GIST Treatment
A multidisciplinary treatment (MDT) model is recommended. The MDT team should include pathologists, radiologists, surgeons, medical oncologists, and gastroenterologists and nuclear medicine physicians. It is recommended to consult relevant specialists at sarcoma and GIST treatment centers or through telemedicine network. The MDT model in China is just in its infancy, and it is unrealistic in China nowadays if it is stipulated by law that all malignant tumor patients should be treated by MDT model, as in the UK. However, for rare diseases like GIST, it is necessary to adopt MDT model in large oncology centers and regions, especially for metastatic recurrence or drug-resistant cases.
Limited GIST
Surgical resection is the standard treatment for limited GIST. It is emphasized that laparoscopic surgery should be in accordance with oncologic principles: laparoscopic surgery for larger GIST is discouraged because of the risk of tumor rupture and because tumor rupture is an extremely high risk factor for tumor recurrence. the NCCN guidelines, on the other hand, recommend that laparoscopic surgery may be considered for GIST in certain special anatomical sites (gastric greater curvature, gastric antrum, jejunum) based on the emphasis on oncologic principles, as appropriate.
The Chinese expert consensus does not routinely recommend laparoscopic surgery, but recommends that it be performed in an experienced center, with a strong recommendation to use a “retrieval pouch” during surgery, with special attention to avoid tumor rupture. Since there is no clear evidence that R1 surgery affects the overall survival of patients, if R0 surgery is expected to seriously affect the organ function of the patient and preoperative targeted therapy is not performed, R1 surgery (specifically, residual tumor cells at the margin of the specimen) is also an option based on adequate communication with the patient, especially for GIST with low risk of recurrence, with a level of evidence of IV-B.
The ESMO guidelines suggest that reoperation is an option for cases after R1 surgery. However, the NCCN does not consider reoperation to be appropriate in these cases. Although the Chinese expert consensus caters to the ESMO recommendations, its operability in clinical practice is limited. An earlier publication by the author (without postoperative adjuvant imatinib) showed a poor prognosis for R1 patients, but there is no data showing a poor prognosis for R1 patients with standardized postoperative adjuvant targeting agents.
For patients with high risk of recurrence GIST, postoperative adjuvant oral imatinib for 3 years is the standard of care with a level of evidence of I-A. Despite this, there is no evidence to date on whether the drug can be stopped after 3 years. A careful analysis of the SSGXVIII study, which is the highest level of clinical evidence, shows that the survival curves of patients in both the 1-year adjuvant and 3-year adjuvant treatment groups showed a precipitous drop around 10 months after discontinuation, which is sufficient to suggest that 3 years of adjuvant therapy is not sufficient for at least some of these patients. Therefore, the author suggests that patients should be adequately communicated with according to their specific situation, especially in some extremely high-risk cases, such as tumor rupture, non-gastric and those occurring in the colorectum, where it is unwise to stop the drug after 3 years.
The ESMO guidelines specifically emphasize patients with intraoperative tumor rupture, which should be considered a very high risk case. The Chinese expert consensus specifically emphasizes that prolonged adjuvant therapy should be considered for patients who have had tumor rupture, and there is no further evidence on the optimal duration of adjuvant therapy for such patients.
One of the shortcomings of the ESMO guidelines is that they do not address the management of side effects of targeted drugs. In contrast, the NCCN guidelines describe in considerable detail the management of imatinib, sunitinib, and regorafenib drug doses and side effects. For example, whether during postoperative adjuvant, or preoperative imatinib treatment, if a serious life-threatening side effect occurs and best supportive care is not well managed, more sunitinib may be considered. In my clinical practice in recent years, I have experienced several consecutive cases of interstitial pneumonia and generalized exfoliative skin dermatitis during postoperative adjuvant imatinib therapy, requiring not only immediate drug interruption but also hormonal therapy for more than 1 year. Therefore, readers are reminded that they should pay attention to such rare side effects.
Genetic testing is critical in determining postoperative adjuvant therapy; for example, patients with GIST with PDGFA D842V mutations are not candidates for any adjuvant therapy. the NCCN guidelines specifically note that dasatinib has been shown to be effective in patients with PDGFA D842V mutations who are highly resistant to imatinib, and therefore may be an option for this group of patients. For patients with GIST with exon 9 mutations, the initial dose of adjuvant therapy is 800 mg/day. Due to physical differences, the Chinese expert consensus recommends an initial dose of 600 mg (same below). Since GIST associated with type I neurofibromatosis is insensitive to imatinib, patients should not receive adjuvant therapy. The suitability of wild-type SDH-negative GIST for adjuvant therapy is inconclusive. In recent years, due to the promotion and popularity of genetic testing technology, Chinese expert consensus likewise recommends genetic testing before the initiation of adjuvant therapy to determine adjuvant treatment options according to different mutation types.
In cases where R0 surgery is not expected to be achieved, or where surgery may severely affect organ function, preoperative oral imatinib is the standard of care, with an evidence level of IV-A. The three major guidelines are in complete agreement on this point, with the Chinese expert consensus listing five conditions for which preoperative therapy is appropriate in more detail. Due to the limited data in the literature on preoperative treatment, both ESMO and NCCN recommend 6-12 months for preoperative treatment based on the findings of the BFR14 clinical trial.
