Systemic Steroid Treatment for Imatinib-Associated Severe Skin Rash in Patients with Gastrointestinal Stromal Tumor: A Phase II Study.

BACKGROUND: To achieve optimal clinical outcomes in patients with gastrointestinal stromal tumor (GIST), it is crucial to maintain sufficient dosing of imatinib. Skin rash is a common imatinib-associated adverse event and may affect compliance. This phase II study was conducted to evaluate whether imatinib-associated severe skin rash can be managed with systemic steroids without dose reduction or interruption of imatinib. This study is registered at ClinicalTrials.gov, number NCT03440515. PATIENTS AND METHODS: Between 2014 and 2016, 29 patients with imatinib-associated severe skin rash were enrolled. Skin rash of grade 2 with grade ≥2 pruritus or of grade 3 was considered severe. Oral prednisolone was administered 30 mg/day for 3 weeks, then tapered off over 12 weeks. The primary endpoint was treatment success rate (TSR). Treatment success was defined as maintaining imatinib for more than 15 weeks after completion of the steroid administration schedule without skin rash that led to additional steroid treatment or dose reduction or interruption of imatinib. RESULTS: Of the 29 patients enrolled, 22 patients with skin rash were treated successfully (TSR, 75.8%), 2 (6.9%) were evaluated as treatment failures, and 5 (17.2%) were not evaluable. The 2-year rash-free and imatinib reduction-free interval rate was 67.2% with median follow-up of 22.0 months (range, 0.4-30.3). Recurrence of severe skin rash occurred in seven patients (24.1%). Systemic steroids were well tolerated except in one patient who experienced pneumocystis pneumonia. CONCLUSION: This study demonstrated that imatinib-associated severe skin rash can be effectively controlled by systemic steroid treatment without interruption or dose reduction of imatinib in patients with GIST. IMPLICATIONS FOR PRACTICE: Imatinib has been the standard treatment of gastrointestinal stromal tumor in both adjuvant and palliative settings. It is crucial to maintain sufficient dosing of imatinib to achieve optimal clinical outcomes. Imatinib commonly causes imatinib-associated skin rash, which may worsen drug compliance. This phase II study demonstrated that systemic steroids could help maintaining the efficacy of imatinib by preventing interruption or dose reduction of imatinib. The present study provides a new administration strategy of systemic steroids and its efficacy and safety data. Thus, this study can be a cornerstone to establish treatment guidelines for imatinib-associated skin rash.

Impact of L-carnitine on imatinib-related muscle cramps in patients with gastrointestinal stromal tumor.

Introduction Muscle cramps constitute one of the leading adverse events of imatinib, the standard first-line treatment for advanced gastrointestinal stromal tumor (GIST). This study aims to assess the impact of L-carnitine on relieving cramps in patients with GIST taking imatinib. Materials and methods We reviewed our prospective database for patients with GIST who took L-carnitine (500-mg tablet, 2-3 times daily) for muscle cramps in Asan Medical Center. The assessment tool included severity by the numeric rating scale (NRS), frequency, duration of cramps, and questionnaire for the disturbance in basic activities of daily living (ADL), instrumental ADL (iADL), outdoor activity, or sleeping before and after L-carnitine treatment. Results We examined 42 patients [median age: 60 (range: 17-81) years; males, 52.4%] who received L-carnitine for cramps on NRS ≥ 4 intensity during 2016-2017. In 83.3% of patients (n = 35), the NRS score declined to <4 points, with 8 patients (19.0%) experiencing complete disappearance of symptoms [median response time: 10 (range: 2-30) days]. Moreover, the median duration of each episode and frequency decreased from 5 to 2 min and from 30 to 3 times per month (P < 0.001), respectively. We observed substantial improvement in all quality-of-life aspects after L-carnitine (ADL, 73.2%-14.6%; iADL, 73.2%-17.1%; sleeping, 78.0%-22.0%; outdoor activity, 68.3%-17.1%; P < 0.001). ConclusionL-carnitine could effectively relieve imatinib-related muscle cramps in patients with GIST. Accordingly, a randomized phase 3 study is currently ongoing (NCT03426722).

MRI in predicting the response of gastrointestinal stromal tumor to targeted therapy: a patient-based multi-parameter study.

