Escalation of radiotherapy dose in large locally advanced drug-resistant gastrointestinal stromal tumors by multi-shell simultaneous integrated boost intensity-modulated technique: a feasibility study.

BACKGROUND: Resistance to conventional dose schemes and radiotoxicity of healthy tissue is a clinical challenge in the radiation therapy of large locally advanced drug-resistant gastrointestinal stromal tumor (LADR-GIST). This study aimed to assess the feasibility of using multi-shell Simultaneous Integrated Boost Intensity-Modulated modality (SIB-IMRT) strategy to provide a safe and effective escalation dose regimen for LADR-GIST. METHODS: 7 patients with LADR-GIST were selected in this study. The modified SIB-IMRT plans for all patients were generated by delivering different escalation-dose gradients to four ring shaped regions (shells) within the gross tumor volume (GTV). The doses of the central volume of the tumor (GTVcenter) were escalated up to 70-92.5 Gy (25 fractions), while the doses of planning target volume (PTV) and shell-1 were kept at 50.0 Gy. Based on different escalation-dose gradients, the modified SIB-IMRT plans were divided into four groups (SIB-IMRT groups). For comparison purposes, plans obtained by conventional IMRT technique (Con-IMRT) with 50 Gy (25 fractions) were also generated for all patients (Con-IMRT group). All plans were normalized to cover 95% of the PTV with the prescribed dose of 50.0 Gy. The equivalent uniform dose (EUD), relative equivalent uniform dose (rEUD), dose volume histogram (DVH), dose profile, conformity index (CI) and monitor unit (MU) were evaluated in five groups. The Friedman Test was performed to determine whether there were significant differences (P < 0.05). RESULTS: Compared with the Con-IMRT group, the EUD of GTV (EUDGTV) and rEUD of SIB-IMRT groups were improved when escalation-dose gradient was increased, and the improvement became significant when the escalation-dose gradient reached 20% of the prescription dose. The rEUD tended to be stable as the escalation-dose gradient went up to 25% of the prescription dose. There were no significant differences in CIs and DVH metrics for OARs between the Con-IMRT group and any SIB-IMRT group, but the significant differences were observed between the SIB10-IMRT group and the SIB25-IMRT group. For the SIB-IMRT groups, as the dose gradient became steeper in the dose profiles, the higher dose was mainly accumulated in the inner part of GTV accompanied with a higher MU. CONCLUSIONS: The proposed multi-shell SIB-IMRT strategy is feasible in dosimetry for LADR-GIST and can acquire higher therapeutic gain without sacrifice of healthy tissues. It appears that the scheme of delivering 20% of the prescribed escalation-dose gradient to the target volume can provide satisfactory dose irradiation for LADR-GIST, and it should be evaluated in future clinical study.

Gastrointestinal stromal tumor with intracranial metastasis: case presentation and systematic review of literature.

BACKGROUND: Intracranial metastasis of Gastrointestinal Stromal Tumors (GISTs) is rare but presents unique treatment challenges. We present a case of intracranial metastasis of GIST with a systematic review of the literature. A literature search using key terms "'gastrointestinal stromal tumor' AND brain AND metastasis"" was conducted through May 2019 via Embase and Pubmed according to PRISMA guidelines. Only cases describing intradural metastases rather than calvarial or intraorbital metastases were included. CASE PRESENTATION: A 57-year-old woman with history of GIST metastatic to the liver presented with a six-week history of left facial weakness, left hearing loss, and left facial numbness, and a one-week history of headaches, gait disturbance, and dizziness. MRI revealed a contrast-enhancing dural-based left middle cranial fossa mass measuring 2.9 cm × 3.1 cm × 3.4 cm with extension into the internal auditory canal and cerebral edema. A left temporal craniotomy was performed to excise the lesion, and the patient was discharged to a rehabilitation facility at her preoperative baseline. Intraoperative pathology revealed a spindle cell neoplasm, postoperative MRI demonstrated gross total resection of the lesion, and microscopic analysis demonstrated sheets of spindled tumor cells with short ovoid, irregular, hyperchromatic nuclei and scattered large atypical nuclei without extensive necrosis. Immunohistochemical staining was positive for KIT proto-oncogene (CD117, c-KIT), and the patient was put on imatinib (400 mg/day). CONCLUSIONS: Of the 18 cases analyzed and our present case, metastasis typically involved the cerebrum with only one in infratentorial elements. The tumors in seven of the cases involved the dura, and one case metastasized to the pituitary. Eight patients died following treatment. Surgery remains the mainstay of intracranial metastatic GIST, however there are many reports of good responses to radiation or chemotherapy alone. More investigation is required to determine the best treatment course for these patients.

