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The biology and treatment of oligometastatic cancer

Diane K. Reyes, Kenneth J. Pienta

Oncotarget · 2015 · Review

doi:10.18632/oncotarget.3455

Abstract

// Diane K. Reyes 1 , Kenneth J. Pienta 1, 2 1 Departments of Urology and Brady Urological Institute, and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA 2 Departments of Pharmacology and Molecular Sciences, and Chemical and Biomolecular Engineering, The Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA Correspondence to: Kenneth J. Pienta, e-mail: kpienta1@jhmi.edu Keywords: metastasis, therapy, tumor, spectrum theory, diaspora Received: February 06, 2015 Accepted: February 24, 2015 Published: April 13, 2015 ABSTRACT Clinical reports of limited and treatable cancer metastases, a disease state that exists in a transitional zone between localized and widespread systemic disease, were noted on occasion historically and are now termed oligometastasis. The ramification of a diagnosis of oligometastasis is a change in treatment paradigm, i.e. if the primary cancer site (if still present) is controlled, or resected, and the metastatic sites are ablated (surgically or with radiation), a prolonged disease-free interval, and perhaps even cure, may be achieved. Contemporary molecular diagnostics are edging closer to being able to determine where an individual metastatic deposit is within the continuum of malignancy. Preclinical models are on the outset of laying the groundwork for understanding the oligometastatic state. Meanwhile, in the clinic, patients are increasingly being designated as having oligometastatic disease and being treated owing to improved diagnostic imaging, novel treatment options with the potential to provide either direct or bridging therapy, and progressively broad definitions of oligometastasis.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

Hellman first proposed the theory of oligometastases in 1995 as a sequel to the spectrum theory of cancer metastasis. Hellman hypothesized that the process of cancer metastases occurred along a continuum, from locally confined cancer to widely metastatic disease. Although the phenomenon of limited and treatable cancer metastases had been noted historically, Hellman and Weichselbaum proposed the term oligometastases, suggesting that in some patients with a limited number of clinically detectable metastatic tumors, the extent of disease exists in a transitional state between localized and widespread systemic disease. In this model local control (LC) of oligometastases would have the potential to yield improved systemic control, going against the dogma that control of oligometastatic disease would not have a therapeutic benefit since it represents a clinical manifestation of a few detectable lesions in the setting of widespread occult disease. Oligometastasis continues to be defined as a state of metastatic disease that is limited in total disease burden, usually by number of clinically evident or radiographic sites (either 1–3 or 1–5), and that is not rapidly spreading to more sites. The clinical implication of oligometastasis suggests that if the primary site (if still present) is controlled, or resected, and the metastatic sites are ablated (surgically or with radiation), there will be a prolonged disease-free interval, and perhaps even cure. As the understanding of the mechanisms underlying cancer metastasis have evolved, possible mechanisms for the oligometastatic state must be explained and examined within that context.

Theories of metastasis

Metastasis is the cause of most cancer-related deaths. In 1889, Stephen Paget theorized that circulating tumor cells would “seed” to an amenable “soil”, suggesting that metastasis was not a matter of chance. Five years later,, in 1894, Halstead theorized that cancer was an orderly disease that progressed in a contiguous manner, by direct extension from the primary tumor through the lymphatics, to the lymph nodes, and then to distant sites. Halstead proposed that breast cancer metastasis was a progressive, anatomical process of contiguous seeding; his hypothesis supported the use of radical surgery and radiotherapy. Radical en bloc surgery, radical hysterectomy, and primary and regional irradiation for several tumor sites were all based on Halstead's theory of tumor spread. James Ewing, in 1928, complemented the Paget and Halstead theories to propose that cancer cells grow at a particular site because they are directed by the direction of blood flow and lymphatics.

The ‘systemic’ theory of metastasis, first suggested by Keynes and further developed by Fisher, held that clinically apparent cancer was a systemic disease, and that small tumors were an early manifestation of systemic disease. In this theory, nodal involvement was not part of an orderly contiguous extension but rather a marker of distant metastases. According to this theory, local control would not impact survival.

In contrast to the ‘Halsted’ theory and the ‘systemic’ theory, the ‘spectrum’ theory of cancer metastases, first described for breast cancer metastases in 1994, held that disease stage at the time of initial disease presentation fell into a spectrum ranging from indolent disease to widely metastatic, with the degree of clonal evolution determining the ability of the tumor to metastasize. The spectrum theory was refined just one year later to describe the limited metastasis of any solid tumor and the term ‘oligometastasis’ was coined.

The spectrum theory conceptualized the entire range of metastatic competence, analogous to a diapason, which is the entire range of an instrument. To that end, the social sciences concept of a diaspora has recently been utilized to inform biologic understanding and therapeutic paradigms of cancer metastasis. A diaspora refers to the scattering or movement of a population from its original homeland. In the case of systemic metastases, the diaspora resembles an imperial colonization in which the populations spread widely and eventually conquer the new host lands (aggressive cancer clones to multiple organs). Oligometastases resemble trading post diasporas, representing a limited number of outposts with limited growth potential (less aggressive cancer clones to few organs). (Table 1, Figure 1). Systemic versus oligometastatic diasporas may be dependent on the types of mutations present in the cancer cells (quality of the diaspora migrants), the quality of the original tumor site (factors in the homeland that cause the population to migrate), and the quality of the new hostland (factors that allow immigrants to establish and flourish) (Table 2).

Biology of systemic and oligometastases

It is now widely accepted that there are discrete steps in tumor metastasis. Initially there is a loss in cellular adhesion, followed by increased motility > invasiveness of the primary tumor > entry into and survival in the circulation > entry into new organs > eventual colonization of these organs. Shortfalls at any stage of this metastatic progression could result in phenotypes of limited metastatic potential. Gupta et al. described specific tumorigenic genes – initiation, progression, and virulence genes – that fulfilled specific roles in the metastatic cascade. Initiation genes afford a selective advantage to primary tumor cells to enter circulation. Progression genes fulfill rate-limiting steps for colonization. Virulence genes provide a selective advantage in cells to colonize a secondary site(s). As Weichselbaum and Hellman noted, this paradigm suggests “that there may be primary tumor cells with a limited capability in one or more of the necessary biological requirements for metastasis; thus proposing a possible biologic explanation of the origin of oligometastases”.

In 2000 and updated in 2011, Hanahan and Weinberg proposed the, widely accepted, ‘hallmarks of cancer’. The original cancer hallmarks consisted of six transformations in cellular physiology that allow cells to survive, proliferate and disseminate, and together support carcinogenesis. The update posited that underlying the original hallmarks were two ‘enabling hallmarks’: ‘genome instability and mutation’ and ‘tumor-promoting inflammation’. Additionally, the update proposed two new ‘emerging hallmarks’: ‘deregulation of cellular energetics’ and ‘avoidance of immune destruction’. The exact sequence in which the transformations occur, and thus the appearance of the ‘hallmarks’ (self-sufficiency in growth signals ↔ insensitivity to anti-growth signals ↔ tissue evasion and metastasis ↔ limitless replicative potential ↔ sustained angiogenesis ↔ evading apoptosis) can vary throughout the course of progression. Despite the ordering, collectively, the hallmarks can terminate into a cancer. However, the ordering and the degree of specific hallmarks, may potentially allow for a subsequent oligometastatic state. For example, cancer cells that lack the hallmarks to actively metastasize still may be able to slough into the circulation and inefficiently establish metastases. Other cells may be less efficient at proliferation, establishing slow growing metastases. Warburg (1956) suggested that “We may have cells which indeed look like cancer cells but are still energetically insufficient… such cells which are clinically not cancer cells, have lately been found not only in the prostate, but also in the lungs, kidney, and stomach of elderly persons such cells have been referred to as “sleeping cancer cells”.

Preclinical models of oligometastasis

Traditional clinicopathologic factors are inadequate when attempting to define the potential underlying biology of oligometastases. Several investigations have demonstrated the marked genetic and epigenetic heterogeneity present in metastatic cancer sites within the same patient. These studies demonstrate that cancer cells at different sites within a patient can have varied malignant potential. Preclinical models of tumors with varying degrees of metastatic potential, including low metastatic potential exist. Using a cell line derived from B16F1 melanoma, Fidler et al. found that variant metastatic cells pre-exist in a heterogeneous primary tumor as opposed to originating through adaption during metastasis from an otherwise homogenous primary tumor. This finding was advanced in later work that showed the KHT sarcoma line demonstrated similar heterogeneity whether grown in vitro or in vivo, which suggested that clonal variation seen in vitro derived from heterogeneity present in the primary tumor. As an extension of this work in the KHT sarcoma line, it was demonstrated that effective metastatic variants developed at a high rate with low frequency, as opposed to the more frequent and stable subpopulations of metastatic variants. In comparing B16 cell lines, Cillo et al. showed that the more highly metastatic, and less genetically stable cell line, generated increased metastatic variants corresponding to increased chemotherapy resistance. Numerous in vitro studies and analyses of animal models have indicated that cells isolated from metastases differ greatly—both genetically and phenotypically—from cells isolated from their parental primary tumors. The preclinical models point toward variation in individual tumor cells' metastatic potential, which supports the concept of oligometastases.

