ONCAlert | Upfront Therapy for mRCC

Oligometastatic Disease in Cancer: Broadening the Path to Cure?

Joshua Bauml, MD; Charu Aggarwal, MD; Tracey L. Evans, MD; Christine Ciunci, MD, MSCE; Linda Miller, RN; Natisha Muhammad, MPH; Faith Mutale, CRNP; Christina Knepley, CRNP; Corey J. Langer, MD; and Ro
Published Online: Apr 27,2018

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 “oligometastatic cancer” 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.22,25,33 This 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.34,35 Ongoing 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).5 Separate 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.6 These 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.36-38 Proving 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,42 angiogenesis 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.44-46 When 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.47 As 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.48 Although 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.51 We 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.52 In both of these ongoing studies, patients begin pembrolizumab at least 4 weeks after completion of other treatments, including LAT.


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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  9. Yu HA, Sima CS, Huang J, et al. 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. J Thorac Oncol. 2013;8(3):346-351. doi: 10.1097/JTO.0b013e31827e1f83.
  10. Gan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys. 2014;88(4):892-898. doi: 10.1016/j.ijrobp.2013.11.010.
  11. Palma DA, Salama JK, Lo SS, et al. The oligometastatic state—separating truth from wishful thinking. Nat Rev Clin Oncol. 2014;11(9):549-557. doi: 10.1038/nrclinonc.2014.96.
  12. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol. 1997;15(3):938-946.
  13. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235(6):759-766.
  14. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239(6):818-825; discussion 825-827.

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Oligometastatic Disease in Cancer: Broadening the Path to Cure?
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