Oligometastatic Disease in Cancer: Broadening the Path to Cure?

Joshua Bauml, MD

ABSTRACT

Emerging data indicate that patients with metastasis to a limited number of sites (termed oligometastatic disease) may have improved outcomes with the use of locally ablative therapy (LAT). In spite of limited, and at times, heterogeneous data, the availability of minimally invasive LAT has led to the widespread adoption of this practice for patients with oligometastatic disease. There are currently no clinical factors that are clear predictors of improved survival after LAT across tumor subtypes. New data suggest that the use of molecular biomarkers and combination therapies improve patient outcomes.

Introduction

Many patients who are diagnosed with cancer either present with or will develop distant metastatic disease.1 In most cases, metastatic disease is considered incurable, so there are 2 paths to increasing the rates of cancer cure. One can either diagnose and treat cancers earlier, before they metastasize, or identify ways to render metastatic disease curable.

At a time when our only therapy for cancer was surgery, Halstead developed his theory of cancer progression, first published in the early 1900s.²According to this paradigm, cancers spread in an orderly fashion initially through the lymphatic system. Therefore, once cancer had spread beyond the localized lymphatic drainage bed, it was a systemic disease for which there was no cure. For the most part, this perspective continues to hold true, with exceptions including germ cell tumors and lymphomas that are exquisitely sensitive to currently available systemic treatments.³Clinical experience, however, has shown that not all patients with metastases have widely disseminated disease. Hellman and Weichselbaum more recently have proposed that cancer metastases fall on a continuum. Although some malignancies feature either a localized or disseminated phenotype, most lie somewhere between these extremes. Some tumors may metastasize only to a limited number of sites, termed oligometastatic cancer. In general, most studies of oligometastatic cancer have included patients with 1 to 5 distinct metastases. With a limited number of metastases, it becomes theoretically possible to treat all detectable tumors with curative intent using locally ablative therapy (LAT).⁴The advent of more advanced imaging techniques means that we may be better able than ever before to identify early and limited metastatic disease.

Discussion

Studies of oligometastatic cancer are limited by some unique aspects of statistical bias and tumor heterogeneity. First, the timing of the appearance of metastases is likely important in determining patient outcome. Metastases that arise coincident with cancer diagnosis are termed synchronous, while those that arise later in the disease are termed metachronous. A study of patients with oligometastatic disease should distinguish between these 2 very different clinical entities. In addition, the organ sites of metastases may be important because they may reflect very different tumor biology. Tumors with a specific molecular genotype may be more likely to develop an oligometastatic phenotype, and metastases to specific organs may in turn have distinct molecular genotypes. Finally, the very definition of a metastatic “site” may be unclear—how, for instance, each study defines patients with multiple involved mediastinal lymph nodes may be inconsistent. Some studies would consider this a single metastasis to the mediastinum, while others may consider each node a distinct metastatic site. The latter interpretation becomes even more complex with confluent nodal conglomerates. Similarly, having several metastases to the liver may reflect a very different tumor biology compared with metastases to multiple organs. It is very difficult to control for this broad scope of biological heterogeneity in large cohorts, especially when the details and significance of tumor molecular profiles are just emerging.5,6

The issue of molecular heterogeneity is of particular importance in a disease such as lung cancer. Lung cancers bearing oncogenic drivers in genes such as EGFR and EML4-ALK may be relatively clonal and homogenous at diagnosis, but with targeted therapy they will almost always develop resistance mutations. Such metachronous sites of “oligo-progression” may be treated definitively with localized therapies to allow for continued administration of the otherwise beneficial targeted agent.^7-10This may be viewed as a type of tumor debulking (and thus not truly curative) approach, which is ultimately still palliative and therefore should be distinguished from the use of LAT to attempt to eliminate all detectable disease, as described in this review.

From a statistical perspective, studies evaluating the role of LAT in oligometastatic cancer often suffer from immortal time bias.¹¹Patients selected for LAT usually receive 1 or more lines of conventional palliative chemotherapy before receiving LAT. Those patients who respond to chemotherapy and continue to exhibit the oligometastatic phenotype are more likely to be selected for LAT. Overall survival (OS) time is measured from the start of palliative chemotherapy initiation, but this statistical approach may overestimate the true survival of this population because it excludes all patients who presented with oligometastatic disease whose disease progressed or who died before they received LAT.

