Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 5, Num. 4, 2009, pp. 267-271

Journal of Cancer Research and Therapeutics, Vol. 5, No. 4, October-December, 2009, pp. 267-271

Original Article

Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors

Seshadri RamakrishnanA, Rajendranath Rejiv

Department of Surgical Oncology, Cancer Institute (WIA), Chennai

Correspondence Address:Department of Surgical Oncology, Cancer Institute (WIA), Annexe Campus, No.18, Sardar Patel Road, Guindy, Chennai - 600 036
ram_a_s@yahoo.com

Code Number: cr09064

PMID: 20160360

DOI: 10.4103/0973-1482.59905

Abstract

Keywords: Gastrointestinal stromal tumors, imatinib, neoadjuvant, surgery

Introduction

Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal neoplasm of the gastrointestinal tract. ^[1] Surgery is the standard treatment in localized nonmetastatic GISTs. ^[2],[3] At presentation, only 70-85% of GISTs are resectable ^[1],[4],[5] and 10-40% of the tumors invade the surrounding organs. ^[2] A large tumor size increases the chance of tumor spill and reduces the chance of complete resection. Incomplete resection and tumor spill are known to have a negative impact on the survival of patients with GISTs. ^[1],[4] Hence, increasing the rate of complete resection without tumor spill, and achieving this by a less radical surgery may improve the chances of survival in locally advanced GISTs. Imatinib mesylate (Gleevec, formerly STI571; Novartis Pharma AG, Basel, Switzerland), a small molecule in the 2-phenylaminopyrimidine class, has been approved for use in the treatment of metastatic GISTs by the United States Food and Drug Administration in 2001. ^[6] Our aim was to study the role of neoadjuvant imatinib mesylate in downsizing tumors in patients with locally advanced nonmetastatic GISTs, thus improving the chance of complete resection.

Materials and Methods

This is a prospective analysis of patients who were diagnosed to have histologically proven locally advanced nonmetastatic GISTs in our institution between 2007 and 2008. All the tumors had positive immunohistochemical staining for c-kit (Dakopats, Denmark). The tumors were considered locally advanced due to their large size with a suspicious involvement of adjacent organs or major blood vessels which would have required a major multiorgan resection with a possibility of tumor spill and incomplete resection. The dose of imatinib used was 400 mg per day, given orally. All the patients had a baseline computerized tomography (CT) scan of the abdomen before starting imatinib therapy and subsequent CT scans were performed at the end of 1 month of treatment and again at 3 months in some patients. The volume of the tumor was calculated using the formula V = 4/3 πr³ , where "r" represents the maximum dimension of the tumor as measured on the CT scan. Surgery was performed when the imaging revealed adequate downsizing of the tumor to permit a less extensive, but complete surgical resection, as assessed by the surgeon, or when two serial CT scans did not show an appreciable decrease in the tumor volume. One patient underwent an emergency surgery due to bleeding from the tumor. Adjuvant imatinib was used in 75% of the patients who underwent a surgery. Survival was calculated from the day of the surgery till the date of the last follow-up.

Results

Six patients with locally advanced nonmetastatic GISTs received neoadjuvant imatinib in our institution between 2007 and 2008. The clinical and treatment characteristics of these patients are detailed in [Table - 1]. None of the six patients had any serious adverse effects due to imatinib. All the six patients had a partial radiological response [Figure - 1], whereas a complete radiological response was not observed in any patient. The median reduction in the tumor volume following imatinib therapy was 40% (range 20-50%). Four of the six patients underwent surgical resection of the residual tumor. Two patients declined surgery even though their tumors had considerably reduced in size to permit a complete resection, and are continuing imatinib. All the four patients who underwent a surgery had a complete resection without tumor spill and with negative margins of resection. Multiorgan resection was needed in two patients. In the remaining two patients, even though the pre-imatinib treatment CT showed a suspicious infiltration of adjacent organs, multiorgan resection was not needed. One patient with a proximal gastric tumor had an attempt at a conservative procedure to spare the gastroesophageal junction, but this was not successful and he finally underwent a total gastrectomy. There was no postoperative morbidity or mortality. A partial pathological response was observed in all four patients, with residual viable tumor cells mixed with varying degrees of myxoid changes, necrosis and hemorrhage in the residual tumor. None of the patients had a complete pathological response. All the operated patients are disease free after a median follow-up of 10.5 months (range 3-20).