Given that stochastic models have been used to predict biologic phenomena, a Bayesian model has been proposed to predict the chance of occult metastases in the presence of detectable oligometastases. Using the size and number of metastases, the proposed model inferred, (1) that the probability of occult metastases may increase substantially with minor increases in metastatic potential and (2) that extended disease-free periods were predictive of a substantial decrease in additional occult disease. Although compelling, such models are in their infancy and as yet remain in pre-clinical testing where the host, tumor and experimental factors are controlled.

Clinical evidence of oligometastasis

Evidence for the evolution of the oligometastatic phenotype comes from various clinical and pre-clinical sources. Recent studies of the molecular biology of renal cell cancer metastasis have implied biologic differences between less and more aggressive metastases, as well as between fewer and multiple metastases. In order to better determine which patients presenting with localized RCC harbor an aggressive tumor and may not benefit from surgery, Kosari et al. using gene expression profiling, found gene expression alterations associated with an aggressive tumor and metastatic potential in the primary tumor. From a cohort of 20 resected pulmonary metastases taken from 18 patients, Wuttig et al demonstrated the predictive potential of identified gene signatures, when comparing disease-free intervals (DFI) and number of metastases, both of which are predictive of prognosis in metastatic RCC (mRCC). There were 306 differentially expressed genes in comparing DFI ≥5 years and DFI ≤9 months, and 135 differentially expressed genes in comparing multiple metastases (≥16) and few metastases (≤8).

In colorectal cancer, there is growing evidence that liver-limited disease is a distinct biological cohort that may benefit from aggressive management. While only a minority of patients are technically resectable, approximately 40% of patients with resected liver limited disease are alive 5 years after diagnosis compared with less than 1% for those with disseminated disease. There is genetic evidence that patients undergoing hepatic resection for metastatic cancer had a different disease than those who did not. For example, it was noted that BRAF V600E mutant tumors, which were typically associated with aggressive biology, rarely came to liver resection. In addition, novel chromosomal aberrations have been identified that are associated with intra- and extra-hepatic recurrence after liver resection.

MicroRNAs, small non-coding RNA known to regulate tumor proliferation and apoptosis, are frequently dysregulated in cancer and metastasis. MicroRNA profiling has shown a possible method to distinguish patients with oligometastases from those with polymetastatic disease. Examples of pro-metastatic microRNAs include microRNA-10b (upregulated in primary breast tumors that had metastasized), microRNA-21 (correlated with advanced stage, incidence of metastases, and poor outcomes in breast and pancreatic tumors), and microRNA-373/520c (increased expression in breast metastases). MicroRNA-210, a known transcriptional target of the HIF-1α signaling pathway, was elevated in sera from patients with metastatic castrate-resistant prostate cancer, as compared to controls, and was correlated with treatment response as assessed by change in PSA. Lussiter et al. found microRNA-200c was associated with polymetastatic progression in a oligometastatic cell line, derived from patients treated with high-dose radiotherapy, tested in a xenograft model. The investigators then stratified patients with resected pulmonary oligometastases into subgroups, based on high-risk versus low-risk of further metastatic progression. Differential microRNA expression patterns were identified between these two groups (high rate of progression (n = 16 prioritized microRNAs) and low rate of progression (n = 32 prioritized microRNAs) and, in an independent dataset, the expression patterns were associated with risk of progression and decreased overall survival. Most recently, Uppal et al. identified three microRNAs overexpressed in clinical metastasis samples from patients with limited metastatic disease. MicroRNA-127–5p, microRNA-544a, and microRNA-655–3p were shown to limit, but not fully inhibit, metastasis in a model of breast cancer lung colonization.

Controversies surrounding the treatment of oligometastatic disease

Hellman theorized that, 1) whereas some tumors were destined to remain localized, 2) other tumors, as they increased in size, acquired an increasingly greater metastatic phenotype, suggesting at an early stage these tumors seeded distant sites with clones that had not reached full metastatic potential, and finally, 3) that some tumors already had occult distant dissemination at the time they are diagnosed. He also proposed that metastatic potential was not only directed by the tumor phenotype, but that it was also influenced by the tumor's location, venous drainage, and host factors. Based on Hellman's theory, later scientists further theorized that tumors in the oligometastatic disease state were tumors early in their evolution of metastatic progression; therefore they produced metastases that were limited in number and location. These data support the presumption of a temporal evolution with an intermediate stage of limited metastatic capacity, where oligometastatic tumors may not have acquired the broad array of genetic changes required to develop widespread metastases.

The clinical implication of the oligometastatic state is that locally ablative therapies, given with the intent of targeting sites of clinically evident metastatic disease could result in long-term survival or cure. Treatment of oligometastatic disease may also result in decreased overall tumor burden, decreasing morbidity and increasing survival. These arguments are opposed by the concept that clinical metastases are evidence of systemic disease and locally directed treatment will not alter the natural history of the disease course within a patient. In this scenario, only systemic therapy may be beneficial. Indeed, oligometastatic treatment paradigms are controversial (due to the limited data available). Without randomized studies, it is impossible to know if treatment of oligometastatic disease helps the patient. In addition, oligometastatic disease may represent indolent disease that does not require potentially toxic treatments.

Patients are increasingly being diagnosed with oligometastatic disease due to the advent of sensitive imaging technologies as well as effective therapies that are allowing patients to live longer with the diagnosis of cancer. In addition, the fact that novel treatment options with acceptable safety profiles, such as stereotactic radiation, cryoablation, and minimally invasive surgery, are available to treat limited metastases, has led to a renewed interest in treating oligometastatic disease. Treatment of oligometastatic disease not only has the potential to prevent further evolution of genetically unstable clones and metastatic spread, it may improve overall disease control and delay more toxic systemic treatment. Finally, the definition of oligometastases had gradually evolved (Table 3), which further inflates the increasing population of patients diagnosed with oligometastasis. In the absence of data to guide decisions, treatment of oligometastatic disease may be seen as a quality-of-life oriented approach, choosing personalized treatments with a reasonable risk to benefit ratio and taking into account the patient's own attitude in guiding them toward more or less, intensive therapy.

Radiation therapy

While much of the literature supporting the oligometastatic states is within the surgical literature, there is an increasing body of literature describing the use of stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS), in addition to conventional fractionated radiotherapy techniques. SBRT is a noninvasive method of delivering high doses of radiation to ablate a target lesion while sparing the neighboring normal tissue, thus reducing long-term effects of radiation on the non-malignant tissues. The radiation is delivered from many beams originating from multiple directions that converge on the target site. Through improved targeting and management of tumor motion, SBRT may improve tumor control and reduce treatment-related toxicity, as compared to conventional fractionated RT. Improved radiation targeting allows for higher-dose, hypofractionated, more efficient treatment regimens that can be delivered within narrow margins sparring adjacent organs. ‘Hypofractionation’ is the delivery of large doses of radiation over a shorter time period as compared to conventional radiation fraction sizes. Therapy can generally be completed in 1–5 sessions, as compared to conventional radiation therapy that is delivered in smaller doses 5 days/week over ≥ 6 weeks.

SBRT can be used to manage oligometastatic disease presentations that would be associated with added morbidity if managed by surgery, such as deep-seated or osseous lesions. Patients who are poor surgical candidates may often be treated with SBRT, given that it is noninvasive and has a modest morbidity profile. Whereas surgery, when used to manage oligometastatic disease, tends to be seen as the gold standard as it allows for pathologic evaluation and assessment of the surgical margins. In addition, lesions greater than 7–8 cm and those difficult to target with SBRT, are better left for surgical management.

