The Role of Adjuvant Therapy for GIST

Jonathan Strosberg, MD:The role of adjuvant therapy for gastrointestinal stromal tumors is fairly controversial. And the reason is that we think that imatinib delays recurrence, suppresses recurrence while you’re taking it, but doesn’t actually eradicate micrometastatic disease. There have been several randomized trials of adjuvant therapy. The first one looked at all patients with tumors greater than 3 cm, randomizing them to 1 year of adjuvant imatinib versus placebo. And the results of that trial showed an improvement in recurrent free survival at 1 year. But with subsequent follow-up, what we found is that recurrence was actually delayed by 1 year, and that overall survival wasn’t impacted.

Another trial, a Scandinavian trial, looked at a much higher-risk population—patients with a relatively high mitotic rate and/or relatively large-sized tumors—intermediate or high recurrence rates tumors randomized into 3 years versus 1 year of adjuvant imatinib. And in this case, the pattern was similar. Because they were higher-risk tumors, there was more of a significance in recurrence free survival. But if we looked at longer term follow-up, what we found, again, is that the recurrence was delayed.

This time there was also a small improvement in overall survival, which was encouraging. But with longer term follow-up, that overall survival benefit is relatively decreased. And also, it was a relatively small trial, not really powered to look at overall survival. So, there remains a lot of questions as to who should receive adjuvant treatment with imatinib—knowing that it’s probably just delaying recurrence—and also the duration of treatment. I personally recommend treating patients mostly with high-intermediate, or very high risk of, recurrence. And in cases where there’s a very high risk of recurrence, I often don’t limit that treatment to 3 years, knowing that if we stop treatment, the likelihood of relapse is fairly high. When we do stop treatment in patients with very high-risk tumors, it’s important to monitor them closely after cessation of adjuvant imatinib. Because you don’t want a situation where they come back 6 months later and suddenly they have a very high burden of disease.

Most patients tolerate imatinib fairly well, but not all do. Some patients develop edema, rash, and fatigue. I think it’s important to lower the dose, fairly proactively, because the benefits of adjuvant therapy are not that well established. We want patients to be able to tolerate treatment well, especially given the fact that many are in treatment for at least 3 years.

If this were my patient, we would have used exactly the same approach. In other words, a patient with a single liver metastasis and a large primary gastric tumor, we would definitely want to proceed with neoadjuvant imatinib to try to shrink the tumor as much as possible, reduce the morbidity of surgery, and then continue with adjuvant imatinib after surgery to try to reduce, as much as possible, the risk of recurrence.

The treatment landscape has just improved substantially with the introduction of the tyrosine kinase inhibitors. But there are still unmet needs. There are patients with primary resistant mutations, such as aPDGFRA-D842Vmutation. Patients with wild-type tumors don’t tend to fare as well with the standard tyrosine kinase inhibitors. There are other mutations suchSDH, for example, that are not well studied or understood. And we need better drugs for secondary-resistant tumors because once patients develop the resistance to imatinib, they still stand to have some benefit from subsequent sunitinib or regorafenib. But time to progression tends to be shorter in the second- and third-line settings than the first-line setting. So, we need drugs that are really designed to target those resistances specifically.

Transcript edited for clarity.

• A 65—year-old male presented with severe abdominal discomfort
  • Past medical history included mild back pain and joint pain that was treated with NSAIDs
• Abdominal CT findings showed a large mass with a diameter of 14 cm involving the cardia, fundus, and body of the stomach; splenic involvement was also noted.
• A small lesion was detected in the liver
• Biopsy and histological examination confirmed that the mass was a gastrointestinal stromal tumor
  • IHC indicated that the tumor was positive for c-KIT
  • Genetic analyses showed a mutation in exon 11 of c-KIT
  • The tumor showed high mitotic activity with >5 mitoses/50 high-power fields
• She was diagnosed with GIST of the stomach and liver metastasis
• Treatment was initiated with neoadjuvant imatinib with the goal to achieve reduction of operative risk for the primary tumor and for functional preservation
  • The tumor size was reduced to 8 cm at 3 months and to 5 cm after 6 months
  • No further reduction was noted at 9 months
• At 10 months, the patient underwent total gastrectomy, splenectomy, and partial hepatectomy