Treatment of metastatic, imatinib refractory, gastrointestinal stroma tumor with image-guided high-dose-rate interstitial brachytherapy.

PURPOSE: Evaluation of efficacy and safety of CT- or MRI-guided high-dose-rate interstitial brachytherapy (iBT) in the treatment of advanced, imatinib refractory, metastatic gastrointestinal stroma tumors (GISTs) was the objective of this retrospective study. METHODS AND MATERIALS: A cumulative number of 40 unresectable metastases (30 hepatic, 10 peritoneal) were treated with iBT in 10 selected patients with histologically proven GISTs. Six patients had peritoneal disease, and 5 patients were even progressing under sunitinib (second line)-thus iBT was applied as a salvage maneuver. IBT uses an interstitially introduced 192iridium source in a high-dose-rate irradiation regime to destroy vital cells in a single fraction. Response to treatment was assessed clinically and with acquisition of MRI/CT every 3 months. RESULTS: Local tumor control was reached in 97.5% of all treated metastases during a median time of 25 months-only one local relapse was observed during followup. The median diameter of the irradiated lesions was 2.4 cm (range 0.6-11.2 cm); a median dose of 15 Gy (range 6.7-21.96 Gy) was applied. The median progression-free survival after iBT was 6.8 (range 3.0-20.2) months; the median overall survival was 37.3 months (range 11.4-89.7). Two major complications (Common Terminology for Adverse Events grade 3) occurred following the intervention: local hemorrhage and pneumothorax, successfully dealt with by angiographic embolization and pleural drainage, respectively. CONCLUSIONS: In selected patients with metastatic, imatinib refractory GISTs, iBT safely enables high rates of local tumor control and presents an alternative, anti-neoplastic treatment option even in a salvage situation.

Radiotherapy for Gastrointestinal Stromal Tumors.

OBJECTIVE: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract, which frequently cause intraabdominal metastases. The current standard of care is surgery for localized cases, and adjuvant imatinib is recommended for tumors with a high risk of recurrence. To date, radiotherapy has not been commonly accepted as a part of multimodality treatment approach other than palliation. However, recently published case reports and some small series suggest that radiotherapy is a valuable option for controlling locally progressive, drug-resistant disease. The aim of this review is to provide a viewpoint from a radiation oncologist concerning the management of GISTs, especially rectal GIST, and clarify the role and technical aspects of radiotherapy in the treatment approach. DATA SOURCES: A comprehensive search in PubMed using the keywords "radiotherapy for rectal GIST" and "rectal GIST" was undertaken. The literature search included the related articles after 1995. STUDY SELECTION: The main articles including rectal GIST case reports and GIST series containing rectal cases were the primary references. RESULTS: Surgery is the mainstay of treatment. However, to date, radiotherapy is included in the multidisciplinary treatment strategy of rectal GISTs in some circumstances with palliative, adjuvant, or definitive intent using different treatment doses and fields. CONCLUSIONS: Recently reported long-term local control rates indicate that GIST is a radiosensitive disease. This makes radiotherapy a valuable alternative in GIST management with curative intent, especially in patients who (1) cannot tolerate or are resistant to chemotherapy agents, (2) have an unresectable disease, (3) have a gross or microscopic residual disease after surgery, and (4) have a recurrent disease.

Targeting Gastrointestinal Stromal Tumor with 68Ga-Labeled Peptides: An In Vitro Study on Gastrointestinal Stromal Tumor-Cell Lines.

