Defining Oligometastatic Gastroesophageal Cancer May Provide Clarity for Treatment Advances

The concept of oligometastastic disease, which refers to a disease state with limited metastatic burden, is not novel and was introduced more than 25 years ago.¹ Aggressive treatment of oligometastatic disease can significantly extend survival in a number of tumor types. Resection of isolated brain metastases has been accepted as a standard approach across tumor types and the resection of liver metastases is an accepted practice during the treatment of oligometastatic colon cancer. However, debate continues as to how to define oligometastatic disease and whether it represents a unique stage between limited-stage and widely metastatic disease.

Recently, an increased interest in oligometastatic states has been fueled by both the development of highly effective noninvasive ablation approaches as well as improvements to systemic therapy. Stereotactic radiotherapy (SBRT) and hypofractionated ablative radiation therapy, which provide ablative doses of radiation with low toxicities, can result in excellent local tumor control and have the potential to eradicate any residual treatment-resistant disease. At the same time, improved systemic therapies can better control micrometastatic disease. For example, it has been demonstrated in preclinical models that immunotherapy, a part of the treatment paradigm for many tumor types, can potentially synergize with radiation therapy (XRT).^2,3

The phase 2 SABR-COMET trial (NCT01446744) was the first prospective randomized study to evaluate whether an aggressive approach to the oligometastatic state using high doses of XRT could improve survival. Patients with metastatic cancers of various primary sites (N = 99) who had at most 5 metastatic lesions were randomized in a 2:1 fashion to an ablative approach with SBRT (n = 66) vs standard treatments (n = 33) after a period of systemic therapy. The impressive trial results included a median overall survival (OS) of 50 months (95% CI, 29-83) in the SBRT group vs 28 months (95% CI, 18-39) in the control cohort (HR, 0.47; 95% CI, 0.27-0.81; P = .006).⁴ It remains to be determined whether these results are applicable to all cancers; however, they certainly warrant further investigation of this approach in a disease-specific setting.

Defining the Oligometastatic State

Esophageal and gastric adenocarcinoma (EGA) is a major health problem worldwide.⁵ In Western countries, lower gastroesophageal adenocarcinoma, which frequently involves the gastroesophageal junction, is the most common site of occurrence and histological subtype of gastroesophageal cancer and the incidence of this cancer in both male and female patients is on the rise.⁶ Stage IV disease is almost universally fatal, with 5-year survival rates of less than 5%. Recently, we have seen a significant rise in the incidence of this disease in younger adults aged less than 50 years, in whom it is frequently diagnosed in advanced stages.⁷

Systemic therapy plays a critical role in the management of metastatic EGA. However, even with recent advances in care, OS for stage IV disease remains less than 1.5 years. Possibly, a subset of patients with EGA are undertreated with current strategies and benefit from more aggressive locoregional therapies in the course of their disease.

There are no standard treatments or definitions of oligometastatic EGA. Multiple literature reports suggest that a subset of patients with EGA who have a limited burden of metastatic disease may benefit from more aggressive management. Surgical resection of oligometastatic disease has been attempted at multiple institutions with promising efficacy results.

Review Data and Ongoing Trials

Results of a systematic review of literature published from 1990 to 2015, as well as a pooled analysis on the role of hepatic metastasis resection across 39 studies that included 480 patients, demonstrated a 5-year OS rate of 27%.⁸ A retrospective study of national series in England with propensity-matched analysis identified 78 patients with EGA and liver resection; in these patients, the 5-year OS rate was 38.5%.⁹ These outcomes compare favorably with what we typically observe in patients with stage IV EGA who are treated with standard systemic therapy alone. However, significant limitations exist with retrospective and single-institution data, and these results should be interpreted with caution.

Recently, a phase 2 prospective trial conducted in Europe—AIO-FLOT3 (NCT00849615)—evaluated surgical resection in patients with limited-stage gastric cancer.¹⁰ The results demonstrated a median OS of 31.3 months in patients with oligometastatic EGA who were able to undergo resection after induction chemotherapy. Based on these promising results, European investigators are examining whether surgical debulking of oligometastatic disease improves outcomes for patients in the randomized phase 3 trial RENAISSANCE (AIO-FLOT5; NCT02578368).¹¹ Patients with protocol- defined oligometastatic disease will receive 2 months of induction chemotherapy (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel; FLOT) and will then be randomized to resection of all metastases followed by continuation of FLOT vs continuation of FLOT alone.

