: A 64-year-old Caucasian male presents to the emergency room with fatigue and abdominal pain. He has no significant past medical history other than well-controlled hypertension that is managed with a beta blocker; he has no significant family history. An abdominal CT scan is performed and this reveals a 12-cm gastric mass involving the cardia and fundus, as well as a 7-cm solitary liver tumor.

A biopsy was performed revealing a gastrointestinal stromal tumor, or GIST, that was KIT-positive by immunohistochemistry, and found to have an

mutation. The tumor was also found to be high-grade, with a greater than 5 per 50 high-power field mitotic rate. The patient was initiated on therapy with imatinib at the 600 mg per day dose; this was well toleratedthe patient maintained therapy for 5 months. At that time, the patient had another CT scan performed of the abdomen that revealed decrease in size of the solitary liver metastasis from 7 cm to 4 cm, with relative stability of the gastric mass. The patient was referred to a surgical oncologist who performed an R0 resection with negative margins of both the liver metastasis and the primary tumor in the stomach. Postoperatively, the patient recovered and was placed on imatinib 800 mg per day.

Patients with gastrointestinal stromal tumors present with a variety of different symptoms, largely depending on the location of the primary tumor. This patient had a primary tumor in the stomach. The patient presented with fatigue, probably related to anemia, as well as abdominal painthis presentation is consistent with a gastrointestinal stromal tumor in this anatomic location.

This patient with GIST was initially treated with 600 mg per day of imatinib, underwent surgical resection and postoperatively was placed on 800 mg per day of imatinib. This management is supported by the GIST metaanalysis that found that patients who have an

mutation benefit from higher doses than 400 mg per day of imatinib, in terms of not only progression-free survival, but overall survival as well.

Diagnosis of Metastatic GIST

: The use of neoadjuvant or preoperative imatinib in patients with gastrointestinal stromal tumor is presented by a number of studiesMcCullough et al&mdash;that support the use of neoadjuvant, as well as adjuvant therapy in patients with gastrointestinal stromal tumor. In my practice, we use preoperative imatinib therapy fairly frequently, and the duration is not written in stone. We typically will treat the patient to maximum tumor shrinkage, which ends up being 6 to 9 months. About 5 months in this case might be a little early, but the patient clearly had substantial tumor regression. At that point in time, proceeding to surgery is very reasonable.

Adjuvant therapy with a primary tumor is supported by the SSG study that found both a recurrence-free survival benefit, and overall survival benefit for patients treated for 3 years versus 1 year. In this specific situation, the patient has a solitary liver metastasisthis would require longer duration therapy, perhaps a lifetime.

For patients in the metastatic setting, there seems to be little benefit in treatment at higher doses than 400 mg per day, if the patient has an

mutation. So, if this patient, in this case, indeed had an

mutation, I would have initiated therapy with a 400 mg per day dose of imatinib and continued that postoperatively.

In August 2016, after 2 years, this patient was found to have multiple peritoneal implants and a new solitary liver lesion by CT scan of the abdomen and pelvis. This patient still had a reasonable quality of life, was able to perform his activities of daily living, and was only limited really in strenuous activity. The patient was initiated on therapy with sunitinib 37.5 mg continuous daily dosing.

Imatinib Therapy for Resectable GIST

: This patient had a CT scan of the abdomen-pelvis performed after 2 years on imatinib therapy, and was determined to have peritoneal implants and a new liver lesion. At this point in time, the patient still had a reasonable quality of life and was able to perform his activities of daily living, other than really strenuous activity. The determination was made to initiate the patient on sunitinib, 37.5-mg continuous daily dosing.

This patient was initiated on 37.5 mg of sunitinib orally, continuous daily dosing after progression on imatinib. Although the initial studies of sunitinib and metastatic gastrointestinal stromal tumor involved the 50-mg dose of sunitinib4 weeks on, 2 weeks off&mdash;subsequent studies support the use of 37.5 mg daily. This is better tolerated in patients and pharmacokinetically appears to be similar to the 50-mg dose. Additionally, patients do not have that 2-weeks off schedule, where the patients are drug-free and the tumors can flare.

