What’s the role of surgery in the management of GIST?
GIST patients have benefited from multiple FDA-approved medications for their disease. However, medication is not the sole tool for disease management – surgery is important as well. Most patients will undergo surgery at some point during their treatment. Most commonly it is used as the initial treatment after a confirmed diagnosis of GIST, especially if the patient has only one tumor that can be removed fairly easily (primary surgery). When there’s a single tumor but surgery appears to be more difficult, the patient may be given imatinib before surgery to try to shrink the tumor and make surgery less complicated. When this happens, the imatinib given prior to surgery is classified as neoadjuvant therapy.
But what if I don’t have only one tumor (metastatic disease)?
In some cases, surgery will be performed for metastatic disease either before or during treatment with imatinib. Data from a study by Park, et.al, (2014), suggest that for some recurrent or metastatic GIST patients, combining surgery with imatinib improves both time to progression and overall survival. See the Surgery and Metastatic GIST section below for more details about this study.
Does having surgery mean I won’t have recurrence and don’t need Gleevec (imatinib)?In a few words, it’s not that simple – recurrence can still occur, and Gleevec (imatinib) is most likely needed depending on your mutation and risk of recurrence category. A more detailed explanation based on numerous studies follows below.
Prior to imatinib, surgery was the only successful treatment option for GIST. However, based on research, we know that even for patients whose tumors are completely removed and have microscopically clean margins, there is a high probability of local tumor recurrence in the abdomen (Blanke, et.al, 2001). How long it takes for the recurrence to happen varies depending on the study – median time to recurrence has been reported as anywhere from 7 months to 2 years. In a large retrospective study, the reported median time to recurrence was 19 months. The median survival is 9 to 12 months for patients with local recurrence, and approximately 20 months for patients with metastatic GIST (DeMatteo, et.al, 2000). There are documented cases of GIST recurrence over 20 years after primary surgery which underscores the need for long-term follow-up of patients after apparently successful tumor resection.
Following the introduction of imatinib, the median survival of patients with metastatic GIST is much improved. In the ACOSOG Z9000 phase II trial for patients who had complete gross resection of a localized, primary GIST and were deemed to be at high risk for postoperative tumor recurrence, taking adjuvant imatinib (preventive imatinib after surgery to remove a primary tumor), the 3-year survival rate was 97% (DeMatteo, et.al, 2013). In the first phase II trial for GIST patients with advanced GIST, the median survival was about 5 years (Blanke, et.al, 2008). The majority of these patients had very advanced GIST as there was no effective therapy prior to this trial.Not all GISTs are sensitive to imatinib and some may require a higher dose of treatment. KIT exon 11 mutations are sensitive to imatinib, whereas those with exon 9 mutations are less sensitive, but higher doses of the drug improve clinical benefit (Heinrich, et.al, 2008). Learn more about GIST mutations here.
See below additional information regarding Gleevec (imatinib) and specific situations such as adjuvant treatment, metastatic treatment, and points about nutrition to consider after surgery.
Taking imatinib after surgery for a primary tumor (Adjuvant Treatment)
Upon completing surgery, patients often go on imatinib (Gleevec). Note that it is a good idea to get a mutational test to see if you have a mutation that responds to imatinib to determine if the treatment will work for you. Click here to learn more about mutations and mutational testing. If they had only one tumor and it hasn’t spread to any other organs (metastasized) then that is termed adjuvant treatment. An article talking specifically about adjuvant treatment and the criteria used to decide whether it is appropriate for a patient can be found below.
Imatinib after surgery (adjuvant imatinib)
On April 12, 2007, the American College of Surgeons announced that the Z9001 phase III adjuvant imatinib trial has successfully met its endpoint. Imatinib does increase time to recurrence in a highly significant manner.
On December 19, 2008, the Federal Drug Administration (FDA) approved Gleevec for adjuvant treatment of GIST in the United States. On May 7, 2009, Glivec (international spelling) received approval from the European Commission (EC) for adjuvant treatment of GIST.
Approval of Gleevec for adjuvant therapy was based on the interim results of the Z9001 phase III adjuvant imatinib trial.
There are a number of factors to consider about whether adjuvant Gleevec (imatinib) is suitable for a particular patient. Some factors that might be considered are:
- How likely is the tumor to reoccur?
- A small GIST tumor with a low mitotic rate found incidentally during surgery might be unlikely to reoccur, or if it did reoccur, it might be many years later.
- A large GIST tumor with a high mitotic rate that ruptured during surgery might be very likely to reoccur. In this scenario a strong case could be made for Gleevec (imatinib) after surgery.
- How likely is the tumor to respond to Gleevec (imatinib)?
- A patient with a less responsive mutational type of tumor might be less inclined to take adjuvant Gleevec (imatinib). See Mutational Testing.
- What is the anxiety level of the patient?
