Surgery for Metastatic GIST

Frequently, GIST is already metastatic at the time of diagnosis. GIST metastases typically involve the liver and/or the peritoneum. In this case the surgeon may not be able to resect all visible tumors. If feasible, resection is advisable, even though surgery for metastatic GIST is not potentially curative, as some GIST cells are certain to remain post-surgery. Therefore, adjuvant imatinib (Gleevec) is the standard of care to attempt to prevent further recurrences.  Surgery for metastases that have been downsized by imatinib or sunitinib therapy has been reported with good results if the resection is done while the tumors are still under control (before drug resistance) and if drug therapy is continued post-surgery (Scaife et al, 2003; Bauer et al, 2005).  One rationale for resecting metastases is to eliminate tumors from which drug-resistant clones might develop.

Raut et al (2005 CTOS presentation; Raut et al, 2006) compared progression-free survival and overall survival for three groups of patients who had surgery after a period of imatinib or sunitinib therapy: 

• stable disease (initially unresectable cases in which drug therapy had shrunk tumors to a potentially resectable state, and all tumors were stable prior to surgery)
• limited progression of disease (initially unesectable cases for whom drug therapy did not render all tumors resectable, with progression of one or more areas of disease while other areas remained under drug control, and the progressing areas had a chance to be completely resected)
• generalized progression (unresectable cases for whom multiple areas of disease showed progression, and surgeons determined that the progressing areas could not be completely resected, but debulking could be done).

Figure 1 from Raut et al (2006) shows the course of GIST after surgery for these three groups of patients.  Note that only 78% of the stable-disease group, 25% of the limited-progression group, and 7% o the general-progression group achieved "no evidence of disease" status following surgery.  The majority of patients (about 60%) with stable disease retained progression-free status 20 months post-surgery, compared to about 20% of patients with limited progression.  However, patients with generalized progression quickly showed additional progression after debulking surgery.

Figure 2 from Raut et al (2006) shows corresponding data for overall survival.  The group with stable disease prior to surgery showed longer survival after surgery than did the group with limited progression.  Although the study did not permit any quantification of how much surgery contributed to lengthening progression-free survival and overall survival, the authors concluded that surgery is worthwhile if all tumor can be removed during a period of stability.  Surgery probably adds to progression-free and overall survival time if done during limited progression.  Surgery's benefit is limited to symptom reduction if there is generalized progression.  The authors urged that prospective trials be undertaken to quantify these benefits.   In conclusion they stated "In conclusion, patients presenting with stable advanced GISTs on KIT-directed therapy experienced prolonged PFS and OS after surgery.  Those with limited disease progression usually progressed within 12 months of surgery, but appear to have an improved OS."

Surgery for Drug-Resistant Tumors 

During imatinib (Gleevec) treatment, a patient’s tumor(s) may be under control for a prolonged period, followed by the emergence of an area of new growth inside of an otherwise controlled tumor. This phenomenon has been referred to as a “nodule within a mass” or as “partial resistance.” You can view an image and read a discussion on pages 9-10 of the CTOS Management of GIST newsletter and in the ESMO guidelines (paragraph 13). For liver metastases, radio frequency ablation of the growing area has been used in such cases. For peritoneal metastases, surgical resection has been used. The patient then continues on imatinib therapy for the tumors still under drug control.  Also see the discussion above regarding the limited-progression group in the study of Raut et al (2005, 2006).

REFERENCES

Bauer S, Hartmann JT, de Wit M, Lang H, Grabellus F, Antoch G, Niebel W, Erhard J, Ebeling P, Zeth M, Taeger G, Seeber S, Flasshove M, Schutte J.
Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib.
Int J Cancer. 2005 Nov 1;117(2):316-25. PMID: 15900603

NCCN, National Comprehensive Cancer Network. 
Soft Tissue Sarcoma Guidelines 

Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D, Fletcher CD,  Demetri GD, Bertagnolli MM.
Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors.
J Clin Oncol. 2006 May 20;24(15):2325-31.
PMID: 16710031

Raut CP, Desai J, Morgan JA, George S, Posner M, Zahrieh D, Fletcher CDM, Demetri GD, Bertagnolli MM.  
Surgical management of advanced GIST following KIT-directed therapy.
Slide show from presentation at 2005 meeting of Connective Tissue Oncology Society.

Scaife CL, Hunt KK, Patel SR, Benjamin RS, Burgess MA, Chen LL, Trent J, Raymond AK, Cormier JN, Pisters PW, Pollock RE, Feig BW.
Is there a role for surgery in patients with "unresectable" cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate?
Am J Surg. 2003 Dec;186(6):665-9.
PMID: 14672776