BACKGROUND: To investigate the performance of quantitative indicators of MRI in early prediction of the response of gastrointestinal stromal tumor (GIST) to targeted therapy in a patient-based study. METHODS: MRI examinations were performed on 62 patients with GIST using 1.5 T scanners before and at two and 12 weeks after treatment with targeted agents. The longest diameter (LD) and contrast-to-noise ratio (CNR) of the tumors were measured by T2-weighted imaging (T2WI), and the apparent diffusion coefficient (ADC) was determined using diffusion-weighted imaging (DWI). The pre-therapy and early percentage changes (%Δ) of the three parameters were compared with regard to their abilities to differentiate responder and non- responder patients, using ROC curves. RESULTS: There were 42 patients in responder and 20 in non-responder group. After two weeks of therapy, the percentage changes in the ADC and LD were significantly different between the two groups (ADC: responder 30% vs. non- responder 1%, Z = - 4.819, P < 0.001; LD: responder - 7% vs. non- responder - 2%, Z = - 3.238, P = 0.001), but not in T2WI-CNR (responder - 3% vs. non-responder 9%, Z = - 0.663, P = 0.508). The AUCs on ROC for %ΔLD, %ΔT2WI-CNR and %ΔADC after two weeks of therapy were 0.756, 0.552 and 0.881, respectively, for response differentiation. When %ΔADC ≥15% was used to predict responder, the PPV was 93.3%. CONCLUSIONS: The percentage change of the ADC after two weeks of therapy outperformed T2WI-CNR and longest diameter in predicting the early response of GIST to targeted therapy.

[Low-Dose and Interval Administration of Imatinib in a Patient with Liver Metastasis of the Gastrointestinal Stromal Tumor of the Stomach - A Case Report].

A 69-year-old woman underwent proximal gastrectomy with distal pancreatectomy and splenectomy for a gastrointestinal stromal tumor of the stomach.Adjuvant imatinib was administered for a year.Two years after resection of the tumor, liver metastasis in S8 was detected.Therefore, imatinib was re-administered at 300mg/day.After a year of re-administration, the patient suffered muscle cramps in the hands, and therefore imatinib was administered with intervals, such as 4 weeks administration and 4 weeks rest.Re -administration of imatinib was effective and her liver metastasis decreased in size.It was not detected with CT after 1 year and 4 months and remained in complete response(CR)for 3 years and 8 months.After she suffered a brain infarction, imatinib administration was stopped for 4 months.Consequently, the liver metastasis was detectable in S8 again.This clinical course suggested that low-dose and interval administration of imatinib is effective in the treat- ment of GIST.

[Gastrointestinal stromal tumors: surgical treatment and targeted therapy]. / Gastrointestinal'nye stromal'nye opukholi: khirurgicheskoe lechenie i targetnaia terapiia.

AIM: To improve surgical and complex treatment of patients with gastrointestinal stromal tumors (GIST). MATERIAL AND METHODS: Our analysis included 97 GIST patients who were at Petrovsky Russian Research Center of Surgery and Moscow City Oncological Hospital #62 from January 2006 to September 2016. RESULTS: Advisability of surgery for GIST patients was confirmed. We have assessed surgical outcomes, defined the indications for adjuvant targeted therapy depending on GIST prognostic risk and additional factors for unfavorable course of disease. CONCLUSION: It was concluded that surgical treatment is preferred for patients with resectable GISTs. Adjuvant therapy is indicated in patients with high risk of progression if mutations indicating tumor sensitivity to the drugs are revealed. Adjuvant targeted therapy is not indicated in patients with low and very low risk of progression.

Successful treatment with personalized dosage of imatinib in elderly patients with gastrointestinal stromal tumors.

Imatinib is the standard first-line therapy for metastatic gastrointestinal stromal tumors. It has markedly improved the prognosis and outcome of patients affected by gastrointestinal stromal tumors, especially in the case of exon 11 KIT mutations. Imatinib-associated adverse events are generally mild to moderate; however, in clinical practice, intolerance caused by chronic toxicities frequently leads to breaks in treatment. This is particularly true in elderly patients in whom age, decline in drug metabolism, and polypharmacy, with a possible drug-drug interaction, may influence the tolerability of imatinib. In the present article, we report our extensive experience with the management of imatinib therapy in a 'real' population, in particular in very elderly patients, discussing whether the use of personalized imatinib dosage could be a safe and advantageous option, enabling continuous administration, thus ensuring effective treatment. Only a few case reports in the literature provide data on outcome with low tailored dosage of imatinib and none of them has been carried out on a Western population. Here, we report four cases treated with low imatinib dosage as a safe and useful option enabling continued treatment with imatinib, improving tolerance, and maintaining good and lasting disease control.