- A patient with more anxiety might derive psychological benefit from adjuvant Gleevec (imatinib) as well as potential medical benefit.
- A patient with less anxiety might be more inclined to take a watchful waiting approach, especially if they were low risk or had a less responsive mutation type.
- After starting adjuvant Gleevec (imatinib), how well is patient tolerating the medication?
- If a patient is not tolerating Gleevec (imatinib) well, then they might stop the medication and take a watchful waiting approach, especially if they were low risk or had a less responsive mutation type.
- If Gleevec (imatinib) is given after surgery that removed all visible tumors, how long should it be continued?
In the ACOSOG Z9001 trial, the patients that received imatinib took it for one year. “After a median follow-up of 19.7 months, the estimated 1-year RFS was 98% in the imatinib arm compared with 83% in the placebo arm” (Reichardt, et.al, 2012). In 2012, Joensuu, et.al, published results of a study comparing 1 year of adjuvant imatinib to 3 years. The results showed that 36 months of imatinib improved RFS and overall survival of GIST patients who have a high risk of GIST recurrence. Other trials are underway comparing longer durations. At this time the optimal duration of treatment is not defined. The FDA prescribing information for Gleevec (imatinib) does not specify a time frame. In the absence of other guidance, we could speculate that for higher risk patients, longer duration times (even indefinitely) might be considered.
Surgery and Metastatic GIST
In some cases, a patient presents with multiple tumors at different locations in the body upon diagnosis. In other cases, a primary tumor is removed, but a patient eventually develops additional tumors throughout the body. In both cases, the patient is said to have metastatic disease. While medication is undoubtedly important in treating metastatic GIST, surgery can be important as well.
Some gastrointestinal stromal tumors (GIST) may present as metastatic at the time of diagnosis. The most common site for metastases are the liver and/or peritoneum. With widespread progression (multi-organ involvement), surgery may not achieve removal of all visible tumors. In this case, the NCCN recommends treatment with imatinib as the standard of care to help prevent further recurrences. If surgery for metastatic GIST becomes viable as determined by healthcare team, resection is advisable to lessen tumor bulk/volume, although this is not potentially curative as some GIST cells may remain post-surgery.
A study by Park, et.al, (2014), demonstrated a likely benefit of surgical resection of residual lesions after disease control with imatinib. The study looked back at 134 advanced GIST patients treated with imatinib or imatinib + surgery. The imatinib group (92 patients) had a median progression-free survival (PFS) of 42.8 months versus 87.7 months in the imatinib + surgery group (p=0.001). Even more importantly, the overall survival times were longer in those receiving both imatinib and surgery (OS not reached) versus imatinib alone (88.8 months).
In the absence of big, randomized (not plausible for this type of study) clinical data, one of the most solid conclusions seems to be that surgery is of little benefit for patients with widespread progression of metastatic disease. Surgery for limited progression (one or two tumors) appears to have some benefit, and surgery for metastatic GISTs which have achieved stability with tyrosine kinase inhibitors (imatinib, sunitinib, etc.) is an individualized case that needs a multi-disciplinary collaboration with recognized GIST experts.
The decision on whether to have surgery for metastatic disease after responding to Gleevec (imatinib) is a complex decision. It involves many factors such as:
- Can all visible disease be removed?
- How complicated is the surgery?
- How likely are complications?
So I’ve had surgery. Now what?
Surgery is an important tool in helping manage GIST, but it also can result in changes in the body that need adjustments. Particularly, as in many cases you’re dealing with the gastrointestinal tract, nutrition is one area that is often impacted significantly. Below is some information that deals specifically with nutritional issues after gastrointestinal surgery:
Nutritional support after GI surgery and other issues
|The removal of the stomach, or other parts of the GI tract can require lifestyle changes, especially when it comes to diet. Managing and understanding how to properly nourish the body is important. Patients who undergo a gastrectomy may have to eat smaller and more frequent meals. They may have more difficulty absorbing some nutrients and may suffer from “dumping syndrome”, which is caused when food moves too rapidly into the small intestines. Almost everyone who had undergone surgery will form a type of scar tissue called adhesions. These adhesions can cause pain and in some cases a bowel obstruction. Not everyone will develop these problems, if they do occur, they may not happen for many years.|
|To learn more about gastrectomy and dumping syndrome Click here|
|To learn more about nutrition after surgery Click here|
|To learn more about adhesions Click here|
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Park SJ, Ryu MH, Ryoo BY, Park YS, Sohn BS, Kim HJ, Kim CW, Kim KH, Yu CS, Yook JH, Kim BS, Kang YK. The role of surgical resection following imatinib treatment in patients with recurrent or metastatic gastrointestinal stromal tumors: results of propensity score analyses. [Abstract] Ann Surg Oncol. 2014 Dec;21(13):4211-7. doi: 10.1245/s10434-014-3866-4. Epub 2014 Jul 1.
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