Retrospective Studies Evaluating Oligometastatic Disease

Many studies have been completed evaluating the role of LAT in oligometastatic cancer. Colorectal cancer (CRC) has a unique vascular anatomy, with both hematogenous and lymphatic drainage passing directly through the liver. Consequently, 38% of CRC metastases are limited to the liver.12 Investigators have observed that some patients with CRC who underwent liver resections for isolated hepatic metastases could have excellent long-term outcomes. In a study of 456 patients with CRC and isolated liver metastases treated at Memorial Sloan Kettering Cancer Center, for example, the 5-year OS was 38%. The 5-year disease-free survival (DFS) rate was 19%, suggesting that some patients might have been cured of their disease by surgical removal of the metastases.¹²In another analysis of 226 patients with CRC and isolated liver metastases treated at Johns Hopkins, the outcomes were similar, with OS and DFS at 5 years of 40% and 20%, respectively. At 10 years, a landmark at which cure is deemed likely to have occurred, the OS rate was 26%.13,14 Patient selection is generally based upon surgical resectability: Patients who are ineligible for surgery or require nonoperative management of hepatic metastases tend to have worse outcomes.1 That being said, there is significant interest in the research community in evaluating nonoperative approaches to liver metastases.¹⁵In summary, incorporating hepatic metastasis resection into the management of advanced CRC appears to be able to cure up to 20% of highly selected patients and has now become the standard of care in CRC with isolated synchronous or metachronous hepatic metastases.¹⁶

A similar approach has evolved for the treatment of isolated brain metastases in patients with cancer. Metastases to the brain are thought to arise as a result of its status as a &ldquo;sanctuary site.&rdquo; Chemotherapy has limited penetrance through the blood-brain barrier. In 1 of the earliest studies, 48 patients, each with a single brain metastasis, were randomized to surgical resection or needle biopsy followed by radiotherapy. The addition of surgery to radiation was associated with a significant improvement in OS (median, 40 vs 15 weeks; P <.01). While DFS was not reported, there was no difference in death rate as a result of systemic disease progression; it seems unlikely that patients were cured using this approach.17 A subsequent study randomized 333 patients, each with 1 to 3 brain metastases, to whole-brain radiotherapy with or without stereotactic radiosurgery (SRS).18 Although there was no difference in OS in the full cohort, those patients who had a single metastatic focus in the brain had improved OS with the addition of SRS. The addition of SRS was also associated with less steroid use and improved performance status. Increasing availability and experience with the use of SRS for tumors in the brain has led to its widespread adoption and use in patients with multiple brain metastases. There are now data documenting the safety and feasibility of using SRS to treat 10 or more brain metastases.^19,20The impact of such an approach on survival remains unclear, however.

Although these reports and studies have encouraged a more aggressive approach to oligometastatic cancer, sometimes with curative intent, the potential, generalized extrapolation of this approach is complex. Most cancers have more diverse metastatic patterns of spread than does CRC. Even among patients with stage IV CRC, for instance, 10% of patients have metastases limited to the lung.²¹The sanctuary site argument used in the aggressive treatment of brain metastases in the management of lung and other cancers has limited extracranial applicability. Despite these reservations, improvement in systemic therapies and greater confidence in our diagnostic imaging modalities have led oncologists to treat oligometastatic cancer ever more aggressively. Improvements in tumor imaging have encouraged oncologists to become more confident than ever that selected patients may, indeed, have a truly limited systemic disease burden.

Multiple retrospective studies have evaluated the impact of LAT among patients with cancer. A retrospective analysis was performed among 309 patients with various tumor subtypes who received stereotactic body radiation therapy (SBRT) to less than or equal to 5 foci of metastatic disease.22 The majority of the patients (>90%) had 1 to 3 metastases, and 63% had experienced metachronous metastasis. The most common site treated was the brain (35%), but a substantial number of patients also had metastasis to lymph nodes (29%), liver (25%), and lung (18%). The median OS was 24 months, and 5-year OS was 19%. It is difficult, however, to compare these findings with any historical control populations given the mixed-tumor cohort.

