Can Locoregional Therapies Be Used in Metastatic Gastroesophageal Cancers?

Elena Elimova, MD, MSc

As part of our coverage of the 2018 Gastrointestinal Cancers Symposium, an American Society of Clinical Oncology–sponsored annual meeting, held January 18–20 in San Francisco, we are speaking with Elena Elimova, MD, MSc, a medical oncologist at the Princess Margaret Hospital in Toronto, where she specializes in the treatment of patients with gastroesophageal cancers. Dr. Elimova will provide a medical oncologist’s perspective on the role of locoregional therapies for patients with metastatic esophageal and gastric cancers at the meeting.

-Interviewed by Anna Azvolinsky

Cancer Network: First, can you talk about the major systemic therapy options for patients who are diagnosed with esophageal and gastric tumors who have advanced disease?

Dr. Elimova: The first thing I want to say is that this is a very exciting time to be a gastrointestinal medical oncologist because approximately 5 years ago there were no proven second-line therapies for gastroesophageal cancers. And today, we have many treatment options. In the first line, we usually use platinum doublets or triplets, depending on local preference. If the patient has HER2-positive disease, we add trastuzumab. In second-line therapy, we use taxanes with or without ramucirumab; for gastric and gastric junction tumors there is now hot-off-the-press evidence that single-agent immunotherapy drugs work in heavily pretreated settings. Additionally, the FOLFIRI regimen (leucovorin, fluorouracil, and irinotecan) is a reasonable treatment option. For my patients, I encourage them to participate in clinical trials because I believe that we can always do better in terms of systemic therapy.

Cancer Network: What are the locoregional therapies available for patients with metastatic esophageal and gastric tumors?

Dr. Elimova: I will start off by saying that if we are talking about locoregional disease, surgery is the mainstay of therapy because that is the main curative option. Our adjunctive therapies are chemotherapy and chemoradiation therapy, which could provide chance for a cure. But to speak specifically about patients who have metastatic disease, locoregional therapies-surgery and radiation therapy-are mainly used to palliate symptoms. For example, for people with severe dysphasia, we may choose to give radiation therapy prior to proceeding to systemic therapy. Another treatment option that is quite interesting is HIPEC-hyperthermic intraperitoneal chemotherapy. Although that is not technically a localized treatment, because the chemotherapy is being given in the peritoneal cavity. This is an area of pretty intense interest in terms of clinical trials, but the clinical trials that have been done to date have actually been negative in gastric cancer.

Cancer Network: In the context of these advanced cancers, what do we know about how locoregional therapies can work together with systemic therapies? Are there certain patients who are eligible for this combination?

Dr. Elimova: That again depends on whether we are talking about metastatic or localized disease. In localized disease, we have level 1 evidence that both chemotherapy and chemoradiation combined with surgery improves overall survival, so these therapies are crucial in the setting of localized disease. When we talk specifically about metastatic disease, unfortunately there is currently no evidence that locoregional therapy, when combined with systemic therapy, improves overall survival of patients with metastatic gastroesophageal malignancies. One example is the REGATTA trial that was mainly done in Asia, which compared chemotherapy alone vs chemotherapy and gastrectomy. Unfortunately, the trial didn’t show any overall survival benefit, so clearly a gastrectomy is not recommended in the setting of advanced disease.

I think one question that exists in a lot of our minds as medical oncologists is whether patients with minimal metastatic disease-for example, patients with peritoneal cytology–only positive disease or patients who might have one supraclavicular lymph node-would benefit from localized therapy in addition to systemic therapies. Currently, the data do not support this approach. Ideally, in patients for whom locoregional therapy is being considered in the context of the presence of metastatic disease, they should be treated on a clinical trial. But, if no such clinical trial exists, at a minimum these patients’ cases should be discussed in a multidisciplinary tumor board prior to determining the next treatment steps because you want the input of your surgical and radiation oncology colleagues.

Cancer Network: What, to your mind, are the unanswered questions about how best to use localized therapies for patients who have advanced disease?

Dr. Elimova: I think the reason that we consider locoregional therapies for metastatic cancer is that we all anecdotally have a patient who usually does well with chemotherapy with some kind of local therapy, and then they have long-term remission. I think the question that we don’t know the answer to today is whether these same patients would have done equally as well if we had just continued their systemic chemotherapy. So, again, I have to say right now that there is no high-level evidence that supports the use of localized therapy in conjunction with systemic therapy for metastatic disease.

I think the major questions that have to be answered are, one, do patients with minimal metastatic disease benefit from local therapy in addition to systemic therapy? Second, what are the best ways to identify patients who are most likely to benefit from this type of approach? Ideally, we may find biomarkers or combinations of biomarkers in conjunction with clinical-pathologic factors or, potentially, imaging. For example, the use of MRI or PET to predict the patients who benefit vs those who don’t. For many of us, the Cancer Genome Atlas data analysis on gastroesophageal tumors was quite exciting but hasn’t translated into a new treatment approach or biomarker use.

Finally, how much systemic therapy should patients get before proceeding with a locoregional approach? I think another interesting question that we are trying to answer now is whether radiotherapy or other ablative therapy that releases tumor antigens would augment the immune response as observed with the abscopal effect. For example, now that we are using immune checkpoint inhibitors, would the use of radiation therapy make those checkpoint inhibitors more effective? I think that is an area that is important to investigate. More than ever it is important to emphasize that we now have effective systemic treatment options for patients with metastatic gastroesophageal tumors. We have to be very careful when we make the decision to add locoregional therapies. At my institution, we discuss all of these patients with both localized disease and those with minimal metastatic disease in a tumor board with a radiation oncologist, a surgeon, and a pathologist prior to making any final treatment decisions. Multidisciplinary care is very important in this disease.

Cancer Network: Thank you so much for joining us today, Dr. Elimova.

Dr. Elimova: Thank you.