Extraintestinal gastrointestinal stromal tumor of undetermined origin: Is the mass resection a wrong approach? A case report and review of the literature.

Gastrointestinal stromal tumor (GIST) was first defined by Mazur et al. in 1983. GIST is evaluated among tumoral lesions that can be acquired or congenital. Those not associated with gastrointestinal system are termed as extragastrointestinal stromal tumor (EGIST). EGISTs can develop on intraperitoneal spaces as omentum, mesenterium and gallbladder and they can occur on retroperitoneum, extraperitoneal (prostate) and intrapelvic organs. Herein, we present a case with EGIST in a 65-year-old male patient located in intrapelvic and retroprostatic area which had no connection with gastrointestinal system as assessed by radiological methods and we discuss its treatment. We reviewed the literature and observed that ours is the first case report on a patient in which the mass was only extirpated rather than performing radical surgery. He is still at the 2. year of his follow-up period without any disease recurrence.

Giant Esophageal GIST: Diagnostic and Therapeutic Challenge - Case Report.

GIST are rare mesenchymal tumors of the digestive tract (less than 1% of the digestive tract neoplasia). Of these, less than 1% are found in the esophagus. Surgery is the main treatment of GIST and is supported by targeted therapy with tyrosine kinase inhibitors like imatinibmesylate. We present the case of a female patient of 51 years, admitted in our clinic for a bulky tumor in the posterior mediastinum, diagnosed after investigations performed for fatigue for the great efforts. Clinical examination was unspecific. Chest X-ray and thoraco-abdominal CT identified a widening of the mediastinum through a posterior mediastinal tumor mass, determining a deviation to the left of the thoracic esophagus without causing not abledysphagia or respiratory symptoms. It was decided surgery by thoracotomy in V right intercostal space and total excision of the tumor was performed. Histopathology examination confirmed the preoperative suspicion of esophageal GIST. Prognosis is reserved, the risk of relapse is very high given the fact that the tumor was extracted fragmented. Currently the patient is under treatment with imatinib mesylate and entered into clinical and imaging follow-up program, according to clinical guidelines.

Laparoscopic sphincter-preserving surgery (intersphincteric resection) after neoadjuvant imatinib treatment for gastrointestinal stromal tumor (GIST) of the rectum.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) of the rectum are rarely found, and radical surgery such as abdominoperineal resection would be necessary for large rectal GIST. On the other hand, therapy for GIST has changed significantly with the use of imatinib. Neoadjuvant imatinib therapy may reduce tumor size and may potentially prevent extended surgery. Moreover, when sphincter-preserving surgery is carried out laparoscopically, it can be performed as minimally invasive surgery with preservation of the anus. METHODS: From 2008 to 2011, five patients with rectal GIST were treated in our hospital. All patients received preoperative imatinib treatment (400 mg/day) and underwent laparoscopic sphincter-preserving surgery after 4-12 months of this treatment. RESULTS: Initial median tumor size was 31 mm (range, 24-88). At the time of operation, the median tumor size was 24 mm (range, 11-52). Sphincter-preserving surgery was performed in all patients. Three patients underwent laparoscopic intersphincteric resection (ISR), and two patients underwent transanal full-thickness local resection and recto-anal anastomosis following laparoscopic ISR. Macroscopically complete resection was achieved, and microscopically, the resection margin was not involved of residual tumors. The median duration of postoperative hospital stay was 16 days (range, 13-30). No recurrence occurred in all patients during 1 to 4 years. CONCLUSIONS: The present study suggests that neoadjuvant imatinib therapy might be effective to prevent extended surgery for rectal GIST, and laparoscopic sphincter-preserving surgery is safe and technically feasible. We recommend a combination of neoadjuvant imatinib therapy and laparoscopic ISR for locally advanced rectal GIST.

Pleural effusion in a patient with metastatic gastrointestinal stromal tumor treated with imatinib: case report.

Gastrointestinal stromal tumors are rare malignancies characterized by c-kit and PDGFR-α mutations targeted by imatinib. Pleural effusion is a very rare side effect of imatinib treatment. A 65-year-old female with metastatic gastrointestinal stromal tumor developed electrolyte imbalance, severe peripheral edema and progressively worsening dyspnea 2 months after starting imatinib. Having excluded cardiovascular and pulmonary disorders, imatinib was discontinued and prednisone 25 mg orally daily was begun. The patient's condition improved substantially over the next 48 h with a progressive decrease in dyspnea and a reduction in pleural effusion and peripheral edema. All side effects had resolved within 1 month. In view of the partial response obtained, the patient re-started imatinib after a 1-week interruption. Prednisone was maintained and there was no further toxicity.