The gastrointestinal stromal tumor (GIST) is a rare disease with limited therapeutic options when resistance to tyrosine kinase inhibitor (TKI) treatment occurs. The authors investigated binding of various 68Ga-labeled peptides, targeting receptors reported to be overexpressed in GIST, in different cell lines. For this purpose, three GIST cell lines were tested: GIST-T1, GIST882 (Imatinib sensitive), and GIST430 (Imatinib resistant). DOTA-NT 8-13 (targeting NTR1), DOTA-TATE (targeting SSTR2), CP04 (a minigastrin derivative targeting CCK2-R), VIP-DOTA (targeting VPAC2-R), and 2 DOTA-bombesin derivatives [targeting gastrin releasing peptide receptors (GRPR)] were radiolabeled with 68Ga and incubated with the respective tumor cell and control cell lines. Membrane-bound and internalized activity was measured. Very low or no specific binding to GIST cells was found for all 68Ga-labeled DOTA peptides except for bombesin derivatives indicating no or very low expression of respective receptors. Related to GRPR a pronounced specific binding to all GIST cell lines with no preference related to TKI resistance status was found, both for an agonist (AMBA) with high internalization and for an antagonist (NeoBOMB1) with mainly membrane-bound activity (with up to >80% bound/mg protein). GRPR expression was confirmed by immunohistochemistry. The results show that radiolabeled bombesin analogues, especially antagonists are very promising candidates for targeting GIST.

Radiotherapy for GIST progressing during or after tyrosine kinase inhibitor therapy: A prospective study.

PURPOSE: Gastrointestinal stromal tumor (GIST) has been considered radiation-resistant, and radiotherapy is recommended only for palliation of bone metastases in current treatment guidelines. No registered prospective trial has evaluated GIST responsiveness to radiotherapy. PATIENTS AND METHODS: Patients with GIST progressing at intra-abdominal sites or the liver were entered to this prospective Phase II multicenter study (identifier NCT00515931). Metastases were treated with external beam radiotherapy using either conformal 3D planning or intensity modulated radiotherapy and conventional fractionation to a cumulative planning target volume dose of approximately 40 Gy. Systemic therapy was maintained unaltered during the study. RESULTS: Of the 25 patients entered, 19 were on concomitant tyrosine kinase inhibitor therapy, most often imatinib. Two (8%) patients achieved partial remission, 20 (80%) had stable target lesion size for ⩾3 months after radiotherapy with a median duration of stabilization of 16 months, and 3 (12%) progressed. The median time to radiotherapy target lesion progression was 4-fold longer than the median time to GIST progression at any site (16 versus 4 months). Radiotherapy was generally well tolerated. CONCLUSIONS: Responses to radiotherapy were infrequent, but most patients had durable stabilization of the target lesions. GIST patients with soft tissue metastases benefit frequently from radiotherapy.

External beam radiation therapy for locally advanced and metastatic gastrointestinal stromal tumors.

BACKGROUND: The role of radiation therapy (RT) in the management of gastrointestinal stromal tumors (GIST) is not well described. Here we report our institutional experience for patients with locally advanced or metastatic GIST treated with RT. METHODS: Between 1997 and 2012, 15 patients with 22 GISTs were treated with RT at our center. The median age was 68 (range, 41-86). Fourteen patients had stage IV disease and 1 patient had stage IIIB disease, per the American Joint Committee on Cancer (AJCC), 7th Edition staging. Tumors were in a variety of locations, and were most commonly referred for palliative treatment. Eighteen of 22 tumors were symptomatic. Prior to RT, 14 of 15 patients received systemic therapy in the form of tyrosine kinase inhibitors (TKIs) (n = 11), chemotherapy (n = 4), or both (n = 1). TKIs were used concurrently for nine tumors (40.9%). No tumors were treated with concurrent chemotherapy. Several fractionation schemes were used, most commonly 3 Gy × 10 (n = 8). Local progression-free survival and overall survival were estimated using the Kaplan-Meier method. Acute toxicity was graded per Common Terminology Criteria for Adverse Events (CTCAE) v4.0. RESULTS: The median follow-up was 5.1 months (range, 1.3-28.3). At the time of analysis, 12 patients have died (80%). The estimated 6-month local progression-free survival and overall survival were 57.0% and 57.8%, respectively. Among the 18 symptomatic tumors, at least partial palliation was achieved in 17 (94.4%), and symptoms were completely palliated in eight (44.4%). Treatment was well tolerated, with no Grade 4 or 5 toxicities. There was no Grade ≥3 toxicity associated with concurrent TKI use. CONCLUSIONS: In this largest series to date of GISTs treated with RT, a high rate of palliation was achieved for symptomatic tumors in a cohort of advanced stage, heavily pretreated patients. Treatment was well tolerated, and concurrent use of tyrosine kinase inhibitor therapy was not associated with additional toxicity. While follow-up was short, durable control is possible for some patients, providing evidence that GIST is not universally radioresistant and that RT can provide an important benefit in patients with progressive or metastatic disease.