Large studies that have focused on a single tumor type may be compared with a more readily available and relevant historical reference population. A retrospective study of 467 patients with breast cancer who underwent a metastatectomy for pulmonary metastases was recently published. Eligible patients were included in this study if they had surgically resectable pulmonary metastases. The 5-year OS rate was 35%.23 This compares favorably with the general population of patients with metastatic breast cancer, in which the 5-year OS is 24%.²⁴In an individual patient-level data meta-analysis of 757 patients with oligometastatic lung cancer (1 to 5 metastases) who received LAT to known metastatic foci, the 5-year OS rate was 29.4%.25 This rate compares very favorably with the general population of patients with metastatic lung cancer, in which the 5-year median OS is 4%.²⁴

In these analyses, it is still impossible to determine whether patients have improved outcomes because of the LAT for oligometastatic cancer or whether the outcomes reflect a positive selection effect for patients with an intrinsically better prognosis because of their oligometastatic phenotype. A propensity score matched analysis of patients with oligometastatic lung cancer tried to directly address the specific impact of LAT by comparing patients with oligometastatic disease who receive LAT with those who do not. The authors were able to match 60 such patients to 14 patients who did not receive LAT for oligometastatic lung cancer. Receipt of LAT was associated with an improved OS (27.1 vs 13.1 months; P <.01) and progression-free survival (PFS) (11.3 vs 8 months; P <.01).²⁶

Randomized Trials of LAT for Oligometastatic Disease

The application of any retrospective study to clinical practice must be done with great caution. As noted earlier, there are multiple unmeasured biases inherent in such studies, regardless of how well they are designed. Randomized trials try to address this shortcoming. A randomized controlled trial has been published evaluating the role of LAT in oligometastatic lung cancer.²⁷All patients received palliative chemotherapy initially; those patients who had persistent oligometastatic disease (ie, did not progress) after chemotherapy were randomized to LAT and chemotherapy versus continued palliative chemotherapy alone. After 49 patients were randomized, the study was halted based on a likely benefit: The median PFS was significantly greater among patients who received LAT (11.9 vs 3.9 months; P = .0054). Although the existence of any randomized study is a great step forward, this study design is difficult to generalize to the overall population of patients with oligometastatic cancer. Seventy-four patients were initially enrolled in the study, of whom 49 were randomized. Most of the patient drop-off was due to progressive disease while receiving palliative chemotherapy, thereby yielding an enriched population of patients with an intrinsically better outcome for the randomized portion of the study. Based upon the positive results from this trial, an additional randomized phase II study in oligometastatic lung cancer underwent an early analysis.²⁸This trial similarly administered LAT after initial chemotherapy (induction), but patients were only enrolled on the study after completion of chemotherapy. Patients were allowed to have up to 6 sites of extracranial disease, with no more than 3 sites in the liver and lung. Twenty-nine patients were randomized to maintenance chemotherapy alone or with SBRT. The addition of SBRT was associated with a statistically significant improvement in PFS.

Three additional randomized trials are currently ongoing and have been presented at least in part. The BR001 study, conducted by the NRG Cooperative Group, is evaluating SBRT among patients with oligometastatic (defined as 2 to 4 metastases) breast, lung, or prostate cancer. A recent publication documented the feasibility of the radiation approach in this study, but clinical outcomes are not yet mature.²⁹There are more focused studies within NRG evaluating SBRT for oligometastatic lung and breast cancers (LU002 and BR002, respectively). The ongoing STOMP and ORIOLE trials evaluate LAT among patients with oligometastatic prostate cancer.^30,31While clinical outcomes data are not yet available, a recent abstract noted that two-thirds of patients with recurrent prostate cancer evaluated for STOMP had oligometastases and were thus potentially eligible.³²The results of these trials are eagerly awaited.

In considering the above data in sum, it seems clear that while there may be a benefit to LAT in some patients with oligometastatic cancer, not all patients are cured with this approach. To improve outcomes and attempt to cure more patients with LAT, we need a better way to select patients for whom curative potential truly exists as opposed to those in whom the development of additional metastatic foci over time is inexorable despite LAT. To this end, we suggest 2 promising areas of future clinical inquiry: improving patient selection for LAT; and incorporating novel therapies, especially immunotherapy, into patient treatment as adjuncts to LAT.

Improving Patient Selection for LAT

Clinical Factors to Choose Patients for LAT

In the Table, we have reviewed the available literature and have sought to identify clinical factors associated with improved outcomes (both OS and PFS) among patients with oligometastatic cancer receiving LAT. To identify relevant studies, we performed a PubMed search for &ldquo;oligometastatic cancer&rdquo; and reviewed the identified studies. This table is not intended to be a comprehensive listing of all studies of patients with oligometastatic cancer; we do not feel that a systematic review of oligometastatic disease across tumor types would be useful because there is simply too much heterogeneity in the literature to justify that approach. The definition of oligometastatic cancer varies between studies, consistent with the lack of an accepted formal definition, with the most common description being 5 metastatic foci or less. We opted to focus our evaluation on studies of the more common tumors, as these were the subtypes with the most extensive literature, and we felt these results would be most generalizable. Many of these studies described both univariate and multivariable analyses; whenever possible, we report multivariable analyses of significance to minimize confounding.

