reported for many years; however, each series was relatively small. In 1986, Hughes and colleagues compiled a registry of 607 patients from 24 institutions who had undergone curative resection for liver metastasis from colorectal cancer; 25% of these patients were disease free at 5 years.3 Poor prognostic factors included positive surgical margins and bilobar disease.3 In 1996, Nordlinger et al.4 published a multi-institutional European registry study of 1,568 patients who underwent liver resection for metastasis; the 5-year survival rate was 28%. Adverse prognostic factors included a positive surgical margin of the resected metastasis, serosal or lymphatic spread of the primary tumor, large size and high number of liver metastasis, high carcinoembryonic antigen (CEA) levels and age (<60 years). In a single institution study that highlighted patients likely to benefit from liver resection, surgeons analyzed results from 1,001 liver resections for metastatic colorectal cancer.5 Poor prognostic factors included the presence of extrahepatic disease, a node-positive primary tumor, size and number of metastatic lesions, a short disease-free interval between the primary tumor and metastasis, and a CEA level of greater than 200 ng/ml. The overall survival rate was 37% at 5 years, and 22% at 10 years.5 The investigators devised risk categories based on these data and the above criteria to determine patients suitable for resection based on the number of risk factors present. In 2005, Pawlik et al.6 analyzed 557 patients from three institutes who underwent liver resection for metastasis. These investigators identified adverse prognostic factors to be a positive surgical margin, more than three metastases and a CEA level of >200 ng/ml. The 5-year survival rate was 58% in patients without any poor prognostic factors. Strikingly, the 5-year survival was 17% in patients with positive surgical margins compared with 63% in patients with negative margins—the width of the margin did not affect the outcome.6 Most of these studies included patients treated before transaxial body imaging (CT and MRI) or PET was frequently used for the detection of metastases and for staging; therefore, it is likely that these advanced imaging and molecular diagnostic techniques could be used to aid the selection of patients for curative treatment of metastatic disease. Indeed, these techniques were used in some patients in the most recent of the studies6 and likely contributed to better patient selection and improved 5-year survival in this study compared with the other trials (Table 1).3, 4, 5
Table 1 | Summary of four large series of resection of hepatic metastasis
Full table
Figures and tables index
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Lung metastases
Pulmonary metastases are a primary cause of death from cancer.7 As for the liver, the lung is also a primary or secondary drainage region for many frequently occurring cancers. Specific genes have been identified that are associated with lung metastases from breast cancer suggesting a genetic basis for metastatic tropism.15, 16 In addition, bone marrow-derived cells might establish a favorable microenvironment in the lung for development of metastasis.17, 18 Successful results of curative resection of lung metastases have been described for almost all types of cancer and these data were summarized in a report from the International Registry of Lung Metastases.7 This report detailed results from pulmonary resection of 5,206 patients with pulmonary metastases with controlled primary tumors and with metastases confined to the lung from a wide variety of histological tumor types. A total of 4,572 patients underwent complete resection, 1,984 had epithelial tumors and 1,917 had sarcomas.7 In this study, patients who underwent complete resection of metastatic tumors had a 5-year survival rate of 36% and a 10-year survival rate of 26% (Figure 1). Patients with fewer metastases and a longer disease-free interval between the primary tumor and appearance of lung metastases had 10-year survival rates as high as 40%. Similar to the liver metastases data, patients with incomplete resection had poor survival rates of 13% and 7% at 5 years and 10 years, respectively. Multiple surgeries were required in some patients and histology had a role in outcome; patients with germ-cell tumors had the best outcome and patients with melanoma had the worst outcome. Curative resection of pulmonary metastases from sarcomas and germ-cell tumors had been reported before the report from the International Registry of Lung Metastases. A subset of patients with tumors considered to be widely metastatic in all instances, such as breast cancer and melanoma, were reported to be cured with surgical resection of lung metastases if certain clinical criteria were used for patient selection (usually the length of the disease-free interval and number of metastases).7
Figure 1 | Survival of patients undergoing pulmonary resection of metastatic tumors.
Each curve represents the survival of patients with an increasing number of risk factors for recurrence as determined by a retrospective review of the data.7 These categories are: group I, a single resectable metastasis with a disease-free interval from primary tumor to metastasis of ≥36 months; group II, multiple metastases or a disease-free interval <36 months; group III, multiple metastases and a disease-free interval <36 months. The size, number and tumor type are risk factors for recurrence. Permission obtained from Elsevier © Pastorino, U. et al. J. Thorac. Cardiovasc. Surg. 113, 37–49 (1997).
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Figures and tables index
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Common clinical prognostic factors emerge from these large investigations of resection and outcome in lung and liver metastasis. These include the number and size of metastasis, the interval from the treatment of the primary tumor to the appearance of metastasis, adequacy of resection of the metastatic tumors, and the presence of multiple metastatic sites. The histology of the primary tumor also seems to influence outcome. These data form the basis of clinical markers for patient selection for the treatment of oligometastatic disease.