Although traditionally radiation therapy was thought to be immunosuppressive, there is increasing pre-clinical and clinical evidence that high dose, hypofractionated radiation –SBRT-may reverse antitumor immunity via CD8+ T-cells and cellular stress signals. Although uncommon, the abscopal effect (regression in tumors distant to the targeted field of radiation) is an example of recovery of anti-tumor immunity following RT. While the exact mechanism is unknown, it has been proposed that the radiation effect may result in the release of anti-tumor proliferative antigens and cytokines. Matzinger theorized a ‘danger model’, which suggested that the immune system is stimulated by injured tissues rather than ‘non-self’, therefore damaged tissues in irradiated sites may stimulate the immune system. Lee et al.demonstrated in a murine model that hypofractionated, high dose RT may possibly reverse T-cell unresponsiveness to primary and metastatic tumors. More specifically, considering that local RT to a tumor may modify its microenvironment by producing inflammatory cytokines that may increase its immune responsiveness, Lugade et al. demonstrated that IFN-γ (a cytokine), following RT, promotes T cell function. It is thought that a tumor has ongoing crosstalk with the immune system-from one end of a spectrum where the immune system eliminates the tumor, to tumor-immune system equilibrium (a subclinical tumor), until selective pressure from the immune system stimulates the evolution of tumor cells resistant to the immune system (clinically detectable). A way to think of how RT may promote immune recovery is that the irradiated tumor is converted into a ‘vaccine’ that promotes tumor specific T cells to bestow immune memory against non-treated tumors.. Thus, an emerging advantage of SBRT is the possibility that it may be exploited to benefit the immune system.

Surgery

Historically, most of the surgical data in regards to oligometastatic disease is centered on hepatic resection.. Perioperative mortality related to hepatic resection has decreased from 20% (before 1980) to 1%. Recent improvement in overall survival, following hepatectomy, are likely from improvements in patient selection (shift in definition of resectability to new criteria based on whether a macroscopic and microscopic complete resection of the liver lesion as well as complete resection of any extrahepatic disease), surgical technique, and more effective adjuvant therapy. The use of portal vein embolization and of neoadjuvant chemotherapy have also expanded the population of patients who are eligible for resection. In a recent series of patients having undergone hepatic resection, despite progression on chemotherapy, the 5-yr survival was 53%.

Secondary resection remains a worthwhile therapeutic goal; patients brought to resection by systemic therapy enjoy comparable long-term survival to patients who had resectable disease at the time of presentation, and far superior to those receiving palliative systemic chemotherapy. 10–20% of patients that develop colorectal liver metastases present with, or are converted by systemic treatment to, an oligometastatic state defined as metastatic lesions that are limited in number and involving only a single organ. This type of disease is potentially amenable to local therapeutic modalities, of which hepatic resection is the most effective.

Cryotherapy

Cryotherapy has been utilized in multiple settings for the ablation of metastatic disease. In the largest series published to date, Littrup and colleagues treated a total of 251 oligometastatic tumors from multiple primary cancers in 126 patients. Sites of treatment included retroperitoneal, superficial, intraperitoneal, bone, and head and neck; average diameter of tumors was 3.4 cm. At 11 months average follow-up (range, 0–82 months), a 10% total recurrence rate (26 of 251) was noted; three occurred within the ablation zone, for a local progression rate of 1.2%. The average time to recurrence was 4.9 months, and, at 21 months, the initial ablation zone had reduced in volume by 93%.

Treatment of oligometastases in different cancers

Anecdotal reports of tumors with limited metastases, having undergone treatment to the metastases and had long-term response date back to the 1930's. Several studies, with a variety of endpoints and meeting different levels of evidence criteria, have been performed in a variety of cancers to treat oligometastatic disease. For each clinical study reviewed, we considered the definition of oligometastasis that was used, the therapy given, and sample size. In order to provide an ordinal categorization to assess the strength of the study designs and of the study endpoints, we used the National Cancer Institute Levels of Evidence for Adult and Pediatric Cancer Treatment Studies ranking system to assess each study. In this system, the strength of the studies in descending order is: randomized controlled trials (double-blinded): Level 1i > randomized controlled trials (non-blinded): Level 1ii > non-randomized controlled clinical trials: Level 2 > case series (population-based, consecutive series): Level 3i > case series (consecutive cases (not population-based)): Level 3ii > case series (nonconsecutive cases): Level 3iii. The system ranks the study endpoints in descending order of strength as follows: total mortality: Level A > cause-specific mortality: Level B > quality of life: Level C > event-free survival: Level Di > disease-free survival: Level Dii > progression-free survival: Level Diii > tumor response rate: Level Div.

Breast cancer

Metastatic breast cancer (MBC) at diagnosis constitutes 3.5–7% of all new breast cancers, while oligometastases comprises 1–3% of the total MCB population. Traditionally MBC patients were managed primarily with systemic modalities, with limited local treatments given only for palliative intent.

We searched PubMed using the terms ‘breast oligometastases’, ‘breast oligometastasis’, and ‘oligometastatic breast cancer’; results were as follows, n = 20, n = 5, and n = 51, respectively. We omitted reviews (including special features), studies including mixed primary tumors, case reports, studies not in the English language, studies not focused on oligometastatic breast cancer, and a survey. There were seven clinical studies remaining; oligometastases held six definitions and each study used a different therapy (Table 4).

The evidence for treatment of oligometastases in breast cancer is weak based on the study designs. There were two prospective studies, however they were both nonconsecutive case series (Level 3iii) as were the remaining studies, with the exception of one consecutive case series (Level 3ii). There was a conglomerate of therapies given for patients diagnosed with oligometastases using various definitions. The fact that overall survival endpoints were reported in all studies was helpful (Level A, n = 7 studies), however, they were not always significant — stronger study designs may have shown whether the survival endpoints were significant. Overall survival (OS) was reported at various intervals making comparisons between studies difficult: median (42.2 months), 20-yr (34%), 5-yr (62%), 4-yr (59%) and 3-yr (73% and 39–57%)).

Lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of death worldwide with > 50% of patients having metastatic disease at diagnosis. The primary treatment for most patients with metastatic NSCLC is palliative chemotherapy (CT), which results in median survivals of 8–11 months. However, multiple studies have demonstrated a subset of long-term survivors with OMLC. Additionally, curative outcomes were documented in patients with treated adrenal metastases.

We searched PubMed using the terms ‘lung oligometastasis’, ‘lung oligometastases’, and ‘oligometastatic lung cancer’; results were as follows, n = 14, n = 90, n = 123, respectively. We omitted reviews, mixed primary tumors, studies not focused on oligometastatic lung cancer, case reports, editorials, studies not in the English language, surveys, commentaries, cost analyses, studies including less than 10 patients, and studies we were unable to retrieve. There were twenty clinical studies remaining (Table 5); oligometastasis held 17 different definitions and each study had a different treatment paradigm.

The evidence for treatment of oligometastases in lung cancer was weak-to-moderate based on the study designs. There were two nonrandomized controlled clinical trials (Level 2), however the sample sizes were small (n = 26 and n = 39, respectively). There was one large study (n = 2176), although it was retrospective and a nonconsecutive case series (Level 3iii). Of the remaining 17 studies, two were population-based consecutive case series (Level 3i), two were non population–based consecutive case series (Level 3ii), and twelve were nonconsecutive case series (Level 3iii), one of which was prospective. Therapies given varied not only among the studies but within most of them as well, for patients with diversely defined oligometastases. Overall survival endpoints (level A) were reported in all but one study, however stronger study designs would have shown whether the survival endpoints were significant. OS was reported as MOS (11.7, 17, 20, 26.4, and 41months and at four intervals in the remaining studies: 5-year (29.4%, 8.3–86%, 44.7%, 38%, 36%, and 24%), 3-year (17.5%, 25%, and 15.8%), 2-year (24%and 38%), 18-month (52.9%) and 1-year (67%and 75%).

Melanoma

Approximately 30% of patients with melanoma will develop metastases. The 5-yr survival of stage IV melanoma is about 5%.

We searched PubMed using the terms ‘melanoma oligometastasis’, ‘melanoma oligometastases’ and ‘oligometastatic melanoma’; results were as follows, n = 5, n = 5, and n = 15, respectively. We omitted reviews, studies including mixed primary tumors, and studies not focused on oligometastatic melanoma. An additional search through the bibliographies of the review papers allowed us to retrieve one additional clinical study for review, therefore we reviewed two clinical studies (Table 6). The two studies differed in their therapies, which included resection, and SRS followed by +/− immunotherapy, and definitions of oligometastases.

The evidence for treatment of oligometastases in melanoma is weak based the two, retrospective studies conducted. Essner et al. was a population-based consecutive case series (Level 3i), which included a large sample size (n = 877), and determined factors prognostic for increased survival. The second study was a nonconsecutive case series (Level 3iii) with a more moderate sample size. The two studies differed in their therapies, definitions of oligometastases, and interval endpoint of OS. Although OS was reported in both studies (Level A), it was reported in different intervals; 2-year (19.7–47%) and 5-year (17–30%).

