The adjuvant treatment landscape of gastrointestinal cancers has recently undergone a transformation, with significant findings from several clinical trials. These studies, in gastric, biliary, pancreatic, and colon cancer looked particularly at the use of treatment in the adjuvant setting after surgical resection and have ultimately changed the standards of care for these patients.
Diane Reidy Lagunes, MD
The adjuvant treatment landscape of gastrointestinal (GI) cancers has recently undergone a transformation, with significant findings from several clinical trials. These studies, in gastric, biliary, pancreatic, and colon cancer looked particularly at the use of treatment in the adjuvant setting after surgical resection and have ultimately changed the standards of care for these patients.
In gastric cancer, the combination of fluorouracil(5-FU), leucovorin, oxaliplatin, and docetaxel, known as FLOT, is now considered the standard of care for patients with locally advanced gastric cancer after demonstrating better outcomes than ECF, the combination of epirubicin, cisplatin, and 5-FU.
In the BILCAP study, investigators found that capecitabine improved outcomes by over 50 months for patients with resected biliary cancer. This has led to another change in standard of care for this patient population, a treatment combination of 5-FU plus capecitabine after surgery.
The ESPAC-4 trial compared the combination of gemcitabine plus capecitabine for patients with resected pancreas cancer to treatment with gemcitabine alone. Findings showed an improvement with the combination as well as a slightly improved overall survival (OS), leading to a new standard of care treatment in the adjuvant setting.
The IDEA collaboration combined data from over 13,000 patients with colon cancer, which were analyzed at the Mayo Clinic to find whether 3-month treatment with FOLFOX or CAPOX was equivalent to a 6-month treatment plan. Investigators found that the results varied between 2 groups of patients: low- and high-risk patients with resected colon cancer. While 3 months was not found to be noninferior, investigators did find significant differences between these 2 groups of patients and determined which treatment duration is ideal for each of them.
In an interview withTargeted Oncology,Diane Reidy Lagunes, MD, associate deputy physician, chief of Clinical Operations and GI Medical Oncologist at Memorial Sloan Kettering Cancer Center, discussed each of these trials and how they are changing the treatment landscape of gastric cancers across the board.
TARGETED ONCOLOGY: Can you explain the updates in the treatment landscape for gastric cancers? What led to this change?
Reidy Lagunes:In gastric cancer, there's been a complete standard of care change, which is very exciting. Our German colleagues had a randomized trial looking at gastric cancer and changing the treatment that we use perioperatively. The standard of care for many years has been from data from the MAGIC trial where they used the combination of ECF before surgery, then surgery, then after surgery. The 5-year OS was still on the order of only about 35%. There was phase II data that suggested the combination FLOT showed very high response rates. That's what the study set out to do. They randomized over 700 patients to look at FLOT compared to ECF prior to surgery, then after surgery.
That study was actually a homerun where the OS increased from 35 months to 51 months. It really showed that not only did it improve outcome, but also the toxicities were not that different. The morbidity and mortality associated with the surgery were not different at all. There were some differences in toxicity, a little bit more neutropenia and infections in the FLOT arm compared to ECF, but ECF had more nausea and vomiting.
The bottom line is that it improved progression-free survival and OS, and it increased the cure rate by using the FLOT method. This has now been changed as the standard of care treatment for our patients with locally advanced gastric cancer.
TARGETED ONCOLOGY: The BILCAP study led to a major change in the treatment paradigm of biliary cancers. What was the rationale for this study, and what were the end results?
Reidy Lagunes:For a long time, we had retrospective data in a metanalysis that suggested giving something after resection for biliary cancer improved outcome. What that something was, we didn't know. There were some reports of radiation with 5-FU, or 5-FU-based therapies alone, or other systemic treatments in the adjuvant setting. This study set out to ask the question of what is the role of capecitabine after biliary resection.
Over 700 patients were randomized to receive a pretty high dose of capecitabine versus observation. The OS was improved over 50 months for patients that received capecitabine. That also has become a standard of care treatment for patients with resected biliary cancer, to use 5-FU regimens with capecitabine.
TARGETED ONCOLOGY: Can you discuss the trial that investigated adjuvant treatment in patients with resected pancreatic cancer?
Reidy Lagunes:This was the ESPAC-4 trial. Since the 90s, gemcitabine has been the backbone of treatment for pancreas cancer, both in the metastatic, as well as the adjuvant setting. There was another study showing that 5-FU was also appropriate for pancreas cancer in the adjuvant setting. ESPAC-4 took what we knew, that gemcitabine by itself improved outcome and 5-FU by itself improved outcome as a resected adjuvant treatment for pancreas cancer after surgery.
Unfortunately, the problem in patients with resected pancreatic cancer is recurrence rates are still very high. ESPAC-4 set out to determine if we could combine gemcitabine plus capecitabine to improve our outcomes in patients with resected pancreas cancer.