Gastrointestinal stromal tumors: evolving role of the multidisciplinary team approach in management.

Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract arising from mesenchymal cells. Treatment options include surgical resection and medical therapy with imatinib. A summary of National Comprehensive Cancer Network and European Society of Medical Oncology clinical practice guidelines relating to GIST management are presented here. A multidisciplinary team of physicians is essential to the successful treatment of GIST. Evidence supports multidisciplinary team management with a gastroenterologist, surgeon, medical oncologist, pathologist and radiologist. Consultations between them are recommended to ensure optimal care of patients with GIST. The role for individual core team workers is highlighted. The benefits of multidisciplinary disease management of patients include reducing recurrent disease, optimizing timing of surgery and organ preservation, prolonging survival for the patient and enhancing response to targeted therapies.

Estudio del anticuerpo DOG1 en el diagnóstico de tumores del estroma gastrointestinal – GIST / The role of the DOG1 antibody in the diagnosis of gastrointestinal stromal tumours – GIST

Los tumores del estroma gastrointestinal (GIST)poseen mutaciones en los genes del receptor de la tirosínquinasa (RTKs) KIT y PDGFRA. La posibilidad debloquear esta actividad ha significado una nueva esperanzaterapéutica. El diagnóstico de GIST recae en laexpresión inmunohistoquímica del c-KIT, pero un 4-15%son c-KIT negativos (aún en presencia de mutación), ysin embargo estos pacientes podrían beneficiarse deltratamiento con inhibidores tirosín quinasa (TKIs).El DOG1 es un nuevo anticuerpo cuya sensibilidady especificidad parece ser superior o igual a la del c-KIT.El objetivo de este trabajo es evaluar la sensibilidad(Se) y especificidad (Sp) de DOG1 en GIST de tipo usual(c-KIT positivos), de tipo inusual (c-KIT negativos) yfrente a otros tumores fusocelulares mesenquimales, ycomparar la validez diagnóstica del DOG1 frente al c-KIT.Estudiamos 40 GIST, 39 c-KIT positivos y un c-KITnegativo. Se realizó un panel inmunohistoquímico conlos anticuerpos: c-KIT, CD34, actina músculo liso, DOG1y S100, en los GIST como en siete tumores fusocelulares.La Se y Sp de GIST para DOG1 fue del 100 y 97,5%para c-KIT. La inmunoreactividad para DOG1 en todoslos tumores fusocelulares fue negativa. La validez diagnósticade DOG1 y C-KIT fue similar a la hora de detectarGIST y no GIST.DOG1 es un marcador específico y sensible para eldiagnóstico y diagnóstico diferencial de GISTs (es capazde detectar algunos GIST sin mutación en RTK).El DOG1 debería de formar parte del panel inmunohistoquímicopara el diagnóstico de GIST(AU)

Gatrointestinal stromal tumours (GIST) harbouroncogenic mutations in tyrosin kynases receptors(RTKs) including KIT and PDGFRA. The inhibition ofthis activity has been regarded as the primary target forthe treatment of these patients. Diagnosis of GIST relieson c-KIT inmunoreactivity; however there is a 4-15% ofGISTs that are C-KIT negative which may lead to underdiagnosisof GISTs and possible withholding of therapy.The novel gene DOG1 has been found overexpressedin GISTs and has potential as a diagnostic markerfor GISTs showing even more sensitivity (Se) and specificity(Sp) than c-KIT for the diagnosis of these tumors.In this study we compared the (Se) and (Sp) of DOG1 intypical and atypical GISTs (c-KIT positive or negative)with c-KIT and other mesenchymal neoplasms in thedifferential diagnosis of GISTsWe examined 40 GIST (39 showed inmunoreactivityfor c-KIT and one was c-KIT negative) and anotherseven fusiform tumors. An inmunohistochemical panelwas performed with c-KIT, CD34, smooth muscle actin,DOG1 and S100 antibodies on both types of neoplasms.The overall Se and Sp of DOG1 and KIT in GISTswere nearly identical: 100 and 97,5%. Negativity forDOG1 was observed in all fusiform mesenchymal neoplasms.DOG1 is highly expressed in GIST and its expressionseems quite specific for these tumours when thedifferential diagnosis includes another mesenchymalneoplasms.DOG1 should be added to the diagnostic panel evaluatingGISTs(AU)