Colorectal cancer

Colorectal cancer is the fourth most common cancer diagnosis in the world (around 1.2 million diagnoses each year), and accounts for the second highest number of deaths. Nearly one-fourth of patients with newly diagnosed colorectal cancer (CRC) will present with synchronous liver metastases. Hepatic resection is considered a standard treatment option for metastatic CRC and can result in 10-year survival rates of 20–26%, and potential cure.

We searched PubMed using the terms ‘colorectal cancer oligometastasis’, ‘colorectal cancer oligometastases’, and ‘oligometastatic colorectal cancer’; results were as follows, n = 5, n = 24, and n = 28, respectively. We omitted reviews, studies including mixed primary tumors, studies not focused on oligometastatic colorectal cancer, case reports, perspectives, pre-clinical reports, and earlier reports if later reports for the same study were available. There were nine studies remaining (Table 7); oligometastasis held 9 different definitions and each study had a different treatment paradigm.

The evidence for treatment of oligometastases in colorectal cancer is weak-to-moderate based on the study designs. There were two prospective, nonrandomized controlled clinical trials (Level 2) studies, however both with small sample sizes (n = 24 and n = 9, respectively) and one prospective nonconsecutive case series (Level 3iii) study with a moderate sample size (n = 82). Salah et al. conducted a pooled analysis of 8 studies with a large sample size (n = 927) and reported 5-yr survival, however it was retrospective and a nonconsecutive case series (Level 3iii). The remaining five studies were (non population-based consecutive case series (Level 3ii) and Level 3iii. Overall survival endpoints (Level A) were reported in all but one study, however stronger study designs would have shown whether the survival endpoints were significant. OS was reported at three intervals: 5-year (52–58%), 54.3%, 39%, 38% and 29%), 3-year (43%), and 1-year (78%) and 53%).

Sarcoma

Soft tissue sarcomas are relatively rare with about 10, 000 cases diagnosed each year in the United States. If diagnosed early, the prognosis is excellent, however, in some subtypes (of which there are greater than 50), up to 50% of patients will develop distant metastases and will have a 5-year survival of below 10%. The median overall survival for patients with advanced and metastatic soft tissue sarcoma is about 12 months.

We searched PubMed using the terms ‘sarcoma oligometastasis’, ‘sarcoma oligometastases’, and ‘oligometastatic sarcoma’; results were as follows, n = 3, n = 3, and n = 13, respectively. We omitted reviews, studies including mixed primary tumors, studies not focused on oligometastatic sarcoma, and case reports. There were two clinical studies remaining (Table 8); both studies used different definitions of oligometastasis and a different treatment paradigm.

The evidence for oligometastases in sarcoma was weak based on the two retrospective studies available for review. Both studies were nonconsecutive case series (Level 3iii). Falk et al. included a moderate sample size (n = 281) and MOS was reported (45.3%) (Level A). The second study was small (n = 16) and the endpoint was time to progression (17–months) (Level Diii).

Renal cell carcinoma

Approximately 25–30% of patients diagnosed with renal cell carcinoma have metastatic disease at initial presentation. Approximately 1/3 with clinically localized primary tumor at diagnosis will eventually develop metastatic disease. Historically patients with metastatic RCC (mRCC) have a poor prognosis, with 5-yr survival rates of ≤ 10%, however prolonged survival has been noted in those with solitary or oligometastatic disease amenable to resection. RCC is often considered resistant to cytotoxic chemoconventional RT and cytokine-based immunotherapy. The lung is the most common site of metastases in mRCC; the second most common is bone. SABR is being suggested as a potential new therapeutic option.

The standard of care in mRCC is systemic therapy; however, in patients with solitary or limited metastases, aggressive local therapies may potentially prolong survival. The literature suggests a survival benefit with surgical metastasectomy, with a reported 5-year survival as high as 45% in those who achieve complete resection.

We searched PubMed using the terms ‘renal cell carcinoma oligometastasis’, ‘renal cell carcinoma oligometastases’, and ‘oligometastatic renal cell carcinoma’; results were as follows, n = 1, n = 9, and n = 3, respectively. We omitted reviews, studies including mixed primary tumors, and studies not focused on oligometastatic renal cell carcinoma. There were three clinical studies remaining (Table 9); each study used a different definition of oligometastases and a different treatment paradigm.

The evidence for treatment of oligometastases in renal cell carcinoma is weak based on the study designs. There were three retrospective studies with smaller sample sizes; a non population-based consecutive case series (Level 3ii) and two nonconsecutive case series (Level 3iii). Overall survival endpoints (Level A) were reported in at three intervals: 5-year (27%), 2-year (86%), and 1-year (83.9%).

Additional searching through the bibliographies of other selected papers allowed us to retrieve two clinical studies that investigated the effects of removal of the primary tumor in patients with metastatic renal cell carcinoma (mRCC) (Table 9). The evidence for removal of the primary tumor in mRCC was strong; both studies were nonblinded randomized controlled clinical trials (Level 1ii), had moderate sample sizes, and reported median OS (17 versus 7 months, and 11.1 versus 8.1 months) (Level A). The therapies given in both studies were similar: nephrectomy + interferon versus interferon only and nephrectomy was followed by interferon versus interferon only. The evidence for oligometastases in RCC was not assessed in these studies. However, they were important studies owing to strong design, with comparable treatments and endpoints, and most importantly they demonstrated that removal of the primary tumor in metastatic disease increased survival.

Prostate cancer

There is a body of evidence, contrary to historical clinical practice, that treating men with metastatic prostate cancer to the lymph nodes at the time of diagnosis with surgery or radiation therapy results in increased long-term survival (Table 10), and Table 11. Historically, the ideal patient to be cured by radical prostatectomy (RP) was one with organ-confined cancer. At that time, the morbidity of RP was substantial; therefore the surgery was generally only offered to those where the probability of cure was high. More recent data, however, show that RP may provide a survival benefit-albeit not a cure — to men with metastatic prostate cancer. Engel et al. conducted a retrospective study (n = 938) and found that in men with prostate cancer and positive lymph nodes, treated with +/− RP, that the 5- and 10-yr survival rates and the prostate cancer specific survival rates, were better in men who had undergone RP. Cadeddu et al conducted a retrospective study (n = 38) and found that in men with prostate cancer and positive lymph nodes, treated with LND +/− RP, that the 5- and 10-yr prostate cancer specific survival was better in men who had undergone LND + RP. Ost et al (2014) conducted a systemic review of the literature of metastasis-directed therapy of regional and distant recurrences after curative treatment for PCa (prostate cancer). They found that salvage LND and RT appear to be safe in treatments for OM PCa recurrence. Culp et al. studied the impact of survival of definitive treatment of the prostate in men diagnosed with metastatic PCa. Using the SEER database, he reviewed 8185 men treated with NSR (no surgery no radiation), brachytherapy, or RT. The 5-year OS and disease specific survival (DSS) was significantly higher in men with metastases having undergone RT.

Zapatero et al., reported on a study of men with intermediate and high risk localized prostate cancer (n = 362), treated with RT + long term ADT versus RT + short term ADT, and found that long term ADT was superior in 5-year biochemical disease free survival, metastasis free survival, and OS.

The standard of care treatment for metastatic prostate cancer is androgen deprivation therapy (ADT). Men with newly diagnosed metastatic prostate cancer, entered into the control arm of the Systemic Therapy Multi-Arm Randomized Controlled Trial (STAMPEDE) and treated with ≥ 2 years of ADT alone, had a 2-year OS of 72%. The response rate for primary hormonal therapy for men with metastatic prostate cancer exceeds 80% and the median duration of response is approximately 18–24 months. In men with prostate cancer with limited metastases, radical prostatectomy may be advantageous in that the primary tumor and its ability to continuously metastasize, to secrete tumor promoting growth factors and immunosuppressive cytokines, and to generate bulk-related morbidity, is removed. Heidenreich et al. recently evaluated survival outcomes following radical prostatectomy (RP) in men with low volume metastatic prostate cancer. RP led to improved progression-free survival, time to castrate resistance and overall survival, as compared to a cohort treated with androgen deprivation therapy alone. Moreover, Abdollah et al. found that in men with pN1 prostate cancer, treated with RP and extended lymph node dissection, adding adjuvant radiotherapy improved cancer-specific mortality.

We searched PubMed using the terms ‘prostate cancer oligometastasis’, ‘prostate cancer oligometastases’, and ‘oligometastatic prostate cancer’; results were as follows, n = 3, n = 19, and n = 22, respectively. We omitted reviews, studies including mixed primary tumors, studies not focused on oligometastatic prostate cancer, case reports, editorials/commentaries, studies that we were not able retrieve, and studies with no results reported. There were ten clinical studies remaining (Table 11); oligometastasis was defined differently in each study and there were 7 different treatment paradigms.