The OS was improved. It was modest; the median overall survival went from 25 to 28 months. Not as good as we like it to be, but when you look at the curves, they unquestionably separate. At a year, the patients that received gemcitabine plus capecitabine do a lot better and will actually go out to 5 years, and those curves definitely separate. That is the new standard of care gemcitabine plus capecitabine for adjuvant treatment of resected pancreas cancer.
We are eagerly awaiting the results for FOLFIRINOX versus gemcitabine in the adjuvant setting to answer the question of if FOLFIRINOX can improveoutcome. That study again only compared gemcitabine and not gemcitabine/capecitabine, so we will have to be cautious in how we determine that data.
TARGETED ONCOLOGY: What data can you share from the study comparing treatment durations in patients with colon cancer?
Reidy Lagunes:The IDEA collaboration was answering the question of if we could use 3 months of adjuvant FOLFOX as compared to 6 months and have the same outcome in our patients with stage 3 colon cancer resected. It was a collaboration that was really commendable. There were 6 randomized studies included in the IDEA collaboration to get that data, which accumulated 13,000 patients, so it was a very, very large study. All of that data was sent to the Mayo Clinic for analysis and they asked the question again: is 3 months equivalent to 6 months of FOLFOX or CAPOX adjuvant treatment?
The answer was a little surprising as it was a noninferiority study with very clear prespecified statistical significance that just missed it when you looked at the data of 13,000 patients. When you look at the curves, they essentially don't separate. Based on the statistical pre-specified numbers that they had, it was not noninferior.
TARGETED ONCOLOGY: Was there any other significant data from this analysis?
Reidy Lagunes:When you looked a little bit more carefully, the study allowed us to look this way: they divided the patients into lower risk or higher risk. Higher-risk patients with resected colon cancer had either T4 or M2 lesions. Lower risk was T1 to T3 and N1. When you looked at the high-risk population of T4/N2, those patients definitely did have a modest but notable improvement when they had 6 months of FOLFOX or CAPOX as compared to 3 months. I think most of us have to have that conversation in patients with T4/N2 disease that 6 months of therapy is probably better than 3 months.
Although this study did not test for this, one of the biggest worries we have is that oxaliplatin can cause permanent neuropathy, so it has to be a conversation with our patients of whether you need the full 12 cycles of oxaliplatin or can you and should you drop the oxaliplatin in the last 3? I think most of us in the clinical practice absolutely do that, that we try in patients with T4/ N2 disease that we give 6 months of treatment, but the last couple of cycles are usually just 5-FU plus leucovorin alone, because the incremental benefit of FOLFOX is really in the 5-FU. The oxaliplatin adds, but it’s very small, and we've known that for many years.
For high risk, 6 months is probably better than 3 months. You have to be very careful of the neuropathy and think about dropping the oxaliplatin toward the end of that if the patients start to get neuropathy.
The one that's a little bit trickier is what do you do with the lower-risk.With 3 versus 6 months when you looked at low-risk T1 to T3 and N1 disease, the curves really didn't separate. There really wasn't a big difference there. So, most of us feel that 3 months is probably equivalent to 6 months in that lower-risk group. Interestingly, when you looked at the data, the patients that got CAPOX as opposed to the FOLFOX did a little bit better. The OS for them was about 85% versus 83%. There may be something about CAPOX in that lower-risk population that is better than FOLFOX. Many of us have that conversation with our patients with stage 3a or 3b to think about CAPOX instead of FOLFOX.
It was a very, very important study, and there's never going to be another study like it after 13,000 patients. We have to interpret the data with caution. In summary, the study was not noninferior, meaning it did not meet its endpoint, which is to say that 3 months is not the same as 6 months, but when you really look at the data, the benefit of the 6 months was really in the T4/N2 data. For patients with T1 to T3 and N1 disease, 3 months is probably sufficient and perhaps having a conversation of CAPOX as opposed to FOLFOX should be considered.
TARGETED ONCOLOGY: How do you see adjuvant therapy evolving across all of these GI cancers?
Reidy Lagunes:I do see adjuvant therapy evolving over the next couple of years. We're learning a lot more. Some of us are a little more envious of other solid tumor malignancies where they have had dramatic changes. In GI oncology, the incremental benefits have been slower to come, but they're there. The benefit, for example, of looking at the quality of life and quantity in studies like IDEA are so important for our patient population. Those were really important studies to do. The role of immunotherapy, for example, in microsatellite instability-high colorectal cancers needs to now be tested in the adjuvant setting, with some very small numbers which is very hard to do, but possible. I think the IDEA collaboration illustrates we can all absolutely work together to answer these important questions, and we should.
Hopefully the biomarkers and other things that help us better define who needs this therapy will be the next step. Maybe with cell-free DNA or maybe with other biomarkers we can start to characterize the patients who will really benefit. I think IDEA really did do that, in saying T4/N2, those are the ones that we really have to focus on. These studies are going to be really important in improving our patient outcomes, but also, importantly, to ensure that their quality of life is maintained even when we cure them.
TARGETED ONCOLOGY: What is the key take away from this information?