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Effectiveness of Surgery for GIST

Prior to the introduction of targeted molecular drug therapies (starting with imatinib/Gleevec), surgery was the only useful treatment for GIST. Surgery is still the cornerstone of GIST treatment whenever resection is possible. Complete removal of a primary tumor is potentially curative, especially when the tumor is small and the risk classification is low (see Table 2 in Prognosis under About GIST). Although recurrence or metastasis is less likely for low-risk GISTs, all GISTs have malignant potential. If recurrence or metastasis does happen, it is usually within the first two years after surgery to remove a primary tumor. However, there are case reports of metastases appearing 10-20 years later. Therefore, long-term monitoring for recurrence is needed.

A number of papers in the medical literature describe patient outcomes after GIST surgery in the pre-imatinib era. However, these papers are difficult to interpret because most of them include some percentage of non-GIST cancers (such as leiomysarcoma) due to the fact that accurate GIST diagnosis became possible only after 1998, when KIT (CD117) expression by GISTs was discovered. In addition, these series tend to be from large cancer centers to which difficult cases are referred; therefore the series have a disproportionate number of high-risk patients and patients whose disease was already metastatic at diagnosis. These factors, plus the current availability of targeted molecular therapy if GIST does recur or metastacize, render the survival statistics from the pre-imatinib era less relevant today.

Recurrence rates for tumors of different sizes and mitotic rates, separated by tumor site, are available in a series of site-specific papers by Miettinen and colleagues at the Armed Forces Institute of Pathology. These papers are noteworthy because they contain very large series of cases broken down into prognostic categories, with follow-up information (Miettinen et al, 1999; Miettinen et al, 2000; Miettinen et al, 2001; Miettinen and Sobin, 2001; Miettinen et al, 2003; Miettinen et al, 2005, Miettinen et al, 2006).

Recent data from Sweden estimate the curative potential of surgery (Nilsson et al, 2005; Bumming et al, 2006).  All KIT-positive GISTs in western Sweden from 1983-2000 were identified by re-examination of original pathology samples, producing a prospective population-based group of tumors.  Of 259 clinical cases 199 were found due to patients' symptoms, while 60 were discovered incidentally durin surgery for other conditions.  In contrast to case series from referral centers, where perhaps half the cases are already metastatic, the Swedish data included only 14.6% (29 of 199) cases already metastatic at diagnosis.  Excluding these and focusing on primary tumors, surgery was curative in over 97% of cases when complete resection could be achieved for patients whose risk group was very low, low, or intermediate (see Prognosis section Table 1).  In the high-risk group, 48 of 60 patients achieved complete resection (80%).  With a median of 8 years of followup post-surgery (range 1.8 to 19.5 years), 37.5% of high-risk patients with complete resection remained free of disease, while 62.5% developed recurrence or metastasis.   Therefore, surgery does have curative potential even for higher-risk primary tumors.

Surgical Considerations

Several excellent recent discussions of surgery for GIST in the targeted-therapy era are available: Scaife et al, 2003; Eisenberg and Judson, 2004; van der Zwan and DeMatteo, 2005; Heinrich and Corless, 2005; Neuhaus et al, 2005; Efron and Lillemoe, 2005, Barnes et al, 2005; the ESMO consensus guidelines published by Blay et al, 2005 (see summary on our site as well as summary slides on our site by Dr. Reichardt ); NCCN Sarcoma Guidelines, version 1.2007; Benjamin et al, 2006; Raut et al, 2006.

For many patients, surgery is scheduled on the basis of imaging results (ultrasound, CT, MRI. etc.) indicating the location of the tumor, but before the exact type of tumor has been diagnosed. Tumor biopsy prior to surgery is safe if it can be done endoscopically (as for gastric tumors). However, preoperative biopsy through the skin of the abdomen (percutaneous biopsy) is not recommended for operable tumors due to the small risk of seeding tumor cells along the biopsy path, plus the risk of tumor rupture into the abdomen. The exception is for inoperable tumors, when identifying the tumor type will affect treatment choices. If the biopsy of an inoperable tumor shows GIST, neo-adjuvant imatinib/Gleevec can be prescribed. For a discussion of biopsy issues, see the NCCN Sarcoma Guidelines and the opinion written by Dr. Christopher Corless for our website (Needle Biopsies).

Goals of surgery include:

  • Complete removal of all tumor
  • Clear surgical margins
  • Avoidance of tumor rupture

Resection is usually segmental for all but the smallest tumors; this means an entire segment of the GI tract is removed (with the tumor attached to it) and the cut ends are reattached. Segmental resection contrasts with wedge (or peri-tumoral) resection, in which the GI tract area immediately around the tumor is removed (with the tumor attached to it) and the edges of the resulting hole are drawn back together. Several authors have reported a poorer prognosis after wedge/peri-tumoral resection than after segmental resection, apparently due to inadequate margins (Bucher, 2005, Aparicio, 2004). Laparoscopic surgery is generally not advised unless the GIST is smaller than 2 cm (NCCN, 2005).

Because GIST does not usually invade adjacent organs or structures, the tumor can often be lifted away from structures it has pressed against. However, if a GIST has adhered to adjacent structures and attempted dissection of the tumor from the normal organs poses a risk of tumor rupture, then an en bloc resection (removing the tumor along with portions of the structures it has adhered to as a single unit) may be required. Lymph node removal is not generally needed, as GIST very rarely spreads via the lymphatic system.