The evidence for treatment of oligometastases in prostate cancer is weak based on the study designs being all nonconsecutive case series (Level 3iii), although Ost el al. included a large sample (450 men). Overall survival endpoints (Level A) were reported in seven studies: 10-year (36% and 64%), 3-year (50%, 77%, and 92%), 29-month (95%), and 2-year (72%).

Currently there are two studies, not yet completed, for which we are anxiously awaiting the results. Decaestecker et al. are conducting the first randomized, phase 2 trial on men with an oligometastatic recurrence to assess the impact of metastases-directed therapy - versus active surveillance - on the start of palliative ADT. Attard et al., as part of the ongoing STAMPEDE trial, describes the addition of a new treatment arm (enzalutamide, abiraterone and prednisone with ADT) for men with newly diagnosed M1 disease.

Current trials of oligometastatic disease

We reviewed clinicaltrials.gov to gauge the ongoing studies for oligometastatic disease. Multiple trials are underway to determine if the treatment of oligometastatic disease is beneficial in cancer as reported on clinicaltrials.gov (see Table 12).

Nine studies are in progress for oligometastatic NSCLC, with therapies ranging from SBRT, to RT, to chemoradiation therapy, to targeted therapy +/− RT, to immunotherapy, to any local therapy. For men with oligometastatic prostate cancer, nine trials are underway investigating a variety of therapies including single agent RT, RT in combination with HT, salvage treatment (surgical or RT) of metastases, and combination of HT + immunotherapy. For women with oligometastatic breast cancer, six studies are currently open investigating several therapies including various chemotherapy regimens, SABR + antibodies, SBRT, chemotherapy + antibodies + RT, targeted therapies and RT. Three studies are studying oligometastatic melanoma, two are investigating immunotherapy + SABT/SRS and the third study is investigating chemotherapy with and without surgery. There are thirteen studies enrolling patients with oligometastases without a specific primary tumor, employing a variety of treatment options. Finally, there is one study each for oligometastatic colorectal cancer using chemoradiation and for oligometastatic pediatric sarcoma using SBRT.

CONCLUSIONS

Hellman proposed that tumors early in the chain of progression may give rise to metastases limited in number and location due to an undeveloped metastatic competence of the cancer “seeds” as well as the restrictive nature of the host tissue at some metastatic sites. The rationales of discrete steps of metastases and the hallmarks of cancer have both provided a biologic framework to support the oligometastatic state. Molecular diagnostics have not yet arrived to the point to determine where an individual metastatic deposit is within the continuum of malignancy, preclinical models are beginning to lay the groundwork of the oligometastatic state.

While Hellman posited that oligometastasis may be underrecognized due to limitations in imaging diagnostics, imaging has advanced to such a degree that we are now in a yin-yang position such that, 1) imaging often likely demonstrates very early findings not likely to manifest into disease and, 2) imaging demonstrates very early disease that is destined to become widespread, which cannot be distinguished from oligometastases.

Hellman described potential cure as an attractive upshot of treating an oligometastatic state, but prolonged survival has been added as a potential benefit. There is an increasing shift toward individualized, multidisciplinary management of OM disease because it is difficult to conduct randomized controlled trials in oligometastatic patients due to the variety of presentations. While other trial designs may be more realistic, such as N of 1 studies, tissue-based approaches, propensity matched analyses and adaptive design methods, Hellman originally endorsed that the ability to identify the oligometastatic state would profit from careful review of past experience, i.e. re-analysis of clinical data found in archival materials to arbitrate when, during the evolution of individual tumors, the oligometastatic state can be found.

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    Ashworth A, Rodrigues G, Boldt G, Palma D. Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. Lung cancer. 2013;82:197-203.

    Not in our library10.1016/j.lungcan.2013.07.026

  77. 77.

    Lanuti M, Sequist LV, Sharma A, Mino-Kenudson M. Case records of the Massachusetts General Hospital. Case 31–2011. A 55-year-old man with oligometastatic lung cancer. The New England journal of medicine. 2011;365:1426-1435.

    Not in our library10.1056/nejmcpc1013930

  78. 78.

    Grossi F, Kubota K, Cappuzzo F, de Marinis F, Gridelli C, Aita M, Douillard JY. Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens. The oncologist. 2010;15:1102-1112.

    Not in our library10.1634/theoncologist.2010-0322

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    Strong VE, D'Angelica M, Tang L, Prete F, Gonen M, Coit D, Touijer KA, Fong Y, Brennan MF. Laparoscopic adrenalectomy for isolated adrenal metastasis. Annals of surgical oncology. 2007;14:3392-3400.

    Not in our library10.1245/s10434-007-9520-7

  80. 80.

    Collen C, Christian N, Schallier D, Meysman M, Duchateau M, Storme G, De Ridder M. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2014;25:1954-1959.

    Not in our library10.1093/annonc/mdu370

  81. 81.

    De Ruysscher D, Wanders R, van Baardwijk A, Dingemans AM, Reymen B, Houben R, Bootsma G, Pitz C, van Eijsden L, Geraedts W, Baumert BG, Lambin P. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450). Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2012;7:1547-1555.

    Not in our library10.1097/jto.0b013e318262caf6

  82. 82.

    Nieder C, Tollali T, Reigstad A, Pawinski A, Haukland E, Dalhaug A. Oligometastatic non-small cell lung cancer: a significant entity outside of specialized cancer centers? Medical principles and practice: international journal of the Kuwait University, Health Science Centre. 2014;23:526-531.

    Not in our library10.1159/000365634

  83. 83.

    Khan AJ, Mehta PS, Zusag TW, Bonomi PD, Penfield Faber L, Shott S, Abrams RA. Long term disease-free survival resulting from combined modality management of patients presenting with oligometastatic, non-small cell lung carcinoma (NSCLC). Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2006;81:163-167.

    Not in our library10.1016/j.radonc.2006.09.006

  84. 84.

    Ashworth AB, Senan S, Palma DA, Riquet M, Ahn YC, Ricardi U, Congedo MT, Gomez DR, Wright GM, Melloni G, Milano MT, Sole CV, De Pas TM, Carter DL, Warner AJ, Rodrigues GB. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clinical lung cancer. 2014;15:346-355.

    Not in our library10.1016/j.cllc.2014.04.003

  85. 85.

    Lopez Guerra JL, Gomez D, Zhuang Y, Hong DS, Heymach JV, Swisher SG, Lin SH, Komaki R, Cox JD, Liao Z. Prognostic impact of radiation therapy to the primary tumor in patients with non-small cell lung cancer and oligometastasis at diagnosis. International journal of radiation oncology, biology, physics. 2012;84:e61-67.

    Not in our library10.1016/j.ijrobp.2012.02.054

  86. 86.

    Collaud S, Stahel R, Inci I, Hillinger S, Schneiter D, Kestenholz P, Weder W. Survival of patients treated surgically for synchronous single-organ metastatic NSCLC and advanced pathologic TN stage. Lung cancer. 2012;78:234-238.

    Not in our library10.1016/j.lungcan.2012.09.011

  87. 87.

    Congedo MT, Cesario A, Lococo F, De Waure C, Apolone G, Meacci E, Cavuto S, Granone P. Surgery for oligometastatic non-small cell lung cancer: long-term results from a single center experience. The Journal of thoracic and cardiovascular surgery. 2012;144:444-452.

    Not in our library10.1016/j.jtcvs.2012.05.051

  88. 88.

    Hasselle MD, Haraf DJ, Rusthoven KE, Golden DW, Salgia R, Villaflor VM, Shah N, Hoffman PC, Chmura SJ, Connell PP, Vokes EE, Weichselbaum RR, Salama JK. Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2012;7:376-381.

    Not in our library10.1097/jto.0b013e31824166a5

  89. 89.

    Griffioen GH, Toguri D, Dahele M, Warner A, de Haan PF, Rodrigues GB, Slotman BJ, Yaremko BP, Senan S, Palma DA. Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): patient outcomes and prognostic factors. Lung cancer. 2013;82:95-102.

    Not in our library10.1016/j.lungcan.2013.07.023

  90. 90.

    Yano T, Okamoto T, Haro A, Fukuyama S, Yoshida T, Kohno M, Maehara Y. Local treatment of oligometastatic recurrence in patients with resected non-small cell lung cancer. Lung cancer. 2013;82:431-435.

    Not in our library10.1016/j.lungcan.2013.08.006

  91. 91.