Prevention and management of adverse events related to regorafenib.

Regorafenib is an oral multikinase inhibitor that has shown antitumor activity in a range of solid tumors. Based on data from phase III clinical trials, regorafenib is indicated for the treatment of adult patients with metastatic colorectal cancer who have previously been treated with, or are not considered candidates for, other available therapies, and in patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other appropriate treatments. A panel of oncology nurses, research coordinators, and other medical oncology experts, experienced in the care of patients treated with regorafenib, met to discuss the best practice for the management of regorafenib-associated adverse events (AEs). The panel agreed that, in clinical trials and daily practice with regorafenib, AEs are common but mostly manageable. The most common and/or important AEs associated with regorafenib were considered to be hand-foot skin reaction, rash or desquamation, stomatitis, diarrhea, hypertension, liver abnormalities, and fatigue. This manuscript describes the experience and recommendations of the panel for managing these AEs in everyday clinical practice. Appropriate education, monitoring, and management are considered essential for reducing the incidence, duration, and severity of regorafenib-associated AEs.

Soft tissue calcification secondary to imatinib mesylate in a patient with gastrointestinal stromal tumor.

Imatinib mesylate has been associated with the changes in bone turnover. We report a case of the development of tissue calcification in a patient on long-term therapy with this drug. A 48-year-old male patient with gastrointestinal stromal tumor and liver metastasis complained of abdominal pain. His treatment included hepatic artery chemoembolization and partial hepatectomy in addition to chronic imatinib mesylate for 4 years. On physical examination, he had a peritoneal mass just beneath the laparotomy incision scar that, after resection, was found to be dystrophic bone formation. Based on the previous studies suggesting bone changes due to chronic therapy with imatinib mesylate, we believe that the patient's new bone formation was causally related to the use of this drug. To our knowledge, there are no similar reported cases in the literature.

Laparoscopic resection of a gastrointestinal stromal tumor of the lower rectum in a patient with coronary artery disease following long-term neoadjuvant imatinib treatment and anticoagulation therapy.

Surgery is the mainstay of treatment for gastrointestinal stromal tumors (GISTs). However, complete resection of rectal GISTs is sometimes difficult because of bulkiness and/or anatomical reasons. Neoadjuvant imatinib therapy has gained attention as an alternative treatment to increase the chance of en bloc resection of rectal GISTs, although it usually takes several months. In this case report, we first demonstrated that neoadjuvant imatinib therapy can be performed safely not only to downsize tumors, but also to allow adequate time for the effective treatment of major comorbid illnesses. A 74-year-old man was diagnosed with a 45 mm GIST of the lower rectum. He also had severe stenosis in the proximal segment of the left anterior descending coronary artery. Following the implantation of a drug-eluting stent, the patient received imatinib together with dual anti-platelet therapy for 12 months without obvious side effects. Follow-up image studies revealed tumor shrinkage as well as stent patency. En bloc resection of the GIST was performed laparoscopically, which preserved the anus. The patient is currently alive without any evidence of relapse for 12 months after surgery.

[A case of rectal gastrointestinal stromal tumor in an elderly patient who was successfully treated with imatinib mesylate with no significant adverse events].

An 89-year-old male patient was found to have a mass with a diameter of 54 mm in the pelvic cavity, connected to the rectum, and was diagnosed with a gastrointestinal stromal tumor (GIST)of the rectum by transrectal biopsy. The patient was treated continuously with 400mg/day of imatinib mesylate with no significant adverse events, and the tumor gradually reduced in size. The tumor reduced in size to a diameter of 24 mm at 57 months post-treatment, and a partial response has been maintained for 60 months. Colorectal GIST is rare, comprising 5% of all GIST cases, and surgical resection is the first choice of treatment. In this case, due to a lack of consent, we chose imatinib mesylate as the treatment. However, imatinib mesylate has been reported to induce adverse events more frequently in older patients, and thus we took care to reduce the treatment dosage. We report this case to highlight that a normal quantity of imatinib mesylate can be administered, with no significant adverse events.

[Clinical experience of imatinib mesylate for metastatic or recurrent gastrointestinal stromal tumor].