As shown in the Table, there are no clinical variables in patients with the oligometastatic disease state that are universally associated with improved outcomes. Although metachronous metastases do seem to be associated with improved outcomes, the immortal time bias is likely a factor here: Such patients may have a slower-growing tumor, and thus an improved outcome in general. Of note, a study involving patients with metachronous oligometastatic breast and prostate cancer did not report improved outcomes. This observation may reflect the improved OS for these 2 cancers in general, where the immortal time bias may exert less of an effect.²⁴

The number and organ sites of metastatic foci also do not seem to be good predictors of cancer outcomes across tumor subtypes. The lack of consistency regarding which metastatic foci are bad or good prognostically makes biological sense when considered from the perspective of lymphatic and hematogenous drainage. Each tumor subtype will vary in its lymphatic drainage. A liver metastasis would likely reflect a different biology in a patient with CRC, where the lymphatic drainage passes through the liver, than in a patient with head and neck cancer, where the primary tumor lymphatic drainage is very different. Beyond this observation, we know that anatomy may predict variability even within a tumor subtype: A patient with a contralateral lymph node involvement generally has a worse prognosis across a wide variety of tumors. In spite of these limitations, there are some interesting observations from the studies described in the Table. In studies of patients with lung or a mixture of diverse cancers, for example, the presence of intracranial metastases was associated with a generally worse prognosis.^22,25,33This is surprising, given the biological rationale and established role of LAT in this disease state. Overall, the only consistent finding from this analysis is inconsistency; it therefore seems unlikely that clinical factors alone will be able to identify patients with oligometastatic cancer who are most likely to be cured or those who are likely to have a significant improvement in DFS from LAT.

Biomarkers to Choose Patients for LAT

Given the apparent heterogeneity and limitations of using standard clinical variables to predict the outcomes of patients with oligometastatic disease, several scientists have sought to discover and validate biomarkers for tumors likely to exhibit an oligometastatic phenotype. It would surely change our management if we could identify high- or low-risk patients using a blood test. Indeed, we are now seeing evidence of testing for both circulating tumor DNA and circulating tumor cells as highly prognostic in other cancers.^34,35Ongoing trials are incorporating these 2 biomarkers and others. Investigators have identified, for instance, a transcriptome expression profile among patients with renal cell carcinoma and isolated pulmonary metastases that is able to differentiate tumors with early or late metastases and an oligometastatic (<8 metastases) versus a more diffusely metastatic phenotype (>16 metastases).⁵Separate investigators have performed microRNA (miRNA) assessment of paraffin blocks of patients with oligometastatic cancer (<5 metastases). The resultant miRNA profile can differentiate oligometastatic from more widely metastatic tumors (>5 metastases), and tumors with each profile exhibit the same phenotype in patient-derived xenograft models. Perhaps most intriguingly, when oligometastatic xenograft models were exposed to a microRNA molecule intended to interfere with the oligometastatic phenotype (miRNA200c), the metastatic phenotype in the model shifted to a more diffuse pattern.⁶These data imply that oligometastatic tumors are biologically different, which suggests that the next step would be to determine if these biomarkers could become validated predictive markers and identify those patients destined to remain oligometastatic and who would therefore potentially derive the most benefit from LAT.

Combination Therapies to Improve LAT

The timing of systemic therapies in relation to LAT is another factor that must be considered when evaluating novel treatments for patients with oligometastatic cancers, because current practices vary widely among tumor subtypes. Adjuvant systemic therapy after metastatectomy in CRC remains the subject of intense clinical investigation.^36-38Proving the value of systemic therapy in a minimal residual disease state is complex, since we cannot observe objective tumor responses. Proving a survival advantage in the adjuvant setting requires large cohorts and usually the passage of significant time. Nevertheless, the clear and established efficacy of adjuvant systemic treatments in cancer makes their addition to LAT a reasonable avenue of research.^38-41

