Margaret VonMehren, M.D.

Surgery, Tyrosine Kinase Inhibitor Therapy or Both?
Margaret von Mehren, MD and James C Watson, MD
Departments of Medical and Surgical Oncology
Fox Chase Cancer Center
Philadelphia, PA

Ten years ago treatment for gastrointestinal stromal tumors (GIST) was primarily surgical.  Nothing else really helped patients in a meaningful way.  Patients whose tumors could be removed completely had the best outcome. However, a large percentage of patients experienced recurrent, metastatic and/or unresectable disease and typically survived less than one year. This served as the impetus for seeking better treatments for GIST.

Work done by Hirota and colleagues in Japan identified a protein receptor on GISTs that was abnormal and caused these tumors to grow unchecked.  This receptor, KIT, and another one identified later, PDGFR, were obvious targets for treatment.  If these receptors could be inhibited, the growth of the tumors could be stopped.  As we now know, imatinib mesylate and sunitinib malate are both drugs that can inhibit the growth of GISTs because they inhibit KIT and PDGFR; sunitinb malate may also stop new blood vessel formation because it also inhibits vascular endothelial growth factor receptors.  These new drugs have caused much excitement for GIST patients and their caregivers.  For many they have lead to long-term control of tumors.  Many thought surgery for this tumor might become obsolete; however, it has become obvious that some tumors may grow and/or metastasize on treatment.  So should we be combining these successful treatments, tyrosine kinase inhibitors and surgery, for the best outcome?  The answer is yes and no, depending on the situation.

For primary GISTs, surgery remains the best treatment choice.  It is the fastest means of removing tumor.  Imatinib is being studied to see if taking it after complete removal of a primary GIST will result in more patients being cured.  The American College of Surgery Oncology Group has studies are underway in the United States with other similar studies ongoing in Europe.  We don’t yet know if imatinib treatment will lead to more cures or if there are some patients that will not benefit from the drug treatment.
Some patients however have very large primary tumors that may require complicated operations that could leave them with long-term side effects.  These patients may benefit from preoperative treatment with imatinib to try to decrease the size of the tumor and simplify the operation that is required to remove the tumor.  This approach was studied in a study sponsored by the Radiation Therapy Oncology Group and the final results are still pending.  Initial experience from this study suggests that tumors may be easier to remove with less blood loss at the time of surgery in patients treated in this manner.  This approach does require close coordination between the surgeon and medical oncologist to ensure that a patient’s tumor does not progress and the opportunity to have the tumor removed missed. 

For patients that are on treatment with imatinib or other drugs for recurrent disease such as sunitinib, surgery to remove disease can be considered; however, not everyone benefits from this approach.  Patients who have one or two tumors exhibiting growth while receiving imatinib or other drug therapy may consider surgery as an option since it is likely that this type of tumor progression reflects localized drug resistance.  Removing the “resistant” tumor(s) serves the same purpose as surgery does in the treatment of primary GIST. Clearly patients have a better outcome if they have effective therapy for any disease that persists.  Patients exhibiting multiple or diffuse tumor growth while receiving drug treatment are not typically helped by surgery since rapid tumor recurrence is typically encountered and surgery is often fraught with increased bleeding and longer post-operative recovery. Under these conditions, surgery should be limited for palliative (i.e. focal point of bowel obstruction) or emergent indications only.

Thankfully over the past decade we have found new treatments that are very effective for GIST.  New ones continue to be tested both in the laboratory and in the clinic.  Our enthusiasm for these new approaches however should not let us forget about the one approach that has always been effective: surgery.