For patient-oriented tips on coping with surgery and a hospital stay, see Before You Go to the Hospital on our website.

Abdominal sarcoma surgery is not an everyday event at community hospitals. Surgeons at sarcoma centers will be much more familiar with and skilled in the resection of GISTs than general surgeons. The larger the GIST, the more important this may be to the patient’s outcome. A tumor that is deemed inoperable by a general surgeon may well be resectable by an expert GIST surgeon. If the patient seeks the opinion of a sarcoma surgeon first, then the patient may save him or herself all the time, expense, and extended recovery from an attempted surgery that turns out to be deemed “exploratory” when the general surgeon opens the abdomen only to decide that the GIST appears too difficult to resect.

Neo-Adjuvant imatinib

Surgical case histories have been published recently describing how shrinkage of a poorly situated GIST via imatinib (Gleevec) therapy can either render a previously inoperable tumor resectable, or reduce the scope of resection by avoiding potentially debilitating sacrifice of normal organs (Wu et al, 2003; Heinrich and Corless, 2005; Lo et al, 2005; Loughrey et al, 2005; Shah et al, 2005; Neuhaus et al, 2005). There is also a neoadjuvant trial sponsored by the Radiation Therapy Oncology Group in which patients receive two months of imatinib prior to surgery and two years of imatinib post-surgery (RTOG S0132).  In a series of 33 patients who took neo-adjuvant imatinib, Hohenberger et al (2009 ASCO abstract 10550) found that 5 of 6 previously inoperable patients became operable, and 21 of 25 other patients were able to have their GISTs removed by a less extensive surgical procedure.

REFERENCES

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Prognostic factors after surgery of primary resectable gastrointestinal stromal tumours.
Eur J Surg Oncol. 2004 Dec;30(10):1098-103.  PMID: 15522557

Barnes G, Bulusu VR, Hardwicj RH, Carroll N, Hatcher H, Earl HM, Save VE, Balan K, Jamieson NV.
Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib.
International Journal of Surgery 2005; 3:206-212. Not indexed in PubMed.

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.
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Benjamin RS, Blanke CD, Blay JY, Bonvalot S, Eisenberg B.
Management of gastrointestinal stromal tumors in the imatinib era: selected case studies.
Oncologist. 2006 Jan;11(1):9-20.  PMID: 16401709

Blay JY, Bonvalot S, Casali P, Choi H, Debiec-Richter M, Dei Tos AP, Emile JF, Gronchi A, Hogendoorn PC, Joensuu H, Le Cesne A, McClure J, Maurel J, Nupponen N, Ray-Coquard I, Reichardt P, Sciot R, Stroobants S, van Glabbeke M, van Oosterom A, Demetri GD; GIST consensus meeting panelists.
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Bucher P, Egger JF, Gervaz P, Ris F, Weintraub D, Villiger P, Buhler LH, Morel P.
An audit of surgical management of gastrointestinal stromal tumours (GIST).
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Bumming P, Ahlman H, Andersson J, Meis-Kindblom JM, Kindblom LG, Nilsson B.
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Efron DT, Lillemoe KD.
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Adv Surg. 2005;39:193-221. PMID: 16250553

Eisenberg BL, Judson I.
Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy.
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Gold JS and DeMatteo RP. 
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Ann Surg. 2006 August; 244(2): 176–184.  free access through PubMed - click title to link.

Heinrich MC, Corless CL.
Gastric GI stromal tumors (GISTs): the role of surgery in the era of targeted therapy.
J Surg Oncol. 2005 Jun 1;90(3):195-207; discussion 207. PMID: 15895440

Lo SS, Papachristou GI, Finkelstein SD, Conroy WP, Schraut WH, Ramanathan RK.
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Loughrey MB, Mitchell C, Mann GB, Michael M, Waring PM.
Gastrointestinal stromal tumour treated with neoadjuvant imatinib.
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Miettinen M, Makhlouf H, Sobin LH, Lasota J.
Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up.
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Miettinen M, Sobin LH, Lasota J.
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Miettinen M, Kopczynski J, Makhlouf HR, Sarlomo-Rikala M, Gyorffy H, Burke A, Sobin LH, Lasota J.
Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases.
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Miettinen M, Sobin LH.
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Miettinen M, Furlong M, Sarlomo-Rikala M, Burke A, Sobin LH, Lasota J.
Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases.
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Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J.
Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas.
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Miettinen M, Monihan JM, Sarlomo-Rikala M, Kovatich AJ, Carr NJ, Emory TS, Sobin LH.
Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases.
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NCCN, National Comprehensive Cancer Network. 
Soft Tissue Sarcoma Guidelines version 2.2006

Neuhaus SJ, Clark MA, Hayes AJ, Thomas JM, Judson I.
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Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, Sablinska K, Kindblom LG.
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Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D, Fletcher CD,  Demetri GD, Bertagnolli MM.
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Raut CP, Desai J, Morgan JA, George S, Posner M, Zahrieh D, Fletcher CDM, Demetri GD, Bertagnolli MM.  
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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.
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Shah JN, Sun W, Seethala RR, Livolsi VA, Fry RD, Ginsberg GG.
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