Molecularly targeted therapy and radiotherapy in the management of localized gastrointestinal stromal tumor (GIST) of the rectum: a case report.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The main treatment for localized gastrointestinal stromal tumors is surgical resection. These tumors respond poorly to conventional cytotoxic chemotherapy agents and to radiotherapy. Imatinib mesylate, a small-molecule kinase inhibitor, has proved useful in the treatment of recurrent or metastatic GISTs and is now being tested in the adjuvant and neoadjuvant setting. The role of radiotherapy in the management of patients with GIST is currently restricted to symptomatic palliation. We present the case of a 54-year-old man affected by rectal GIST extending to the anal canal, with constipation, hematochezia, and anal pain. He received imatinib, 400 mg orally per day, for a week before and during radiation therapy. Irradiation was delivered to the gross tumor volume by 3D conformal therapy. The planned total dose was 50.4 Gy in fractions of 1.8 Gy daily. We observed a partial clinical response 3 weeks after the end of combination treatment. The patient then underwent a sphincter-saving surgical procedure. There was no perioperative morbidity and a complete pathological response was obtained. At the present time, the role of radiotherapy in the management of patients with GIST is restricted to symptomatic palliation. The introduction of molecularly targeted therapy combined with radiation therapy could improve the outcomes for patients diagnosed with GIST.

Locally advanced and metastatic sarcoma (adult type) including gastrointestinal stromal tumors.

STS belong to the most challenging diseases in oncology that demand all resources of modern clinical oncology. With the improvement of surgical techniques and radiation therapy the majority of patients with localized disease can be cured. However, for patients with locally advanced or metastatic disease chemotherapeutic treatments have not greatly changed the poor outcome of the disease. The introduction of combined chemoradiotherapy as well as isolated limb-perfusion has improved the limb-salvage rate in locally advanced disease but the impact of systemic chemotherapy on overall survival remains a subject of dispute. For patients with metastatic sarcoma long-term survival can only be achieved in a small number of patients with mostly resectable disease. The list of effective drugs for palliative treatment in general still remains short and the duration of remissions usually does not exceed several months. The lack of alternative chemotherapeutic drugs imposes a considerable challenge in daily clinical practice with many young patients exhibiting a good performance status but progressive disease after standard treatment. A variety of new drugs or drug combinations seem to exhibit considerable activity in certain histological sarcoma subtypes, which may soon broaden the armamentarium of drugs for a subset of patients. However, with the vastly improved understanding of the biology and pathology of soft tissue sarcoma an era of opportunities seems to have begun and the recent success in the treatment of gastrointestinal stromal tumors impressively shows how fast a gain in the understanding of oncogenic mechanisms may translate into a highly efficient, clinically useful treatment.

Perisacral gastrointestinal stromal tumor with intracranial metastasis. Case report.

A 68-year-old woman presented with an extremely rare intracranial metastasis from a gastrointestinal stromal tumor (GIST) manifesting as left hemiparesis 2 years after resection of a sacral tumor adjacent to the coccygeal bone. Magnetic resonance imaging revealed an intracranial tumor in the right parietal lobe. Craniotomy was performed to completely remove the tumor. Although the tumor was located extra-axially, only internal carotid angiography showed mass staining. Seven months after surgery, the tumor recurred. Repeat craniotomy was performed to remove the recurrent tumor. Immunohistochemical analysis showed that the tumor cells were positive for c-kit and CD34, and the tumors were identified as intracranial metastasis of GIST. Following the second intracranial surgery, the patient developed severe lower back pain caused by metastatic tumor invading the lumbar spine and ureter. To avoid surgical complications and to reduce tumor volume, imatinib mesylate (Gleevec) was administered. The severe pain was relieved, although the tumor was not reduced. In this case, the extra-axial tumor was fed only by the internal carotid artery.