The Chinese expert consensus recommends performing surgery at around 6 months. However, in clinical practice, the decision should be made on a patient-by-patient basis, and there are few cases treated by the author in which preoperative treatment exceeds one year. It is strongly recommended to do genetic testing before the start of preoperative treatment to exclude insensitive or resistant mutation types, and the initial dose should be adjusted to 800 mg for cases with exon 9 mutation. patients undergoing preoperative treatment should be evaluated promptly for efficacy, with special attention to timely screening of those who are ineffective to targeted therapy to avoid delaying the timing of surgery, and functional imaging can promptly assess tumor response to treatment within weeks. Functional imaging can assess the tumor response to treatment within weeks.
The ESMO guidelines suggest that it is safe to stop the drug for a few days or even one day. The NCCN guidelines specifically state that surgery is safe immediately after Imatinib is stopped, and that oral Imatinib can be resumed immediately after surgery, but other TKIs, such as Sunitinib or Regorafenib, need to be stopped for 1 week before surgery. The timing of reintroduction needs to be based on the patient’s recovery or clinical judgment. The Chinese expert consensus recommends stopping the drug for one week to reduce the side effects of tissue edema caused by the drug on the surgery. The author has experienced cases of patients taking sunitinib who were operated after 1 week of drug discontinuation and still experienced multiple enterocutaneous fistulas and wound-delayed prognosis. Therefore, it is recommended that patients who are taking oral sunitinib must allow sufficient preoperative discontinuation time to ensure surgical safety.
Metastatic GIST
For patients with inoperable and metastatic GIST due to local progression, oral imatinib is the standard of care even if the patient has received previous adjuvant treatment with imatinib and no recurrence of metastasis has occurred during the dosing period, the standard dose is 400 mg, evidence level I-A. For exon 9 mutations, the initial dose should be 800 mg. Once treatment is started, it is important not to interrupt or reduce the dose.
Interruption of treatment may result in rapid tumor growth, and physicians should promptly inform patients of the importance of treatment compliance, be aware of the interaction of other concomitant medications and food with imatinib, and promptly manage side effects. Retrospective data show that cases in which plasma drug concentrations are not achieved have a poor prognosis. Blood concentration monitoring is recommended in patients taking divided doses in the following three situations: 1) patients on other concomitant medications that may affect imatinib blood concentrations or patients who have undergone prior surgery; 2) unintended severe toxicity; and 3) 400 mg progression that forces a dose increase to 800 mg.
Because of the potential for secondary drug resistance, efficacy should be closely monitored during the initial period of targeted therapy. In patients who respond well to treatment, complete resection of residual metastatic lesions may provide a survival benefit. Due to the lack of sufficient evidence, the timing of surgical intervention and case selection need to be individualized based on adequate communication with the patient. Limited evidence suggests that surgical intervention may be one of the options for selected cases of limited progression on continuous imatinib therapy, for which the level of evidence is only V-C.
Once tumor progression or imatinib intolerance has been established, the standard second-line treatment is sunitinib with a level of evidence of I-B. A 4-week dosing and 2-week rest regimen is generally used. Although randomized controlled studies are lacking, the data suggest that 37.5 mg/day, taken continuously by mouth, may be more effective and better tolerated by patients. The latter may therefore be an alternative. Prospective placebo-controlled randomized studies have confirmed that regorafenib 160 mg/day taken continuously for 3 weeks with a one-week break significantly prolongs the time free of disease progression in patients progressing on sunitinib treatment.
Because regorafenib has become clinically available in Europe, this regimen is recommended as the standard third-line treatment option for cases of imatinib and sunitinib resistance or disease progression with a level of evidence of I-B. NCCN guidelines similarly recommend regorafenib as an indication for disease progression after imatinib and sunitinib. However, regorafenib has not been available in mainland China to date.
Studies from Korea have shown that patients with disease progression after imatinib and sunitinib can still benefit from reintroduction of oral imatinib, a treatment model referred to as the GSG (imatinib-sunitinib-imatinib) model. The NCCN guidelines recommend sorafenib, nilotinib and dasatinib as options after disease progression following imatinib, sunitinib and regorafenib treatment, the latter being particularly indicated for PDGFA D842V mutation.
Efficacy assessment
The 2014 edition of the ESMO guidelines has no more updates, with a special emphasis on the fact that accurate assessment is not easy and often requires the use of an experienced specialist or team. Most cases will show a reduction in tumor volume after effective use of anti-TKI drugs, but some cases will only show a change in tumor density on CT scan, and this change may predict that tumor shrinkage will occur. These imaging changes should be considered as a tumor response to the drug.
For a given case, the presence of a decrease in tumor density on CT scan, even if the tumor volume has increased, is indicative of an effective treatment. In individual cases, a general decrease in tumor density may result in what appears to be a “neo-nodule”. PET-CT can provide very sensitive early evidence of tumor response, especially for cases undergoing translational therapy. It is important to note that tumor progression is not always accompanied by an increase in volume, and that some areas of increased tumor density within the tumor may indicate tumor progression.