Discussion

GISTs account for 6% of all sarcomas. ^[1] They arise from the precursor mesenchymal stem cells residing in the wall of the gut, which also differentiate into the interstitial cells of Cajal. ^[7] At the molecular level, GISTs have a gain of function mutation in the KIT protooncogene ^[8] which results in a ligand-independent activation of the abnormal KIT protein, causing uninterrupted tyrosine kinase-mediated intracellular signaling. Surgery is the standard initial treatment for nonmetastatic GISTs and entails a complete resection of the tumor without tumor spill. ^{[2],[3],[5],[9]} A complete resection improves the survival in patients with GISTs. ^{[1],[4],[10],[11]} Pierie et al. reported 5-year survival rates of 42% and 9% after a complete and an incomplete resection of GIST, respectively. ^[11] In their series of 200 patients with GISTs, Dematteo et al.^[1] reported a median survival of 66 months after a complete resection and 22 months after an incomplete resection. Tumor spill during the surgery also increases the chance of peritoneal recurrence and reduces the survival. Ng et al. reported that tumor rupture reduced the median survival from 46 to 17 months, which was comparable to the median survival after an incomplete resection (21 months). ^[4]

However, only 70-85% of patients with localized GISTs can undergo a complete resection. ^{[1],[10],[11],[12]} Crosby et al.^[10] reported that 48% of patients in their series had locally advanced nonmetastatic disease and of these, only 79% could undergo a complete resection. They also reported that the survival of patients with locally advanced disease was not significantly different from that of patients with localized disease. Therefore, methods to downsize locally advanced tumors in order to bring them into the purview of surgery may improve the rates of a complete resection and hence the survival in patients with locally advanced GISTs. Imatinib mesylate, a small multiringed molecule, is a KIT-receptor tyrosine kinase inhibitor which competes with ATP for its kinase-binding site, and prevents the kinase from transferring phosphate from ATP to tyrosine residues of substrates, thus inhibiting downstream signaling. ^[2] It has been approved for use in metastatic GISTs, ^[6] where it has been shown to decrease the size of the tumors by at least 50%. ^[13],[14] The first report of neoadjuvant imatinib in locally advanced GISTs was by Bumming et al. ^[15] He reported a patient with an unresectable ileal GIST with liver metastasis. After the use of neoadjuvant imatinib for 12 weeks, the primary tumor had reduced in size from 35 to 18 cm, and was resected completely. However, there are very few reports of the use of neoadjuvant imatinib exclusively in locally advanced nonmetastatic GISTs [Table - 2]. Katz et al.^[16] described the successful complete resection of two locally advanced unresectable nonmetastatic gastric GISTs after the use of neoadjuvant imatinib for 7 months, which led to an almost 50% reduction in the tumor size. The largest series so far comprises only 14 patients. ^[19] In our series, all the patients who underwent a surgery had a complete resection. The median reduction in the tumor volume in our series was probably less due to the shorter duration of treatment with imatinib.

The definition of unresectable GISTs varies in different reports. Andtbacka et al.^[20] defined unresectability as the presence of radiological evidence of a significant involvement of a single organ with size ≥5 cm or extension to adjacent organs. Another report defines unresectability on the basis of size, need for adjacent organ resection, or major vessel involvement. ^[17] In the present series, the tumors were considered unresectable due to the large size and the involvement of adjacent organs and/or major blood vessels. The European Society of Medical Oncology (ESMO) consensus conference on GISTs stated that there is no reliable definition for locally advanced nonmetastatic versus localized, resectable disease due to diversity in the size, site, and extension of these lesions. ^[3] The dose of imatinib that we used (400 mg) is similar to that used in other series. It has, however, been shown that GISTs harboring exon 11 KIT mutations respond better to imatinib and also have a better survival compared to those with exon 9 KIT mutation or no detectable mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA). ^[24] We did not include mutation analysis as a part of our study since it is not mandatory for diagnosing GISTs, especially since all our patients had positive immunostaining for c-kit. Also, we started with the standard dose of imatinib (400 mg) and in case there was no clinical or radiological response to this dose, we had the option of increasing the dose. However, recent evidence has shown that patients with exon 9 mutation may benefit from a dose of 800 mg imatinib daily. ^[25] Hence, analysis of KIT and PDGFRA mutations can be useful in determining the dose and possible resistance to imatinib in the neoadjuvant sitting as well and should be incorporated in future studies of neoadjuvant imatinib. The response to imatinib is predicted by a combination of symptomatic improvement (clinical response), decrease in the tumor Houndsfield units on the CT scan (radiological response), and reduced FDG uptake in a positron emission tomography (PET) scan (metabolic response). ^[3] A CT scan is the imaging modality of choice in determining response, although for a short-term follow-up, a PET scan may predict the response better. It has been reported that the RECIST criteria for the assessment of response to treatment in solid tumors is unreliable for monitoring GISTs during imatinib treatment as it underestimates the tumor response. ^[26] The Choi criteria, which is a 10% decrease in the unidimensional tumor size or a 15% decrease in the tumor density on contrast-enhanced CT, have been reported to be more accurate and sensitive than RECIST criteria for assessing response to imatinib. ^[27] A FDG-PET scan is sensitive and specific for early tumor response, but it may be inaccurate in predicting residual disease. ^[20],[26] CT findings in responding tumors include a reduction in the tumor density, in the solid enhancing nodules, and in the tumor vessels. ^{[3],[20],[26]}

