Gastrointestinal Stromal Tumors Clinical Practice Guidelines (ESMO/EURACAN/GENTURIS, 2021)

European Society for Medical Oncology, European Reference Network for Rare Adult Solid Cancers, and European Reference Network for Genetic Tumour Risk Syndromes

These are some of the highlights of the guidelines without analysis or commentary. For more information, go directly to the guidelines by clicking the link in the reference.

December 03, 2021

Guidelines for the diagnosis, treatment, and follow-up of gastrointestinal stromal tumors (GISTs) were published in September 2021 by the European Society for Medical Oncology (ESMO), European Reference Network for Rare Adult Solid Cancers (EURACAN), and European Reference Network for Genetic Tumour Risk Syndromes (GENTURIS) in Annals of Oncology.[1] Select recommendations are outlined below.

Diagnosis and Pathology/Molecular Biology

Endoscopic ultrasound (EUS) is the standard approach for evaluating patients with esophagogastric or duodenal nodules smaller than 2 cm.

In the setting of a biopsy diagnosis of GIST, perform resection unless a major morbidity is expected. If a biopsy is not achievable, active surveillance is a valid option.

For tumors at least 2 cm in size, biopsy/excision is the standard approach.

Except for nonrectal GISTs smaller than 2 cm, including mutational analysis in the diagnostic work-up of all GISTs should be considered standard practice.

Management of Local/Locoregional Disease

Complete surgical excision of localized GISTs, without dissection of clinically negative lymph nodes, is standard treatment, with the goal of R0 excision (ie, an excision whose margins are clear of tumor cells at least at the site of origin in the GI tract).

If laparoscopic excision is planned, the technique needs to follow the principles of oncological surgery.

For low-risk GISTs in unfavorable sites, joint decision making with the patient may make possibly R1 (microscopically positive) margins acceptable.

For patients with a significant relapse risk, standard treatment is adjuvant therapy with imatinib 400 mg/day for 3 years. In the setting of KIT exon 9 mutation, adjuvant imatinib at a higher dose of 800 mg daily for 3 years may be considered.

Adjuvant therapy is not recommended for PDGFRA exon 18 D842V-mutated GISTs. In addition, avoid adjuvant treatment in type 1 neurofibromatosis (NF1)-related and succinate dehydrogenase (SDH) expression-negative GISTs.

Consider adjuvant imatinib therapy for those at a very high risk of relapse due to tumor rupture at the time of surgery.

If R0 surgery is not feasible or implies major sequelae and the tumor harbors a sensitive mutation, preoperative treatment with imatinib is standard. In the setting of PDGFRA-D842V mutation, neoadjuvant avapritinib may be considered.

Management of Advanced/Metastatic Disease

Imatinib is the standard first-line treatment for those with locally advanced, inoperable, and metastatic lesions, except for GIST without KIT/PDGFRA mutations or with a PDGFRA exon 18 D842V mutation. The standard dose is 400 mg daily.

Imatinib is the standard treatment for those with metastatic disease who have had all lesions surgically excised and the tumor bears a sensitive genotype. However, surgery is not recommended as a primary approach in the metastatic setting.

Standard first-line treatment for patients with KIT exon 9 mutation is imatinib 800 mg daily. For patients with PDGFRA exon 18 D842V mutations, it is avapritinib 300 mg daily.

In the metastatic setting, continue treatment indefinitely, unless intolerance is present or there is a specific patient request to interrupt. Individualize surgery of residual metastatic disease.

Consider surgical excision of progressing disease for cases with limited progression, while continuing imatinib.

In the setting of tumor progression on 400 mg of imatinib, the dose can be increased to 800 mg daily (except for insensitive mutations). With confirmation of progression or the presence of rare intolerance on imatinib, standard second-line therapy is sunitinib 50 mg daily 4 weeks on/2 weeks off; an alternative schedule is 37.5 mg once daily.

Regorafenib 160 mg daily for 3 of every 4 weeks is the standard third-line therapy for those whose condition is progressing on or refractory to imatinib and sunitinib.

Ripretinib 150 mg daily is the standard fourth-line treatment in patients whose condition is progressing on or intolerant to imatinib, sunitinib, and regorafenib.

SDH-deficient GISTs are insensitive to imatinib and can have some sensitivity to sunitinib and regorafenib.

NTRK-rearranged GISTs are sensitive to therapy with NTRK inhibitors (eg, larotrectinib, entrectinib). BRAF-mutated GISTs benefit from BRAF inhibitors (including BRAF–MEK inhibitor combinations).

Rechallenge with imatinib (to which the patient has already been exposed with evidence of response) or treatment continuation beyond progression is an option.

In select patients, radiotherapy may be considered as a palliative resource.

Follow-up

No published data exists to indicate what the optimal routine follow-up policy is for surgically treated patients with localized disease.

The liver and/or peritoneum are often the sites of relapses. The speed at which relapses occur is likely affected by the mitotic rate. Relapses in high-risk patients tend to occur within 1-3 years from the completion of adjuvant therapy; relapses in low-risk patients may occur later.

It is likely that very low-risk GISTs do not need routine follow-up, but the risk is not zero. Consider factors such as x-ray exposure, particularly in the setting of low-risk GIST; an option is abdominal magnetic resonance imaging.

For more information, please go to Gastrointestinal Stromal Tumors (GISTs), Gastrointestinal Stromal Tumors (Leiomyoma/Leiomyosarcoma) Imaging, Gastrointestinal Stromal Tumors (GISTs) Staging, and Gastrointestinal Stromal Tumors Treatment Protocols.

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