    Yu HA, Sima CS, Huang J, Solomon SB, Rimner A, Paik P, Pietanza MC, Azzoli CG, Rizvi NA, Krug LM, Miller VA, Kris MG, Riely GJ. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2013;8:346-351.

    Not in our library10.1097/jto.0b013e31827e1f83

  92. 92.

    Gray PJ, Mak RH, Yeap BY, Cryer SK, Pinnell NE, Christianson LW, Sher DJ, Arvold ND, Baldini EH, Chen AB, Kozono DE, Swanson SJ, Jackman DM, Alexander BM. Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival. Lung cancer. 2014;85:239-244.

    Not in our library10.1016/j.lungcan.2014.06.001

  93. 93.

    Cheufou DH, Welter S, Chalvatzoulis E, Christof D, Theegarten D, Stamatis G. Surgery of primary lung cancer with oligometastatic m1b synchronous single brain metastasis: analysis of 37 cases. The Thoracic and cardiovascular surgeon. 2014;62:612-615.

    Not in our library10.1055/s-0034-1377060

  94. 94.

    Parikh RB, Cronin AM, Kozono DE, Oxnard GR, Mak RH, Jackman DM, Lo PC, Baldini EH, Johnson BE, Chen AB. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. International journal of radiation oncology, biology, physics. 2014;89:880-887.

    Not in our library10.1016/j.ijrobp.2014.04.007

  95. 95.

    Sheu T, Heymach JV, Swisher SG, Rao G, Weinberg JS, Mehran R, McAleer MF, Liao Z, Aloia TA, Gomez DR. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small cell lung cancer that did not progress after front-line chemotherapy. International journal of radiation oncology, biology, physics. 2014;90:850-857.

    Not in our library10.1016/j.ijrobp.2014.07.012

  96. 96.

    Tonnies M, Pfannschmidt J, Bauer TT, Kollmeier J, Tonnies S, Kaiser D. Metastasectomy for synchronous solitary non-small cell lung cancer metastases. The Annals of thoracic surgery. 2014;98:249-256.

    Not in our library10.1016/j.athoracsur.2014.03.028

  97. 97.

    Ouyang WW, Su SF, Ma Z, Hu YX, Lu B, Li QS, Geng YC, Li HQ. Prognosis of non-small cell lung cancer patients with bone oligometastases treated concurrently with thoracic three-dimensional radiotherapy and chemotherapy. Radiation oncology. 2014;9:147.

    Not in our library10.1186/1748-717x-9-147

  98. 98.

    Endo C, Hasumi T, Matsumura Y, Sato N, Deguchi H, Oizumi H, Sagawa M, Tsushima T, Takahashi S, Shibuya J, Hirose M, Kondo T. A prospective study of surgical procedures for patients with oligometastatic non-small cell lung cancer. The Annals of thoracic surgery. 2014;98:258-264.

    Not in our library10.1016/j.athoracsur.2014.01.052

  99. 99.

    Essner R, Lee JH, Wanek LA, Itakura H, Morton DL. Contemporary surgical treatment of advanced-stage melanoma. Archives of surgery. 2004;139:961-966.

    Not in our library10.1001/archsurg.139.9.961

  100. 100.

    Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. Journal of neurosurgery. 2012;117:227-233.

    Not in our library10.3171/2012.5.jns111929

  101. 101.

    Engel J, Bastian PJ, Baur H, Beer V, Chaussy C, Gschwend JE, Oberneder R, Rothenberger KH, Stief CG, Holzel D. Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer. European urology. 2010;57:754-761.

    Not in our library10.1016/j.eururo.2009.12.034

  102. 102.

    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA: a cancer journal for clinicians. 2009;59:225-249.

    Not in our library10.3322/caac.20006

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    Timmerman RD, Bizekis CS, Pass HI, Fong Y, Dupuy DE, Dawson LA, Lu D. Local surgical, ablative, and radiation treatment of metastases. CA: a cancer journal for clinicians. 2009;59:145-170.

    Not in our library10.3322/caac.20013

  104. 104.
    Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer · 2012
    Not checked
  105. 105.

    Hughes KS, Simon R, Songhorabodi S, Adson MA, Ilstrup DM, Fortner JG, Maclean BJ, Foster JH, Daly JM, Fitzherbert D, et al. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery. 1986;100:278-284.

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  106. 106.

    Nordlinger B, Guiguet M, Vaillant JC, Balladur P, Boudjema K, Bachellier P, Jaeck D. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer. 1996;77:1254-1262.

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    Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309-318.

    Not in our library10.1097/00000658-199909000-00004

  108. 108.

    Pawlik TM, Scoggins CR, Zorzi D, Abdalla EK, Andres A, Eng C, Curley SA, Loyer EM, Muratore A, Mentha G, Capussotti L, Vauthey JN. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715-722.

    Not in our library10.1097/01.sla.0000160703.75808.7d

  109. 109.

    Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D'Angelica M. Actual 10-year survival after resection of colorectal liver metastases defines cure. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2007;25:4575-4580.

    Not in our library10.1200/jco.2007.11.0833

  110. 110.

    Dellas K, Reese T, Richter M, Arnold D, Dunst J. Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study. Radiation oncology. 2012;7:83.

    Not in our library10.1186/1748-717x-7-83

  111. 111.

    Comito T, Cozzi L, Clerici E, Campisi MC, Liardo RL, Navarria P, Ascolese A, Tozzi A, Iftode C, De Rose F, Villa E, Personeni N, Rimassa L, Santoro A, Fogliata A, Mancosu P, et al. Stereotactic Ablative Radiotherapy (SABR) in inoperable oligometastatic disease from colorectal cancer: a safe and effective approach. BMC cancer. 2014;14:619.

    Not in our library10.1186/1471-2407-14-619

  112. 112.

    Salah S, Watanabe K, Welter S, Park JS, Park JW, Zabaleta J, Ardissone F, Kim J, Riquet M, Nojiri K, Gisabella M, Kim SY, Tanaka K, Al-Haj Ali B. Colorectal cancer pulmonary oligometastases: pooled analysis and construction of a clinical lung metastasectomy prognostic model. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2012;23:2649-2655.

    Not in our library10.1093/annonc/mds100

  113. 113.

    Van den Begin R, Engels B, Gevaert T, Duchateau M, Tournel K, Verellen D, Storme G, De Ridder M. Impact of inadequate respiratory motion management in SBRT for oligometastatic colorectal cancer. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2014;113:235-239.

    Not in our library10.1016/j.radonc.2014.11.005

  114. 114.

    Filippi AR, Badellino S, Ceccarelli M, Guarneri A, Franco P, Monagheddu C, Spadi R, Ragona R, Racca P, Ricardi U. Stereotactic Ablative Radiation Therapy as First Local Therapy for Lung Oligometastases From Colorectal Cancer: A Single-Institution Cohort Study. International journal of radiation oncology, biology, physics. 2014.

    Not in our library10.1016/j.ijrobp.2014.10.046

  115. 115.

    Salah S, Watanabe K, Park JS, Addasi A, Park JW, Zabaleta J, Ardissone F, Kim J, Riquet M, Nojiri K, Gisabella M, Kim SY, Tanaka K. Repeated resection of colorectal cancer pulmonary oligometastases: pooled analysis and prognostic assessment. Annals of surgical oncology. 2013;20:1955-1961.

    Not in our library10.1245/s10434-012-2860-y

  116. 116.

    Bae SH, Kim MS, Cho CK, Kang JK, Kang HJ, Kim YH, Shin US, Moon SM, Lee DH. High dose stereotactic body radiotherapy using three fractions for colorectal oligometastases. Journal of surgical oncology. 2012;106:138-143.

    Not in our library10.1002/jso.23058

  117. 117.

    Kang JK, Kim MS, Kim JH, Yoo SY, Cho CK, Yang KM, Yoo HJ, Seo YS, Lee DH, Kang HJ, Kim YH, Shin US. Oligometastases confined one organ from colorectal cancer treated by SBRT. Clinical & experimental metastasis. 2010;27:273-278.

    Not in our library10.1007/s10585-010-9325-0

  118. 118.

    Hohenberger P, Kasper B, Ahrar K. Surgical management and minimally invasive approaches for the treatment of metastatic sarcoma. American Society of Clinical Oncology educational book / ASCO American Society of Clinical Oncology Meeting. 2013;457-464.

    Not in our library10.14694/edbook_am.2013.33.457

  119. 119.

    Falk AT, Moureau-Zabotto L, Ouali M, Penel N, Italiano A, Bay JO, Olivier T, Sunyach MP, Boudou-Roquette P, Salas S, Le Maignan C, Ducassou A, Isambert N, Kalbacher E, Pan C, Saada E, et al. Effect on survival of local ablative treatment of metastases from sarcomas: a study of the French sarcoma group. Clinical oncology. 2015;27:48-55.