The optimal timing of the surgery following neoadjuvant imatinib is debatable. Theoretically, the surgery should be performed in the window period, i.e. after maximum response, but before the development of secondary resistance. This is usually around 6-12 months. ^[21,28] However, secondary KIT mutations have been identified even after 10 months of neoadjuvant imatinib therapy. ^[29] Hence, surgery should be performed as soon as there is sufficient shrinkage to perform complete resection. ^[3] The cessation of tumor shrinkage on successive imaging or CT findings like the formation of new nodules or tumor growth after a period of shrinkage may represent the beginning of secondary resistance and should prompt evaluation for surgery. ^[29]

Practically, therefore, surgical resection is best performed when two successive radiological imaging studies done at 2 to 3 monthly intervals do not show further regression in the tumor. ^[17],[20] The main advantage of neoadjuvant imatinib in locally advanced GISTs is the reduction in the tumor volume, which allows a more complete and less extensive resection. ^[9],[20] It can also allow organ conservation, especially in GISTs of the rectum or gastroesophageal junction. ^[23],[30] It has also been suggested that due to the bystander effect of imatinib on vascular endothelial growth factor, there may be an antiangiogenic effect which may reduce the possibility of bleeding during surgery. ^[31] Neoadjuvant imatinib has the possibility of eradicating micrometastatic disease. ^[9] Debulking with imatinib may help optimize the timing of surgery and avoid emergency surgery in patients with large GISTs which predisposes them to hemorrhage or rupture. ^[5] However, the disadvantages could include a sudden increase in the size or increased chance of rupture due to treatment-induced myxoid changes, and chance of secondary mutation. ^{[3],[28],[29]}

The preliminary results of the RTOG 0132/ACRIN 6665 nonrandomized prospective study of neoadjuvant imatinib have been recently published. ^[32] This trial used 600 mg imatinib as neoadjuvant therapy in patients with potentially resectable intermediate- to high-risk primary GISTs and potentially resectable recurrent/metastatic GISTs. In the 30 patients with primary GISTs, neoadjuvant imatinib induced a 7% partial response rate. The 3-year progression-free survival was 68% and estimated overall survival at 3 years was 84% in this subgroup. A complete resection was possible in 77% of these patients and partial organ preservation and function sparing was reported in many patients. Our study is different from this trial as we have only included patients with unresectable nonmetastatic primary GISTs. Although our series is small, we have been able to demonstrate the successful use of neoadjuvant imatinib in unresectable nonmetastatic GISTs. However, a longer follow-up is needed to determine the effect of neoadjuvant imatinib on long-term survival in these patients.

Conclusion

In summary, neoadjuvant imatinib in locally advanced nonmetastatic unresectable GISTs can help to downsize the tumor, thereby increasing the rates of complete resection without spill and reducing the extent of surgery. A close interaction between the surgeon and the medical oncologist is needed to ensure that surgery is performed at the appropriate time, following a major response but before the development of resistance. The use of KIT mutation analysis may help in determining the sensitivity to imatinib and in choosing the appropriate dose.

References

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