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Response to chemotherapy
In our original article on oligometastasis,2 we speculated that a state of oligometastasis might be created following cytoreduction as a consequence of excellent responses to systemic treatments and when local treatments might add to cure. One interesting example of this concept is the neoadjuvant chemotherapy treatment of patients with liver metastasis who then undergo resection. For example, Giacchetti et al.19 reported that of 151 patients with liver metastasis who were unresectable (owing to the size or multinodularity of the metastasis) who received chemotherapy (oxaliplatin, 5-fluorouracil and leucovorin), 77 became resectable and complete resection was achieved in 58 patients.19 Almost all patients who were not operated on died within 5 years but 50% of patients who achieved a response to chemotherapy and were resected were alive at 5 years. Negative predictors for survival in patients undergoing chemotherapy before liver resection included tumor progression during chemotherapy and the presence of celiac or para-aortic lymph-node metastasis even if the liver and nodal tumors were stabilized by chemotherapy.19 Administration of cetuximab with or without chemotherapy in patients with liver metastasis who failed first-line chemotherapy resulted in a small percentage of patients sufficiently downstaged to undergo curative surgery; eight out of 11 patients who had complete surgical resection were alive at 36 months.20
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The biology of metastasis
Paget first hypothesized the 'seed and soil' hypothesis, which suggested that metastases were not random and not solely dependent on circulatory patterns, but rather an interaction between the tumor cell and the targeted organ.21 In this concept, certain tumors have a predilection for metastasis to particular organs that support the secondary growth of cells from the primary tumor. The selective process is driven by a tumor microenvironment that is hypoxic and acidic with immune-derived cells and other host-derived cells that promote tumor growth and suppresses host immunity. Tumor diversity is driven by the genetic instability of the tumor cells due to telomere erosion, mutations in tumor-suppressor and DNA-repair genes, and intrinsic tumor metabolism (aerobic glycolyis) that is toxic to surrounding normal cells.18, 22, 23 The evolutionary value to the primary tumor of harboring clones that metastasize may not necessarily directly aid in the growth of the primary tumor. The capacity for metastatic spread is likely an epiphenomenon of the genetic instability of the primary tumor resulting in the capacity to grow and invade and give rise to cells capable of distant metastases.
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Steps in metastasis
Many investigators have hypothesized and have provided evidence to support the various steps in the metastatic cascade. These 'discreet steps' in metastasis have been elegantly summarized by Gupta and Massagué.24 These steps include loss of cellular adhesion, increased motility, invasiveness of the primary tumor, entry into and survival in the circulation, entry into new organs and eventual colonization of these organs. Gupta and Massagué have defined a useful framework to categorize genes that have roles in the various stages of metastasis.24 They term genes that confer a selective advantage to the primary tumor cells as metastasis 'initiation' genes; metastasis 'progression' genes are those that fulfill rate-limiting functions in colonization; and metastasis 'virulence' genes are those that provide an advantage in metastasis colonization but not necessarily an advantage in the growth of the primary tumor. Metastasis colonization requires a selective advantage in the evolution of the primary tumor to be preserved and amplified during tumor progression.24 The following characteristics of the metastatic phenotype are altered cell adhesion, intravasation, survival in the circulation, extravasation, seeding in a distant site, invasion, and development of the appropriate microenvironment in host organs. These processes have been reviewed by others in this focus issue and elsewhere. These data indicate that there are primary tumor cells that have limited capability in one or more of the necessary biological requirements for metastasis; thus the origin of oligometastases. Tumor dormancy may be a particular example of limited metastatic capacity.
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Dormancy
Cells that escape from the primary tumor may be present at distant organs as cellular aggregates without forming established tumors.25, 26 Several hypotheses might explain this phenomenon:27, 28, 29 the tumor cells fail to signal appropriate angiogenic cues or the rate of blood vessel formation equals the apoptosis in tumor endothelia and adequate neovasculature does not form; the local microenvironment does not support metastatic growth (for example it does not have appropriate environmental growth factors or cell contact structures); and the immune system monitors tumors and eliminates incipient tumor cells (surveillance), keeps tumors at a small or microscopic size (equilibrium; perhaps analogous to dormancy), or allows escape to established tumor growth.29 Within the context of dormancy, these processes might have an effect on the number, location, and timing of appearance of metastases; interferon signaling is a key component of these processes.29
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Models and molecules
Investigations of laboratory and molecular determinants of oligometastasis are limited. However, Fidler and Kripke30 compared the metastatic ability of different tumor-cell clones derived from B16F1 melanoma. They noted a wide variation in the ability of these clones to colonize the lung (from 3.5 to 260 lung colonies per mouse) and concluded that the B16F1 cell line is heterogenous with regard to the metastasis-forming ability of pre-existing tumor clones.30 These results were confirmed and expanded upon by several investigators using KHT sarcoma cells, which varied widely in metastatic potential (lung colonization).31, 32 Cillo et al.33 noted that clones that had a high metastatic potential were more resistant to chemotherapy than cells derived from clones of low metastatic potential. In addition, Khodarev et al.34 used the B16F1 mouse melanoma model to show that repeated passage through the lungs evolved a more 'aggressive' phenotype defined by an increase of efficiency in lung colonization and conferred resistance to radiotherapy and chemotherapy on the more highly metastatic clones; this finding is consistent with earlier reports.34 Of interest is the finding that clones that give rise to widely metastatic tumors overexpressed genes known to be induced by interferon, which had previously been associated with resistance to radiotherapy and chemotherapy in murine models and in human databases and tumor samples.35, 36
Considered together, these reports suggest that there are large differences between metastatic capability in tumor cells in experimental models, consistent with the concept of oligometastases. Genes that govern the metastatic process are of great interest; however, genes that govern the number of metastases have not been studied in detail. Recently, Wuttig et al.37 used samples from 18 patients with renal cell carcinoma to identify genes that characterized 'few' (less than eight) or 'many' (>16) pulmonary metastases. DNA-array analysis on fresh samples obtained from pulmonary resection of metastasis revealed 135 genes that were differentially expressed between the 'few' and 'many' metastasis groups. Using gene ontology enrichment analysis the researchers demonstrated that polymetastatic tumors were enriched by genes that positively regulate the cell cycle, indicating an increase in growth potential in polymetastasis versus oligometastasis.37 Based on a meta-analysis of these data37 and previously published data,38 an 11-gene classifier was established to predict the number of metastases in patients with renal cell carcinoma. Ideally, prospective trials will collect fresh-frozen tumor specimens for molecular analysis to validate this signature as well as identify other genes and gene families involved in oligometastasis.