This patient, after initiation of sunitinib, should be monitored by CT scan of the abdomen-pelvis, chest X-ray, and laboratory testing to include a CBC, a chemistry, and a magnesium. Additionally, we perform a thyroid-stimulating hormone test, generally every 3 months, to detect hypothyroidism at an early stage. Patients with GIST often have anemia. Patients with GIST take kinase inhibitors like sunitinib, and these can all cause severe fatigue. And so, we try to address the fatigue by managing the hypothyroidism that might be due to sunitinib, as well as managing the anemia with a thorough workup of etiology including iron deficiency, B12 deficiency, folate deficiency, and supplementation of any of these if they are low. If this patient continues to have fatigue, we may refer the patient to our fatigue clinic.

When a patient&rsquo;s tumor becomes resistant to imatinib therapy, this may be due to a situation called secondary resistance. This situation is due to the selection of a resistant clone that has a mutation in a different site from the initial

, but then after selection on imatinib this resistant clone emerges due to a new mutation, typically an

of the same KIT allele. This is an important mechanism of resistance because these secondary mutations are at sites where imatinib binds. In the presence of this mutation, imatinib is not able to bind effectively to the KIT protein and inhibit it, thus the patient becomes resistant to imatinib.

secondary mutations, seem to be more sensitive to sunitinib. So, in this case using sunitinib, 37.5 mg, continuous daily dosing is a reasonable second-line therapy and would be recommended.

Sunitinib Therapy at Progression of Metastatic GIST

: At his 6-month follow-up on sunitinib therapy, the patient was evaluated in clinic. He was found to have a slight decrease in his ability to perform his activities of daily living. Additionally, a CT scan of the abdomen and pelvis was performed and revealed an increase in size of the multiple peritoneal implants, as well as a 2-cm increase in size of the liver lesions.

The patient was then referred to a GIST specialty center, where his therapy was changed from sunitinib to regorafenib160 mg per day, 3 weeks on, 1 week off. The patient was then followed up again after an additional 6 months with a new CT scan of the abdomen and pelvis, that revealed a slight regression of the peritoneal implants and disappearance of the liver lesion.

The appropriate treatment option for a patient with metastatic GIST at the time of progression on sunitinib is regorafenib 160 mg per day, 3 weeks on and 1 week off. Regorafenib was superior to placebo in patients who participated with metastatic GIST on the GRID study.

In the GRID study, patients with metastatic GIST progressing on sunitinib were randomized to either regorafenib160 mg a day, 3 weeks on, 1 week off&mdash;or placebo in the 2:1 fashion. The patients that were randomized to regorafenib experienced a progression-free survival of 4.8 months on median, while the patients treated with placebo only had a 0.9-month median progression-free survival. Additionally, side effect profiles that were found to be due to regorafenib, rather than placebo, included hypertension, hand-foot syndrome, and diarrhea.

Other than treatment with regorafenib, the patient could have been retreated with imatinib. However, this might not make sense because the patient may have one of the secondary mutations that would still render imatinib resistance to the tumor. Additionally, data from the CROSSOVER study of increasing imatinib from 400 mg to 800 mg really only resulted in an approximate 3-month progression-free survival, which is inferior to regorafenib.

Third-Line Therapy for GIST

: Regorafenib is a multi-targeted kinase inhibitor that inhibits not only KIT and GI stromal tumor, but also VEGF receptor, PDGF receptor, and several other kinases. This broad inhibitory profile also leads to certain predictable toxicities including hypertension, diarrhea, hand-foot syndrome, fatigue, rash, and hypothyroidism.

These toxicities can be relatively well managed. We manage hypertension with antihypertensives, we manage diarrhea with antidiarrheals, and we manage hypothyroidism with thyroid replacement therapy. We manage anemia, initially, by a workup to determine the cause of the anemia, and if it&rsquo;s B12, folate or iron deficiency, we replete those. And we generally manage rash with over-the-counter hydrocortisone and occasionally prescription steroids.