We examined the clinical results of 15 patients treated with imatinib mesylate for metastatic or recurrent gastrointestinal stromal tumors(GIST)at the Osaka City General Hospital. Treatment with imatinib was initiated at 400 mg daily; however, in case of severe adverse events, the dose was gradually reduced to 300 mg or 200 mg to reach a tolerable dose so that administration could be continued for as long as possible. Assessments were performed according to the Response Evaluation Criteria in Solid Tumors(RECIST)and Choi criteria. According to the assessment by the RECIST criteria, clinical response(CR)was observed in 1 patient; partial response(PR), in 5 patients; stable disease(SD), in 6 patients; and progressive disease(PD), in 3 patients; the response rate was 40%. However, as per the Choi criteria, CR was observed in 1 patient; PR, in 11 patients; SD, in 1 patient; and PD, in 2 patients; the response rate was 80%. The median period of progression-free survival was 2,031 days and the 5-year survival rate was 80.0%. Grade 3 or higher adverse reactions observed included leukopenia(1 case), neutropenia( 2 cases), and anemia(1 case). In 6 patients(40%), the dose of imatinib was reduced to 300 mg or less; however, no significant difference in progression-free survival was observed between the 200/300mg group and 400/800mg group. Choi criteria are useful in assessing the response of advanced GIST to imatinib mesylate, and reducing the dose of imatinib mesylate to 200/300mg daily might be sufficient for treating patients who experience severe adverse reactions.

[Long-term survival in a case of recurrent gastrointestinal stromal tumor treated with intermittent or low-dose imatinib].

A 65-year-old woman with a gastrointestinal stromal tumor(GIST)underwent a total gastrectomy in 1999. In 2004, she was diagnosed with an intra-abdominal recurrence and was treated with 300mg/day of imatinib. Because of the side effects of imatinib, we interrupted the treatment and were forced to reduce the dose from 300mg/day to 100mg/day. However, at present, the tumor remains controlled. In conclusion, this case suggested that, even if given irregularly or at a low-dose, continuous treatment with imatinib might contribute to long-term survival in patients with GIST.

Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors.

BACKGROUND: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. PATIENTS AND METHODS: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped>14 days before starting BIIB021. RESULTS: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 µmol and the mean AUC was 2.9 µmol h. Cmax>1.5 µmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. CONCLUSIONS: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.

Sunitinib as first-line neoadjuvant therapy in two patients with rectal stromal tumors.

In the treatment of rectal stromal tumors, which account for approximately 5% of gastrointestinal stromal tumors, molecular-targeted neoadjuvant therapy should be considered if the tumor is too large to achieve R0 grade resection or multiple visceral resection is required. Currently, imatinib is generally recommended as the first-line agent for such therapy. Although it has been reported that neoadjuvant therapy in patients experiencing imatinib resistance or intolerable adverse events can be successfully achieved by switching to sunitinib, first-line use of sunitinib for neoadjuvant therapy of gastrointestinal stromal tumors has not previously been reported. In this case report, first-line sunitinib neoadjuvant therapy of two patients who had very large rectal stromal tumors at sites close to the prostate and bladder produced good clinical outcomes.

[A case of multiple liver metastases after resection of gastrointestinal stromal tumor of the small intestine that was successfully treated with imatinib mesylate].

A 73-year-old man was found to have an intestinal tumor, approximately 10 cm in diameter, on computed tomography (CT). In September 2001, he underwent partial resection of the jejunum with partial colectomy and left nephrectomy. Pathological examination showed 2 mitoses per 50 high-power fields, and immunohistochemical analysis showed positive staining for c-kit. Based on the above findings, the tumor was diagnosed as a high-risk malignant gastrointestinal stromal tumor( GIST) of the small intestine; the patient was followed up and no adjuvant therapy was administered. In October 2005, an abdominal CT scan revealed 2 tumors with diameters of 21 and 28 mm in the S8 and S7 region of the liver, respectively, and the patient was diagnosed with liver metastases from GIST. After obtaining adequate informed consent, chemotherapy with imatinib (400 mg/day) was initiated. Although the patient experienced partial response (PR) 2 months after the treatment, grade 3 neutropenia and general fatigue were observed. Therefore, the treatment schedule was changed to 1 week of therapy, followed by 1 week of rest. At present, at 91 months after the diagnosis of liver metastases, the patient shows no signs of recurrence. Therefore, it is important that adjuvant chemotherapy should be considered for the treatment of patients with high-risk malignant GIST.