Initial Treatment

Surgery for Operable Disease | Neoadjuvant Gleevec | Adjuvant Treatment | Unresectable or Metastatic Disease | Where Should Patients be Treated? | References

Most GIST patients will only have a single tumor at the time of diagnosis. A significant minority (approximately 20%) however, will already have metastases at the time of diagnosis. Initial treatment will be dependent on several factors including:

• Whether a patient has metastases or not
• The expected difficulty of the surgery
• The size of the primary tumor
• The general health of the patient

Surgery for Operable Disease

Surgery is typically the standard initial treatment for GIST. In some cases, a patient might have had surgery to remove a mass and received a GIST diagnosis after surgery. In other cases, Gleevec may be given prior to surgery with the goal of reducing the size of the tumor(s) to make surgery easier. This is called "neoadjuvant Gleevec". Neoadjuvant Gleevec is not a FDA listed indication for Gleevec, however it seems to be fairly commonly done. Gleevec therapy prior to surgery is discussed in the NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors (2010)5.

According to the recent Journal of National Comprehensive Cancer Network guidelines on GIST , (primary) GISTs greater than 2cm in size should be removed (resected), however, the management of incidentally encountered GISTs less than 2 cm in size remains controversial¹. Long-term follow-up of a large number of GIST patients found little or no risk of progressive disease (metastasis or tumor-related death) with primary tumors less than 2 cm in size as long as they also had a low mitotic rate (less than 5 per 50 HPFs).

Surgery for primary GIST offers the best chance of a "cure" or long-term benefit. The risk of a recurrence after surgery is related to the tumor size, how fast the tumor is growing (mitotic rate) and tumor location. See the Diagnosis and Risk Assessment section for details.

GIST tumors are often surrounded by a "pseudocapsule". The goal of surgery is complete removal of the tumor with an intact pseudocapsule. The margins of the resected tissue should be free of tumor (negative microscopic margins).

See the Surgery section of the web site.

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Gleevec prior to Surgery

Some patients that don't have metastatic disease will have large or difficult to remove tumors at the time of diagnosis. In cases where surgery seems likely to cause significant loss of function (such as the total removal of the stomach) medical treatment with Gleevec is sometimes considered prior to surgery. Gleevec has a high response rate with about 2/3 of patients experiencing significant shrinkage (see the table below). Patients must be monitored closely to ensure that they are not progressing. According to the JNCCN guidelines; "Patients can be treated with imatinib until the optimal time for surgery (when the GIST becomes resectable and the chance of morbidity is acceptable), which can take as long as 6 to 12 months." According the the JNCCN guidelines, "For both large tumors and poorly positioned small GISTs that are considered marginally resectable on technical grounds, neoadjuvant imatinib is recommended. Patients with primary localized GIST whose tumors are deemed unresectable should also start imatinib."

In the 2004 ESMO (European) guidelines on GIST, the panelists recommended:

"Imatinib may be used, however, by multidisciplinary teams experienced in the management of GIST, imatinib treatment, surgery of digestive tract tumors and with the difficulties in the evaluation of imatinib response, in particular when function sparing surgery is the goal; this may be particularly frequent for rectal or esphageal tumors. However, some patients who have either unresectable GIST or GIST for which surgery would lead to a marked loss of organ function (e.g. a rectal GIST, when the anal sphincter cannot be preserved) may be treated with preoperative imatinib in an attempt to achieve cytoreduction and organ preservation. In these cases, a careful pretreatment and rapid treatment response assessment by PET and CT scan should be performed, with decisions being taken in a multidisciplinary discussion."

In the 2010 NCCN Task Force Report, (PDF) the authors noted:

"Some patients may require extensive surgery for a poorly situated tumor. The operative risks and anticipated postoperative recovery must be weighed against the oncologic benefit of tumor resection. For instance, a tumor located near the gastroesophageal junction may require a proximal or total gastrectomy.
Pancreaticoduodenectomy may be necessary to remove a duodenal GIST. Occasionally, an abdominoperineal resection is needed for a low rectal GIST. In these situations, preoperative multidisciplinary review is critical, because these patients may be spared radical resection even after experiencing a partial response to preoperative imatinib."

Notes: A phase II neoadjuvant trial (RTOG-S0132) is closed to recruitment. This trial is ongoing but not recruiting patients. The early results were published in the Journal of Surgical Oncology.