One of the more severe toxicities with agents like regorafenib and sunitinib is hand-foot syndrome. Hand-foot syndrome is a thickening of the calluses on the palms of the hands and the soles of the feet that, if unchecked, can become quite painful. We manage hand-foot syndrome very early and very aggressively with creams and lotions that contain urea. You&rsquo;re looking for 20% or more concentration of urea to really solubilize the carotene that builds up in these calluses. It&rsquo;s also common for us to refer patients to a podiatrist to manage calluses before they can get out of control. Because if unchecked, these thickened calluses can crack, become extremely painful, and even infected.

If the side effects of regorafenib cannot be managed by the supportive care approaches, then one may have to undertake a dose reduction. Standard dose reduction would be to reduce from 160 mg daily to 120 mg daily, and maintain 3 weeks on, 1 week off.

This patient developed severe diarrhea with greater than 10 stools per day that could not be effectively managed with Imodium (loperamide), Lomotil (atropine/diphenoxylate), or even tincture of opium. This required a dose reduction from 160 mg per day to 120 mg per day, 3 weeks on and 1 week off.

Toxicity Management for GIST Third-Line Therapy

: Multidisciplinary management of patients with GIST is generally optimal. Patients should be managed at a GIST center where they have access to surgeons, radiologists, as well as pathologists and nurses who are experienced with gastrointestinal stromal tumor. This is evidence in this case of a patient with GIST who initially responded to imatinib, and we saw regression of a solitary liver metastasis. These are the types of patients who benefit from multidisciplinary resection of a metastatic lesion, as long as it&rsquo;s responding to a TKI, like imatinib.

Multidisciplinary management of patients with GIST is really optimal. This requires good communication between the surgeons, the pathologists, the radiologists, and the medical oncologists. We accomplish that often by multidisciplinary tumor boards, where all of the GIST specialists meet together in 1 room to go over a patient&rsquo;s case from all of their individual expertise. At the end of the conference, we have a plan in place that takes advantage of published literature and our individual experiences, to give the patient really the best chance of surviving the longest from gastrointestinal stromal tumor.

The nurse and the nurse practitioner are critical members of the multidisciplinary team. The nurse and the nurse practitioner may be the first one to get a phone call from the patient who has developed a toxicity. For instance, if the patient has developed hypertension, the nurse or nurse practitioner may be able to call in an antihypertensive agent, such that the hypertension doesn&rsquo;t get out of control and the patient doesn&rsquo;t have long-term toxicity from hypertension.

GIST patients are often co-managed by a community oncologist and a GIST specialist at an academic center. This co-management is critical because at the academic center, we have a multidisciplinary GIST team that can help delineate the treatment plan at the time of diagnosis, ensure the correct diagnosis, and determine the appropriate therapeutic options and monitoring going forward. After the patient has been on therapy for some time, the patient may develop resistance, and referral to a GIST specialty center could help determine whether there&rsquo;s a clinical trial available or a new agent that might make sense for this patient.

Referral to a GIST center also allows in-depth mutation testing of the patient&rsquo;s tumors. This is critical because GIST now really is a category of 9 or 10 different types of GIST, that are characterized by their individual unique mutations. The most common mutation is the gene called KIT, which we treat because it&rsquo;s sensitive to imatinib. However, if a patient has another common mutation, such as

, that mutation is generally resistant to imatinib, and the patient should be referred to a GIST center for a clinical trial.

, which could be treated by an alternative targeted therapy such as a RAF inhibitor or a Pi3K inhibitor. And then there&rsquo;s this type of GIST called SDH-deficient GIST that is much more difficult to manage, and we&rsquo;re really starting to really try to understand it at a biological level. These tumors may be more sensitive to a medication like regorafenib, rather than imatinib.

Recurrent Metastatic Gastrointestinal Stromal Tumor

Diagnosis of Metastatic GIST

Imatinib Therapy for Resectable GIST

Sunitinib Therapy at Progression of Metastatic GIST

Third-Line Therapy for GIST

Toxicity Management for GIST Third-Line Therapy

Multidisciplinary Management of GIST