    Not in our library10.1016/j.clon.2014.09.010

  120. 120.

    Rhomberg W, Eiter H, Schmid F, Saely CH. Combined vindesine and razoxane shows antimetastatic activity in advanced soft tissue sarcomas. Clinical & experimental metastasis. 2008;25:75-80.

    Not in our library10.1007/s10585-007-9103-9

  121. 121.

    Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. The New England journal of medicine. 1996;335:865-875.

    Not in our library10.1056/nejm199609193351207

  122. 122.

    Ranck MC, Golden DW, Corbin KS, Hasselle MD, Liauw SL, Stadler WM, Hahn OM, Weichselbaum RR, Salama JK. Stereotactic body radiotherapy for the treatment of oligometastatic renal cell carcinoma. American journal of clinical oncology. 2013;36:589-595.

    Not in our library10.1097/coc.0b013e31825d52b2

  123. 123.

    Thibault I, Al-Omair A, Masucci GL, Masson-Cote L, Lochray F, Korol R, Cheng L, Xu W, Yee A, Fehlings MG, Bjarnason GA, Sahgal A. Spine stereotactic body radiotherapy for renal cell cancer spinal metastases: analysis of outcomes and risk of vertebral compression fracture. Journal of neurosurgery Spine. 2014;21:711-718.

    Not in our library10.3171/2014.7.spine13895

  124. 124.

    Bang HJ, Littrup PJ, Goodrich DJ, Currier BP, Aoun HD, Heilbrun LK, Vaishampayan U, Adam B, Goodman AC. Percutaneous cryoablation of metastatic renal cell carcinoma for local tumor control: feasibility, outcomes, and estimated cost-effectiveness for palliation. Journal of vascular and interventional radiology: JVIR. 2012;23:770-777.

    Not in our library10.1016/j.jvir.2012.03.002

  125. 125.

    Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon- alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358:966-970.

    Not in our library10.1016/s0140-6736(01)06103-7

  126. 126.

    Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. The New England journal of medicine. 2001;345:1655-1659.

    Not in our library10.1056/nejmoa003013

  127. 127.

    Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F, Fossa SD. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009;373:301-308.

    Not in our library10.1016/s0140-6736(08)61815-2

  128. 128.

    Vickers A, Bennette C, Steineck G, Adami HO, Johansson JE, Bill-Axelson A, Palmgren J, Garmo H, Holmberg L. Individualized estimation of the benefit of radical prostatectomy from the Scandinavian Prostate Cancer Group randomized trial. European urology. 2012;62:204-209.

    Not in our library10.1016/j.eururo.2012.04.024

  129. 129.

    Zelefsky MJ, Eastham JA, Cronin AM, Fuks Z, Zhang Z, Yamada Y, Vickers A, Scardino PT. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:1508-1513.

    Not in our library10.1200/jco.2009.22.2265

  130. 130.

    Pierorazio PM, Lin BM, Mullins JK, Hyndman ME, Schaeffer EM, Han M, Partin AW, Pavlovich CP. Preoperative characteristics of men with unfavorable high-Gleason prostate cancer at radical prostatectomy. Urologic oncology. 2013;31:589-594.

    Not in our library10.1016/j.urolonc.2011.05.002

  131. 131.

    Shao YH, Kim S, Moore DF, Shih W, Lin Y, Stein M, Kim IY, Lu-Yao GL. Cancer-specific survival after metastasis following primary radical prostatectomy compared with radiation therapy in prostate cancer patients: results of a population-based, propensity score-matched analysis. European urology. 2014;65:693-700.

    Not in our library10.1016/j.eururo.2013.05.023

  132. 132.

    Cadeddu JA, Partin AW, Epstein JI, Walsh PC. Stage D1 (T1-3, N1-3, M0) prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy. Urology. 1997;50:251-255.

    Not in our library10.1016/s0090-4295(97)00186-6

  133. 133.

    Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ, Roach M, Briganti A. Metastasis-directed Therapy of Regional and Distant Recurrences After Curative Treatment of Prostate Cancer: A Systematic Review of the Literature. European urology. 2014.

    Not in our library10.1016/j.eururo.2014.09.004

  134. 134.

    Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. European urology. 2014;65:1058-1066.

    Not in our library10.1016/j.eururo.2013.11.012

  135. 135.

    Zapatero A, Guerrero A, Maldonado J, Alvarez A, San Segundo C.G, Rodriguez M.C, Macias V, Pedro-Olive A, Casas F, Boladeras A, de Vidales C.M, de la Torre M.V, Calvo F.A. Randomized Phase III Trial of Adjuvant Androgen Deprivation in Combination with High-dose Conformal Radiotherapy in Intermediate and High Risk Localized Prostate Cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2014;32:52.

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  136. 136.

    McKay RR, Choueiri TK, Taplin ME. Rationale for and review of neoadjuvant therapy prior to radical prostatectomy for patients with high-risk prostate cancer. Drugs. 2013;73:1417-1430.

    Not in our library10.1007/s40265-013-0107-2

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    James ND, Spears MR, Clarke NW, Dearnaley DP, De Bono JS, Gale J, Hetherington J, Hoskin PJ, Jones RJ, Laing R, Lester JF, McLaren D, Parker CC, Parmar MK, Ritchie AW, Russell JM, et al. Survival with Newly Diagnosed Metastatic Prostate Cancer in the “Docetaxel Era”: Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). European urology. 2014.

    Not in our library10.1016/j.eururo.2014.09.032

  138. 138.

    Maximum androgen blockade in advanced prostate cancer. an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet. 2000;355:1491-1498.

    Not in our library

  139. 139.

    Heidenreich A, Pfister D, Brehmer B, Porres D. [Cytoreductive radical prostatectomy for prostate cancer with minimal osseous metastases: Results of a first feasibility and case control study]. Der Urologe Ausg A. 2015;54:14-21.

    Not in our library10.1007/s00120-014-3697-8

  140. 140.

    Abdollah F, Karnes RJ, Suardi N, Cozzarini C, Gandaglia G, Fossati N, Vizziello D, Sun M, Karakiewicz PI, Menon M, Montorsi F, Briganti A. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2014;32:3939-3947.

    Not in our library10.1200/jco.2013.54.7893

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    Schick U, Jorcano S, Nouet P, Rouzaud M, Vees H, Zilli T, Ratib O, Weber DC, Miralbell R. Androgen deprivation and high-dose radiotherapy for oligometastatic prostate cancer patients with less than five regional and/or distant metastases. Acta oncologica. 2013;52:1622-1628.

    Not in our library10.3109/0284186x.2013.764010

  142. 142.

    Ost P, Decaestecker K, Lambert B, Fonteyne V, Delrue L, Lumen N, Ameye F, De Meerleer G. Prognostic factors influencing prostate cancer-specific survival in non-castrate patients with metastatic prostate cancer. The Prostate. 2014;74:297-305.

    Not in our library10.1002/pros.22750

  143. 143.

    Ponti E, Ingrosso G, Carosi A, Di Murro L, Lancia A, Pietrasanta F, Santoni R. Salvage Stereotactic Body Radiotherapy for Patients With Prostate Cancer With Isolated Lymph Node Metastasis: A Single-Center Experience. Clinical genitourinary cancer. 2014.

    Not in our library10.1016/j.clgc.2014.12.014

  144. 144.
    Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence · 2014
    No notice
  145. 145.

    Ahmed KA, Barney BM, Davis BJ, Park SS, Kwon ED, Olivier KR. Stereotactic body radiation therapy in the treatment of oligometastatic prostate cancer. Frontiers in oncology. 2012;2:215.

    Not in our library10.3389/fonc.2012.00215

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    Berkovic P, De Meerleer G, Delrue L, Lambert B, Fonteyne V, Lumen N, Decaestecker K, Villeirs G, Vuye P, Ost P. Salvage stereotactic body radiotherapy for patients with limited prostate cancer metastases: deferring androgen deprivation therapy. Clinical genitourinary cancer. 2013;11:27-32.

    Not in our library10.1016/j.clgc.2012.08.003

  147. 147.

    Jereczek-Fossa BA, Piperno G, Ronchi S, Catalano G, Fodor C, Cambria R, Fossati Ing P, Gherardi F, Alterio D, Zerini D, Garibaldi C, Baroni G, De Cobelli O, Orecchia R. Linac-based stereotactic body radiotherapy for oligometastatic patients with single abdominal lymph node recurrent cancer. American journal of clinical oncology. 2014;37:227-233.

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  148. 148.

