ASCO 2018: Oligometastasis from Conception to Treatment

Chicago, IL (UroToday.com) Ralph R. Weichselbaum, MD gave an interesting overview of oligometastatic disease in different cancers. The topics covered in this talk included the oligometastasis hypothesis, biological basis of oligometastasis, evidence for the use of ablative therapies in the curative treatment of patients with oligometastasis, and integration of cytoreductive therapy with systemic therapy.

He began with a short overview of metastasis in general. Metastasis accounts for 85-90% of cancer mortality. It is regarded as widely disseminated and incurable in adult solid tumors. The treatment is with systemic therapies and it is usually not curative, except chemotherapy for germ cell tumors and the rising use and accompanying good results seen in the use of immune-oncology.

The concept of oligometastasis was introduced initially in 1995 by Hellman S et al. [1] demonstrating it to be a state of disease with limited amount of metastatic disease. It was also suggested that patients with oligometastatic disease should be amenable to a curative therapeutic strategy.

Dr. Weichselbaum continued to discuss the oligometastasis hypothesis and characteristics. Metastasis represents a spectrum of disease which incorporates the number of metastasis, organs involved, and the pace of progression. Subsets of patients with limited (oligometastatic) disease are potentially curable with metastasis-directed therapies. Cytoreduction with systemic agents can produce an oligo state (oligo-progressive); resistant clones eliminated with metastasis-directed therapies.

In order for metastatic cells to survive, they need to leave the primary tumor, intravasate, grow a secondary tumor, extravasate, adhere to blood vessel walls and circulate in the blood (Figure 1).

image 5Figure 1: Oligometastasis development
Fortunately, this is not a very efficient process. Despite this, according to a recent estimation, there are over 90,000 oligometastatic diseas presentation in the 4 most common cancers in the US every year. This includes 10000 prostate cancer patients, 14000 Breast cancer patients, 14000 colorectal cancer patients, and 50000 lung cancer patients.

Dr. Weichselbaum went on to describe some of the research he was involved in trying to understand the pathogenesis of oligometastasis. This involved taking human tumor samples, extracting micro RNA from it to predict target genes. Later, this would be used for in vitro phenotype and target experimentations and culminate in in vivo experiments in mice. These experiments eventually showed that oligometastasis don’t only have a size, but also a time dimension, and different oligometastasis develop at different rates. The slow progressing metastasis progress at a rate of 0.6 metastasis per year, while the rapidly progressing metastasis progress at a rate of 3.6 metastasis per year. Further experiments demonstrated that patterns of differently expressed micro RNAs correlate with phenotype and survival.

In conclusion of this topic, Dr. Weichselbaum stated that molecular subtypes complement clinical risk stratification and gene expression informs therapy. Oligometastasis phenotype is suggested to harbor a complex relationship between tumor and host, with a potential effect of the immune status on disease extent. Lastly, molecular analysis should be performed to categorize the spectrum of metastatic states, ranging from oligo to poly.

Dr. Weichselbaum moved on to discuss the role of ablative therapy in the oligometastatic state. There have been several trials demonstrating improved progression free survival in oligometastatic patients with different cancers, being treated with ablative therapy (in the form of radiotherapy). These include the MDACC/Colorado trial, which is a phase 2 oligometastatic trial in non- small cell lung cancer (NSCLC) [2], The UTSouthwestern trial in NSCLC as well [3], and the STOMP [4] and ORIOLE [5] trials in oligometastatic prostate cancer.

In conclusion, there is evidence to show that some patients with oligometastatic disease can be cured with ablative therapy. These patients can likely be identified through clinical features and molecular parameters.

Lastly, Dr. Wiechselbaum discussed the antitumor immunity effect that radiotherapy can create and enhance, including immunosuppressive beneficial responses. Radiotherapy can initiate cytokine and chemokine production in the tumor microenvironment. It has been shown that DNA from irradiated tumors improves the function of antigen presenting cells (APC) (Figure 2).

image 5bFigure 2: DNA from irradiated tumors improves the function of antigen presenting cells

Furthermore, it has been demonstrated that radiotherapy can cause induction of PD-L1. In fact, radiotherapy and PD-L1 blockade synergistically and systematically amplify the antitumor effect. Dr. Wiechselbaum suggests that in order for us to cure more metastatic disease, we are required to potentiate immunotherapy with a combined treatment of radiotherapy, and later on perform cytoreductive therapy, and treat all metastasis and tumor locations.

In conclusion, radiation is a powerful local cytotoxin, which can be used to boost anti-tumor immunity locally. Radiotherapy drives T cells into tumors through T cell attractive chemokines and APC attractive chemokines. Radiotherapy improves T cell function directly through re-priming and can kill immune resistant cells. Lastly, Dr. Wiechselbaum emphasized that it is important to treat all sites of visible disease using image guided radiotherapy/surgery, and thereby amplify local and systemic immunity. For this treatment to be successful, we need to diagnose and identify all metastasis sites with better imaging and software/hardware integration.
Our future goals and areas of investigation should include further research of metastasis -directed therapy to decrease tumor cell burden, and perform clinical and molecular classification of the spectrum of metastasis, so that we can also treat polymetastatic, and not just oligometastatic patients.

Presented by: Ralph R. Weichselbaum, University of Chicago, MD

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References:

[1] Hellman et al. Oligometastasis. J Clin Oncol 13 (1)8-10, 1995
[2] Gomez et al. Lancet Oncology 2016
[3] Lyengar et al. Jama Oncol 2018
[4] Ost et al. J clin Oncology 2018
[5] Radwan et al. BMC cancer 2017
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