CAUTION: A study with breast cancer cells in mice published in 2012 in the journal Cancer Cell raises the possibility that treatment with imatinib or other drugs that target PDGFRß may increase the risk of metastatic spread6. If true, we could speculate that the greatest risk/benefit ratio (higher risk) might occur for neoadjuvant treatment with Gleevec. As previously noted, multidisciplinary review to consider all of the know risks and benefits is highly recommended prior to pre-operative Gleevec. Gleevec has proved to greatly extend overall survival for metastatic GIST and also to extend survival when used for at least 3 years as adjuvant treatment. See LRG story LRG responds to recent Cancer Cell coverage.

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Adjuvant Treatment

Many GIST patients have surgery to remove a primary tumor and do not have detectable metastases at the time of surgery. On December 19th, 2008, the FDA approved Gleevec as adjuvant therapy for patients in the United States. Adjuvant therapy refers to additional treatment given after a main mode of therapy (the main treatment is usually surgery). For example, Gleevec given after surgery in hopes of preventing or delaying a recurrence is called adjuvant therapy. For further discussion about adjuvant treatment with Gleevec see the Preventative Treatment section of this website.

Unresectable or Metastatic Disease

Gleevec is the standard treatment for unresectable or metastatic GIST. If an unresectable primary tumor undergoes significant shrinkage after treatment with Gleevec, then surgery can be reconsidered. With metastatic GIST, Gleevec is continued lifelong or until progression. Patients that can't tolerate Gleevec can try Sutent (approved for Gleevec-resistant GIST or GIST patients that can't tolerate Gleevec in many countries).

Where should patients be treated?

According to the 2011 NCCN guidelines, "All patients should be evaluated by a multidisciplinary team with expertise in sarcoma". Since GIST is a sarcoma, doctors that specialize in sarcoma typically have lots of GIST experience.

A local team of doctors is also necessary and provides most of the hands on care. This usually includes an oncologist and a surgeon. Other doctors including pathologists and radiologists are consulted as needed.

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References

1.NCCN Task Force Report: Optimal Management of Patients with Gastrointestinal Stromal Tumor (GIST)—Update of the NCCN Clinical Practice Guidelines (July, 2007)

George D. Demetri, MD; Robert S. Benjamin, MD; Charles D. Blanke, MD; Jean-Yves Blay, MD, PhD; Paolo Casali, MD; Haesun Choi, MD; Christopher L. Corless, MD, PhD; Maria Debiec-Rychter, MD, PhD; Ronald P. DeMatteo, MD; David S. Ettinger, MD; George A. Fisher, MD, PhD; Christopher D.M. Fletcher, MD, FRCPath; Alessandro Gronchi, MD; Peter Hohenberger, MD, PhD; Miranda Hughes, PhD; Heikki Joensuu, MD; Ian Judson, MD, FRCP; Axel Le Cesne, MD; Robert G. Maki, MD, PhD; Michael Morse, MD; Alberto S. Pappo, MD; Peter W.T. Pisters, MD; Chandrajit P. Raut, MD, MSc; Peter Reichardt, MD, PhD; Douglas S. Tyler, MD; Annick D. Van den Abbeele, MD; Margaret von Mehren, MD; Jeffrey D. Wayne, MD; and John Zalcberg, MBBS, PhD

2. Outcome of Advanced Gastrointestinal Stromal Tumor (GIST) Patients Treated With Imatinib Mesylate:Four-Year Follow-Up of a Phase II Randomized Trial Poster PDF 71KB ASCO 2006 Presentation

3. Consensus meeting for the management of gastrointestinal stromal tumors Report of the GIST Consensus Conference of 20–21 March 2004, under the auspices of ESMO
J.-Y. Blay, S. Bonvalot, P. Casali, H. Choi, M. Debiec-Richter, A. P. Dei Tos, J.-F. Emile, A. Gronchi, P. C. W. Hogendoorn, H. Joensuu, A. Le Cesne, J. Mac Clure, J. Maurel, N. Nupponen, I. Ray-Coquard, P. Reichardt, R. Sciot, S. Stroobants, M. van Glabbeke, A. van Oosterom & G. D. Demetri

4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Soft Tissue Sarcoma, Version 2.2011, NCCN.org
Margaret von Mehren et al.

5. NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors

George D. Demetri, MD; Margaret von Mehren, MD; Cristina R. Antonescu, MD; Ronald P. DeMatteo, MD; Kristen N. Ganjoo, MD;
Robert G. Maki, MD, PhD; Peter W.T. Pisters, MD; Chandrajit P. Raut, MD, MSc; Richard F. Riedel, MD; Scott Schuetze, MD, PhD;
Hema M. Sundar, PhD; Jonathan C. Trent, MD, PhD; and Jeffrey D. Wayne, MD

6. Pericyte Depletion Results in Hypoxia-Associated Epithelial-to-Mesenchymal Transition and Metastasis Mediated by Met Signaling Pathway
Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R.