    Tabata K, Niibe Y, Satoh T, Tsumura H, Ikeda M, Minamida S, Fujita T, Ishii D, Iwamura M, Hayakawa K, Baba S. Radiotherapy for oligometastases and oligo-recurrence of bone in prostate cancer. Pulmonary medicine. 2012;2012:541656.

    Not in our library10.1155/2012/541656

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    Singh D, Yi WS, Brasacchio RA, Muhs AG, Smudzin T, Williams JP, Messing E, Okunieff P. Is there a favorable subset of patients with prostate cancer who develop oligometastases? International journal of radiation oncology, biology, physics. 2004;58:3-10.

    Not in our library10.1016/s0360-3016(03)01442-1

  150. 150.

    Decaestecker K, De Meerleer G, Ameye F, Fonteyne V, Lambert B, Joniau S, Delrue L, Billiet I, Duthoy W, Junius S, Huysse W, Lumen N, Ost P. Surveillance or metastasis-directed Therapy for OligoMetastatic Prostate cancer recurrence (STOMP): study protocol for a randomized phase II trial. BMC cancer. 2014;14:671.

    Not in our library10.1186/1471-2407-14-671

  151. 151.

    Attard G, Sydes MR, Mason MD, Clarke NW, Aebersold D, de Bono JS, Dearnaley DP, Parker CC, Ritchie AW, Russell JM, Thalmann G, Cassoly E, Millman R, Matheson D, Schiavone F, Spears MR, et al. Combining Enzalutamide with Abiraterone, Prednisone, and Androgen Deprivation Therapy in the STAMPEDE Trial. European urology. 2014.

    Not in our library10.1016/j.eururo.2014.05.038

  152. 152.

    ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  153. 153.

    ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  154. 154.

    Stereotactic Body Radiation Therapy After Surgery in Treating Patients With Stage III-IV Non-small Cell Lung Cancer. 2000–.

    Not in our library

  155. 155.

    Stereotactic Body Radiation Therapy (SBRT) in Metastatic Non-small Cell Lung Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  156. 156.

    Radiation Therapy or Observation After Chemotherapy in Treating Patients With Stage IV Non-Small Cell Lung Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  157. 157.

    Concurrent and Non-concurrent Chemo-radiotherapy or Radiotherapy Alone for Patients With Oligo-metastatic Stage IV Non-small Cell Lung Cancer (NSCLC). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  158. 158.

    The Optimal Intervention Time of Radiotherapy for Oligometastatic Stage IV Non-small Cell Lung Cancer（NSCLC) (OITROLC). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  159. 159.

    The Value of Radiotherapy in the Oligometastatic Non-squamous Non-small Cell Lung Cancer With Clinical Benefits From Erlotinib as Second-line Treatment (ROLE). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  160. 160.

    Phase II Study of Pembrolizumab After Curative Intent Treatment for Oligometastatic Non-Small Cell Lung Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  161. 161.

    Oligometastatic Disease. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  162. 162.

    Radiotherapy for Oligometastatic Prostate Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  163. 163.

    Monitoring Anti-Prostate Cancer Immunity Following Stereotactic Body Radiotherapy (SBRT). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  164. 164.

    Phase II Study of SBRT as Treatment for Oligometastases in Prostate Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  165. 165.

    Percutaneous High-dose Radiotherapy in Patients With Oligometastases of Prostate Carcinoma (Oli-P). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  166. 166.

    Salvage Radiotherapy Combined With Hormonotherapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  167. 167.

    Intensity-Modulated Radiation Therapy in Treating Patients Undergoing Androgen Deprivation Therapy for Metastatic Prostate Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  168. 168.

    Intensity-Modulated Radiation Therapy in Treating Patients Undergoing Androgen Deprivation Therapy for Metastatic Prostate Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  169. 169.

    Non-systemic Treatment for Patients With Low-volume Metastatic Prostate Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  170. 170.

    Combining Ipilimumab, Degarelix, and Radical Prostatectomy in Men With Newly Diagnosed Metastatic Castration Sensitive Prostate Cancer or Ipilimumab and Degarelix in Men With Biochemically Recurrent Castration Sensitive Prostate Cancer After Radical Prostatectomy. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  171. 171.

    High Dose Chemotherapy in Oligo-metastatic Homologous Recombination Deficient Breast Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  172. 172.

    A Pilot Study of Stereotactic Ablation for Oligometastatic Breast Neoplasia in Combination With the Anti-PD-1 Antibody MK-3475. (BOSTON II). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  173. 173.

    Trial of Superiority of Stereotactic Body Radiation Therapy in Patients With Breast Cancer (STEREO-SEIN). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  174. 174.

    Combination Chemotherapy With or Without Trastuzumab Followed By an Autologous Stem Cell Transplant and Radiation Therapy in Treating Patients With Stage III or Stage IV Breast Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  175. 175.

    Defining the HER2 Positive (+) Breast Cancer Kinome Response to Trastuzumab, Pertuzumab, Combination Trastuzumab +Pertuzumab, or Combination Trastuzumab + Lapatinib. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  176. 176.

    Hypofractionated Image Guided Radiation Therapy in Treating Patients With Stage IV Breast Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  177. 177.

    Concurrent Ipilimumab and Stereotactic Ablative Radiation Therapy (SART) for Oligometastatic But Unresectable Melanoma. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  178. 178.

    Stereotactic Radiation Therapy and Ipilimumab in Treating Patients With Metastatic Melanoma. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  179. 179.

    Combi-Neo Study for Stage IV Melanoma. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  180. 180.

    Stereotactic Body Radiation With Nelfinavir for Oligometastases. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  181. 181.

    Radiosurgery for Patients With Oligometastatic Disease at Initial Presentation. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  182. 182.

    Radiosurgery for Patients Recurrent Oligometastatic Disease. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  183. 183.

    Non-interventional Observational Study of Stereotactic Body Radiotherapy (SBRT) for Oligometastatic Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  184. 184.

    5 Fraction Stereotactic Body Radiation Therapy for Oligometastases Regimen, for Extra-Cranial Oligometastases. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  185. 185.

    Prospective Clinical Registry for Oligometastic Disease, Consolidation Therapy, Debulking Prior to Chemotherapy, or Re-Irradiation. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  186. 186.

    Definitive Therapy for Oligometastatic Solid Malignancies. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  187. 187.

    Sutent and Radiation as Treatment for Limited Extent Metastatic Cancer. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  188. 188.

    Assessment of Toxicity of the Immunocytokine L19-IL2 Administered Directly After the Course of Stereotactic Ablative Body Radiotherapy in Patients Suffering From Oligometastatic Solid Tumour. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  189. 189.

    A Randomized Phase II Study of Stereotactic Ablative Body Radiotherapy for Metastases to the Lung, (TROG 13.01 SAFRON II). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  190. 190.

    Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Tumors (SABR-COMET). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  191. 191.

    Adaptive MRI-Guided SBRT for Unresectable Primary or Oligometastatic Central Thorax and Abdominal Malignancies. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  192. 192.

    St. John's Mercy Research Institute SLICgI. Stereotactic Body Radiotherapy for Liver Tumors. 2000–.

    Not in our library

  193. 193.

    Chemoradiotherapy for Patients With Oligometastatic Colorectal Cancer (OLGA). ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  194. 194.

    Stereotactic Radiation Therapy for Pediatric Sarcomas. ClinicalTrials.gov [Internet]. 2000–.

    Not in our library

  195. 195.

    Niibe Y, Hayakawa K. Oligometastases and oligo-recurrence: the new era of cancer therapy. Japanese journal of clinical oncology. 2010;40:107-111.

    Not in our library10.1093/jjco/hyp167

  196. 196.

    Niibe Y, Chang JY. Novel insights of oligometastases and oligo-recurrence and review of the literature. Pulmonary medicine. 2012;2012:261096.

    Not in our library10.1155/2012/261096

  197. 197.

    Palma DA, Salama JK, Lo SS, Senan S, Treasure T, Govindan R, Weichselbaum R. The oligometastatic state - separating truth from wishful thinking. Nature reviews Clinical oncology. 2014;11:549-557.

    Not in our library10.1038/nrclinonc.2014.96

  198. 198.

    Mohler JL, Kantoff PW, Armstrong AJ, Bahnson RR, Cohen M, D'Amico AV, Eastham JA, Enke CA, Farrington TA, Higano CS, Horwitz EM, Kawachi MH, Kuettel M, Lee RJ, Macvicar GR, Malcolm AW, et al. Prostate cancer, version 1.2014. Journal of the National Comprehensive Cancer Network: JNCCN. 2013;11:1471-1479.

    Not in our library10.6004/jnccn.2013.0174

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