Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up
- Study type
- Clinical guideline
- Study name
- ESMO GIST 2022
- Design
- ESMO clinical practice guideline developed with EURACAN and GENTURIS at a virtual expert consensus meeting (5 December 2020); levels of evidence I to V, grades of recommendation A to E, ESMO-MCBS and ESCAT scores
- Source
- Ann Oncol · 2022
In plain words
This guideline is the European experts' summary on GIST: testing the tumour's genes in every patient, complete surgery for GIST that has not spread, 3 years of imatinib after surgery in high-risk patients, imatinib every day and without stopping for GIST that has spread, and the next drugs (sunitinib, regorafenib and ripretinib) if imatinib stops working. With certain gene changes, another drug such as avapritinib is needed.
Key points
Key guideline recommendations
- IV, C
Endoscopic ultrasound is the standard approach for oesophagogastric or duodenal nodules under 2 cm; if a biopsy confirms GIST, resection is performed unless major morbidity is expected, and if a biopsy is not feasible, active surveillance is a valid alternative.
- IV, C
Biopsy or excision is the standard approach to tumours of 2 cm or more.
- II, A
Mutational analysis should be considered standard practice in the diagnostic work-up of all GISTs (possibly excluding non-rectal GISTs under 2 cm).
- III, A
The standard treatment of localised GIST is complete surgical excision without dissection of clinically negative lymph nodes; R0 excision is the goal. Laparoscopic excision must follow the principles of oncological surgery [III, A].
- IV, B
In low-risk GISTs in unfavourable locations, possibly R1 margins can be accepted after a shared decision with the patient.
- I, A
Adjuvant imatinib 400 mg daily for 3 years is the standard treatment for patients with a significant risk of relapse (ESMO-MCBS: A).
- II, B
With a KIT exon 9 mutation, adjuvant imatinib at the higher dose of 800 mg daily for 3 years may be considered (ESCAT: I-A).
- IV, D
PDGFRA exon 18 D842V-mutated GIST should not receive adjuvant therapy; adjuvant treatment should also be avoided in NF1-related and SDH-negative GIST.
- IV, A
Patients at very high risk of relapse because of tumour rupture at surgery should be considered for adjuvant imatinib.
- III, A
If R0 surgery is not feasible or implies major sequelae and the tumour has a sensitive mutation, preoperative imatinib is standard; with a PDGFRA D842V mutation, neoadjuvant avapritinib may be considered.
- I, A
Imatinib is the standard first-line treatment for locally advanced, inoperable and metastatic disease, except for GIST without KIT/PDGFRA mutations or with a PDGFRA exon 18 D842V mutation; the standard dose is 400 mg daily.
- III, B
The standard first-line treatment with a KIT exon 9 mutation is imatinib 800 mg daily (ESCAT: I-A).
- III, A
The standard first-line treatment with a PDGFRA exon 18 D842V mutation is avapritinib 300 mg daily (ESMO-MCBS: 3; ESCAT: I-B).
- I, A
In the metastatic setting, treatment should be continued indefinitely, unless there is intolerance or a specific patient request to stop; surgery of residual metastatic disease should be individualised [III, C].
- III, B
On progression with imatinib 400 mg, the dose can be increased to 800 mg daily (except for insensitive mutations).
- I, A
In confirmed progression or rare intolerance of imatinib, the standard second-line treatment is sunitinib 50 mg daily on a 4 weeks on, 2 weeks off schedule or, as an alternative schedule, 37.5 mg once daily (ESMO-MCBS: 3).
- I, A
Regorafenib 160 mg daily for 3 out of every 4 weeks is the standard third-line treatment, and ripretinib 150 mg daily is the standard fourth-line treatment (ESMO-MCBS: 3).
- III, B
SDH-deficient GISTs are insensitive to imatinib and may have some sensitivity to sunitinib and regorafenib [III, B]; NTRK-rearranged GISTs are sensitive to NTRK inhibitors [III, A], and BRAF-mutated GISTs benefit from BRAF inhibitors [V, B].
- II, B
Rechallenge with imatinib or continuation of treatment beyond progression is an option.
Study population
Patients with gastrointestinal stromal tumour (GIST) at all stages: small nodules, localised resectable disease, locally advanced and metastatic disease, including GISTs without KIT/PDGFRA mutations (SDH-deficient, NF1, BRAF, NTRK) and paediatric GIST.
Endpoints
This is a guideline with no predefined endpoints; recommendations carry a level of evidence, a grade of recommendation, an ESMO-MCBS score and, for genomic alterations, an ESCAT score.
Safety and side effects
Important adverse events of avapritinib are neurocognitive toxicity, brain bleeds and seizures, which need to be recognised early. Imatinib dose intensity should be maintained by proper management of side effects, with dose reductions and interruptions for severe, persistent toxicity; patients should know about drug and food interactions. TKI combinations outside clinical studies are discouraged because of considerable toxicity.
Clinical significance and place in guidelines
This is the main European reference for GIST and made KIT/PDGFRA mutational analysis a standard part of diagnosis. Treatment sequence in advanced disease: imatinib 400 mg (800 mg with KIT exon 9), avapritinib 300 mg in PDGFRA D842V, then sunitinib, regorafenib and ripretinib; adjuvant imatinib for 3 years when the risk of relapse is significant, and no adjuvant therapy in insensitive genotypes.
Limitations
The evidence behind some recommendations (such as adjuvant 800 mg in exon 9, the treatment of SDH-deficient GIST or surgery for metastatic disease) is non-randomised or limited. The optimal follow-up schedule is not known and the proposed schedules reflect institutional practice. The guideline was developed in December 2020.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.