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Temporal evolution
Recently, insights into the evolution of metastasis in pancreatic cancer were reported;39, 40 this is particularly interesting since oligometastases are rarely observed in pancreatic cancer. Two research groups analyzed somatic mutations in genes and constructed clonal evolutionary maps derived from primary and metastatic tumors.39, 40 They reported that pancreatic tumors contain geographically separate subclones within the primary tumor that are present many years before metastases become evident. As an example, it was demonstrated that long time periods existed between the appearance of the tumor and the initial metastasis. Also, different metastatic clones may appear at different time periods. It is suggested that there may be a hierarchy of metastatic sites for pancreatic cancer with peritoneal metastases occurring first, then hepatic, and finally pulmonary metastases.40 The nature of this hierarchy is likely to vary with primary tumor histology and location; the latter because of different vascular drainage, local hypoxia and possible local stromal interactions. For example, adrenal metastases may occur early in the process in non-small-cell lung cancer, while for colon cancer the site of early metastases is the liver, perhaps owing to the portal drainage pattern. Other examples include the lungs as an initial site for soft-tissue and bone sarcomas perhaps because of the venous return from the tumor going first through the pulmonary circulation or from local stromal considerations. Such considerations of the sites and mechanisms of metastases early in the metastatic progression should produce opportunities for site-specific analyses of metastases from different primary tumors as well as analysis of differential gene expression as a function of the site of the primary tumor and of oligometastases. These observations put a special emphasis on the early detection of the oligometastatic state and local control of the primary tumor because if metastasis is hierarchal in time and number, ablation of 'early' metastasis might be curative. Since the metastatic tumor clone arises from the primary tumor, control of the primary tumor takes on special importance in the cure of oligometastasis and perhaps also polymetastatic disease. We are conducting investigations that are ongoing to study differences between oligometastases and polymetastases in both clinical material and experimental tumor models.
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Conclusions
The metastases that we define as oligometastases have long been recognized as potentially curable but were considered to be rare exceptions to the cancer metastasis paradigm. However, the oligometastatic state is becoming more frequently identified with more-sensitive methods of detecting such oligometastases. As newer methods of analyzing patients with metastatic disease develop (for example the analysis of circulating tumor cells), the oligometastatic state should be identified even earlier. As indicated above, new molecular analysis of pancreatic cancer suggests that there are temporal differences in the appearance of metastases based on tumor genetics. These data suggest a potential stepwise progression with intermediate stages of limited metastatic capacity. It seems quite possible that metastases from tumors with such limited capacities might be separated from those much further along in malignant progression. If this seems possible, then clinicians will be able to limit ablative local treatment to only those patients with true oligometastases. Finally, there seems to be another type of oligometastasis evolving; those limited remaining tumor deposits following successful eradication of all other apparent and occult cancer cells by systemic means. It is important to study both types of limited metastases but recognize that the true oligometastases are present because of limited metastatic competence while induced oligometastases following otherwise successful systemic treatment have more extensive malignant capacities and were spared from eradication by pharmacological means, local immunological conditions, or from the development of resistant clones. The strategy and tactics of treatment of these two types might be different as well as the likelihood of therapy success.
Author contributions
Both authors contributed to researching data for the article, discussion of the content, and writing and editing the manuscript.
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Acknowledgments
The authors are supported by grants from the Ludwig Foundation for Cancer Research, the Lung Cancer Research Foundation, and a generous gift from the Foglia Foundation.
Competing interests statement
The authors declare competing interests.
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Published online 22 March 2011
Re: Overthrowing the king and the queen
Linear Mode