Tyrosine Kinase Inhibitors in Combination with LAT

Tyrosine kinase inhibitors (TKIs) represent 1 appealing modality to combine with LAT: The adverse effect (AE) profile is often better than that of cytotoxic chemotherapy, and when given to the appropriate patient population, beneficial clinical responses can be significant. Sunitinib is a TKI targeting multiple receptors including VEGFR-2s. Given the clear association between angiogenesis and the metastatic spread of cancer,⁴²angiogenesis is a reasonable therapeutic target in this setting. A recent study evaluated 46 patients with oligometastatic cancer who were treated with a combination of stereotactic body radiotherapy to all metastatic sites and sunitinib. The primary endpoint of the trial was OS. Patients were eligible if their cancer (any histologic subtype) exhibited 5 or fewer active sites of metastasis, each less than 6 cm. The most common cancers treated on this trial were head and neck, liver, lung, kidney, and prostate. Patients received 37.5 mg sunitinib daily for 28 days, followed by a 2-week break. SBRT was performed on days 8 to 12 and 15 to 19. After the first cycle, sunitinib was continued at the discretion of the treating physician in the absence of disease progression or intolerable toxicity. The AE profile of the combination of SBRT and sunitinib was not significantly greater than what would have been expected for each of the individual modalities. The 4-year PFS and OS rates were 34% and 29%, respectively. On multivariable analysis, the only factor associated with improved cancer outcomes was tumor type: Patients with prostate or kidney cancers were most likely to benefit.⁴³

The outcomes in this study were limited by the relatively small sample size and the relatively modest single-agent activity of sunitinib outside of renal cell carcinoma. It may be more reasonable to use TKIs in diseases where they have substantial single-agent activity. An ongoing study (NCT02314364) is evaluating SBRT in patients with oncogene-driven lung cancer, concurrent with a standard-of-care TKI (eg, erlotinib, crizotinib). As described above, such patients often receive LAT given the unique observed clinical response patterns in patients receiving TKIs who manifest isolated oligoprogression.^8-10

Immunotherapy in Combination with LAT

Immunotherapy is changing the entire landscape of cancer care. Monoclonal antibodies targeting the PD-1 pathway have activity in a wide range of malignancies and a generally favorable AE profile compared with chemotherapy.^44-46When viewed through the prism of LAT, immunotherapy has another significant benefit: laboratory and some clinical data suggest that combination with LAT may induce an abscopal effect.⁴⁷As such, even if there are metastatic foci too small to identify with modern imaging techniques, the combination of LAT with immunotherapy could theoretically lead to disease eradication. The preliminary results from the PACIFIC trial, which randomized patients with locally advanced lung cancer to durvalumab or placebo after concurrent chemoradiotherapy, support such an approach.⁴⁸Although not an oligometastatic disease state, locally advanced lung cancer is associated with a low cure rate and is usually associated with latent metastatic disease too small to be detected even with contemporary imaging. In the PACIFIC trial, the addition of durvalumab was associated with a marked improvement in PFS.

The ideal method for combining immunotherapy with radiation remains an unanswered question. Other studies have documented the relatively safe and effective combination of SBRT with immunotherapy.^49,50

Our group has completed enrollment to an ongoing study evaluating pembrolizumab (a PD-1 inhibitor) in patients with oligometastatic lung cancer who have completed LAT (NCT02316002). Preliminary results of this study were recently presented in abstract form at the 2017 World Conference on Lung Cancer.⁵¹We reported an 18-month PFS of 64% and an 18-month OS of 79%. Appropriate comparisons with historical controls will require more prolonged follow-up. We are also participating in a randomized study evaluating pembrolizumab versus placebo in patients with head and neck cancer at high risk for recurrence following standard adjuvant therapy. Patients with oligometastatic disease will also be included in this trial (NCT02841748), based upon emerging data that patients with oligometastatic head and neck cancer related to human papilloma virus can have prolonged responses to LAT.⁵²In both of these ongoing studies, patients begin pembrolizumab at least 4 weeks after completion of other treatments, including LAT.

Conclusions

Further efforts will be needed to identify those patients with oligometastatic cancer most likely to benefit from LAT. Analysis of existing clinical data in various studies suggest that the facile identification of an obvious predictive clinical factor is unlikely for most cancers. We strongly recommend that the research community first agree on a common nomenclature to achieve some consistency as results are interpreted and reported. We also recommend that the oligometastatic state be more precisely defined, such as a cancer with up to 4 metastatic foci. Better patient selection at the time of diagnosis and a combination of systemic treatments with LAT, including immunotherapy, is likely to enhance patient outcomes further.

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