It is increasingly recognized that distant metastasis may not always be numerous and widespread. A clinically-limited number of metastases have been designated as “oligometastasis” (Hellman and Weichselbaum 2011), a concept that certain metastases may originate from cells with limited potential for dissemination or/and represent intermediate state in the widespread metastases dissemination. Clinical evidence supports the idea that some oligometastases are curable.
Currently, clinical criteria have been used to select patients with limited metastases for the local therapies of curative intent. Despite the selection criteria, survival rates of only 25% demonstrate that the majority of patients selected for therapy are not cured. A method for accurate classification of oligo- and poly- metastatic patients could have important clinical implications in both assignment of therapy prognosis as well as therapeutic targets for metastasis. To establish a molecular classification and mechanistic explanation of oligo- and polymetastatic progression, we are studying microRNAs, - small non-coding RNA molecules regulating gene expression through binding with messenger RNAs. Using microRNAs profiling researchers in LCMR found patterns of these regulatory molecules which are expressed differently in patients with oligometastases as compared with polymetastatic patients. Based on these differentially expressed microRNAs currently two projects are under development: The design of molecular markers for prediction of oligo- vs polymetastatic dissemination of cancer and the identification of down-stream genes and pathways which may be used for targeted suppression of metastases development. As part of this project we propose to use an annotated data set of colon cancer oligo and poly liver metastasis from the University of Chicago. We propose to extract microRNAs and perform RNA seq to establish the molecular basis of oligometastasis in an organ disease specific situation.
This work was/is being done in collaboration with Mitchell Posner (Surgical Oncology); Mark Ferguson (Thoracic Surgery); Nikolai Khodarev, Steve Chmura, and Joe Salama (Radiation Oncology); and Yves Lussier (Bioinformatics at the University of Illinois, Chicago). We are expanding our investigation to a broader definition of the role of microRNA within the metastatic cascade with Center co-director Geoffrey Greene.
Treatment of oligometastasis with stereotactic body radiotherapy (SBRT)
One of the most promising treatments for oligometastasis is SBRT, which offers greater precision and allows much higher doses to limited target volumes than previous radiation delivery technologies. In an initial study of the safety and effectiveness of metastasis-directed SBRT for multisite extracranial oligometastasis, we reported progression-free survival rates of 33.3% and 22.0% at the one and two year follow up time The overall survival rates were 81.5% and 56.7%. Of the patients whose tumors did progress, 72% did so in limited (1-3) metastatic sites. Remarkably with treatment the 5 year survival rate of these 61 patients is 25%. This study considered with the previous biological studies suggest that the oligometastatic state exists and that some patients may experience a survival benefit from SBRT or surgery.
We have also investigated the use of SBRT for the treatment of oligometastatic renal cell carcinoma. Although renal cell carcinoma (RCC) is widely considered to be radioresistant, SBRT can control intracranial metastases associated with RCC. In this study, patients with RCC and limited metastases were treated on a 3-fraction dose-escalation protocol or an off protocol with 10 fractions of 5Gy. The treatment was well tolerated by most patients, with the most common acute toxicity being fatigue. After two years, local tumor (irradiated metastasis) control was 91.4% and the overall survival rate was 85%. Those patients who underwent treatment for all metastatic sites had a 2 year lesion control rate of 100% and distant control rate of 35.7%.
In another clinical investigation of SBRT for patients with limited volume metastatic non-small cell lung cancer (NSCLC), we reported that SBRT provides durable lesion control and may provide some patients with long-term progression-free survival. The 18-month local control, distant control, overall survival and progression-free survival rates were 66.1%, 31.7%, 52.9% and 28.0%. In the previous section on radiotherapy and immunity we noted that large fraction sizes may induce anti-tumor immunity. We are planning clinical studies in oligometastasis with immune modifiers.
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