There are also promising data for consolidative XRT for patients with EGA, including results of a case series from The University of Texas MD Anderson Cancer Center. The series described 101 long-term survivors with oligometastatic EGA who received consolidative radiation therapy to all sites of disease during their treatment continuum.¹² Using radiation therapy provides a number of advantages over resection in this setting, including shorter interruptions in systemic therapy and less associated morbidity.

The ongoing phase 3 trial EA2183 (NCT04248452) is the first prospective study to determine the benefits of aggressive nonsurgical debulking of oligometastatic EGA. Patients with 3 or fewer metastases are treated with induction systemic therapy, and those who do not have progression after 4 months of treatment are then randomized 2:1 to either consolidative XRT to all sites of disease or continuation of systemic therapy. The primary end point of this study is OS. This trial is actively enrolling patients in multiple United States sites. Investigators are in the process of updating study protocol to allow nivolumab (Opdivo) in addition to chemotherapy. This amendment follows the FDA approval of firstline nivolumab for patients with EGA based on the results of the phase 3 CheckMate 649 study (NCT02872116).¹³ EA2813 is an instrumental study that has a potential to prolong OS and change the standard of care in a subset of patients with EGA.

At this time, the definition of and approach to oligometastatic EGA remain to be determined. Oligometastatic state in any disease is more than just a number of metastatic sites seen on scans. Tumor biology is critical for oligometastatic designation. Ongoing research with novel biomarkers, including circulating tumor cell and circulating tumor DNA, will likely be instrumental in refining oligometastatic classification in the future, and ongoing studies, such as EA2183 and AIO-FLOT35, are essential for studying oligometastatic EGA in a prospective scientific manner.

References

1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1):8-10. doi:10.1200/JCO.1995.13.1.8
2. Sharabi AB, Lin M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16(13):e498-e509. doi:10.1016/S14702045(15)00007-8
3. Kelly RJ, Zaidi A, Smith MA, et al. The dynamic and transient immune microenvironment in locally advanced esophageal adenocarcinoma post chemoradiation. Ann Surg. 2018;268(6):992-999. doi:10.1097/ SLA.0000000000002410
4. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomied trial. 2020;38(25):2830-2838. doi:10.1200/ JCO.20.00818
5. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1)9-29. doi:10.3322/caac.21208
6. Raman R, Deorah S, McDowell BD, Hejleh TA, Lynch CF, Gupta A. Changing incidence of esophageal cancer among white women: analysis of SEER data (1992-2010). Contemp Oncol (Pozn). 2015;19(4):338-340. doi:10.5114/wo.2015.54390
7. Codipilly DC, Sawas T, Dhaliwal L, et al. Epidemiology and outcomes of young-onset esophageal adenocarcinoma: an analysis from a population-based database. Cancer Epidemiol Biomarkers Prev. 2021;30(1):142-149. doi:10.1158/10559965.EPI-20-0944
8. Markar SR, Mikhail S, Malietzis G, et al. Influence of surgical resection of hepatic metastases from gastric adenocarcinoma on long-term survival: systematic review and pooled analysis. Ann Surg. 2016;263(6):1092-1101. doi:10.1097/ SLA.0000000000001542
9. Markar SR, Mackenzie H, Mikhail S, et al. Surgical resection of hepatic metastases from gastric cancer: outcomes from national series in England. Gastric Cancer. 2017;20(2):379386. doi:10.1007/s10120-016-0604-6
10. Al-Batran SE, Homann N, Pauligk C, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial. JAMA Oncol. 2017;3(9):1237-1244. doi:10.1001/jamaoncol.2017.0515
11. Al-Batran SE, Goetze T, Mueller DW, et al. The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI. BMC Cancer. 2017;17(1):893. doi:10.1186/s12885-017-3918-9
12. Kaya DM, Wang X, Harada K, et al. 101 long-term survivors who had metastatic gastroesophageal cancer and received local consolidative therapy. Oncology. 2017;93(4):243-248. doi:10.1159/000475550
13. FDA approves nivolumab for resected esophageal or GEJ cancer. FDA. May 20, 2021. Accessed June 15, 2021. https:// www.fda.gov/drugs/resources-information-approved-drugs/ fda-approves-nivolumab-resected-esophageal-or-gej-cancer