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10.1245/s10434-006-9047-3
Annals of Surgical Oncology 13:1596-1603 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Impact of Surgery on Advanced Gastrointestinal Stromal Tumors (GIST) in the Imatinib Era

S. Bonvalot1, H. Eldweny1, C. Le Péchoux2, D. Vanel3, P. Terrier4, A. Cavalcanti1, C. Robert5, N. Lassau3 and A. Le Cesne5

1 Department of Surgery, Institut Gustave Roussy, 94805 Villejuif, France
2 Radiotherapy, Institut Gustave Roussy, Villejuif, France
3 Radiology, Institut Gustave Roussy, Villejuif, France
4 Pathology, Institut Gustave Roussy, Villejuif, France
5 Medical Oncology, Institut Gustave Roussy, Villejuif, France

Correspondence: Address correspondence and reprint requests to: Sylvie Bonvalot; E-mail: bonvalot{at}igr.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: The role for surgery in patients with "unresectable" gastrointestinal stromal tumors (GIST) treated with imatinib is still not defined. The objective of this retrospective study was to evaluate the feasibility and benefit of this secondary surgery.

Methods: Progression-free survival (PFS) in a group of patients who underwent secondary surgery was compared to that of patients treated exclusively with imatinib.

Results: Of 180 patients with unresectable GIST treated with Imatinib, 22 (12%) underwent secondary surgery, following which one patient achieved a complete radiological response, 19 achieved a partial response (PR), in one patient the disease was stable, and in one patient there was reactivation of local occlusive disease after an initial PR. No patient with overall progression was to undergo surgery. At the beginning of imatinib therapy, five patients with metastases underwent emergency surgery [hemorrhage (n = 3) due to rupture of large necrotic masses], which ultimately resulted in three of the five patients dying postoperatively. A macroscopically complete resection was achieved in all primary tumors (5/5) and in ten of the 17 metastases. Pathological analysis revealed two complete response (CR) and 17 PR, and no treatment effect was evidenced in three patients. Two-year overall survival after surgery was 62%. The median PFS calculated from the initiation of imatinib therapy was 18.7 months for all operated patients and 23.4 months after planned surgery.

Conclusion: Primary tumors that become amenable to surgery with prior imatinib therapy, evolving necrosis and localized progression (to avoid life-threatening complications) could benefit from this secondary surgery. For the majority of other residual lesions, the potential benefit of secondary surgery should be evaluated in randomized studies in the future since PFS is similar to that reported among non-operated patients.

Key Words: Gastrointestinal stromal tumor • Surgery • Imatinib • Gleevec


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Before the imatinib era, gastrointestinal stromal tumors (GIST) were notoriously resistant to chemotherapy, and surgery was the only recognized treatment whatever the initial disease stage.1 However, more than 50% of GIST patients presented with locally advanced, recurrent, or metastatic disease portending an overall dismal prognosis.2 Imatinib has dramatically altered the clinical strategy for GIST and has now been approved for the management of unresectable tumors. Since its introduction in 2000 when, for the first time, a GIST patient was successfully treated with imatinib,3 this drug has demonstrated an efficacy in metastatic GIST4,5 and is also under investigation as induction and adjuvant therapy.6

Patients enrolled in the initial studies evaluating imatinib were not eligible for surgery because most had very advanced tumors. However, the extraordinary clinical responses obtained with imatinib in locally advanced primaries and recurrences surpassed expectations and raised the question of secondary surgery. Furthermore, complete responses (CR) to imatinib therapy were restricted to a few patients,4,5 and it is now known that 2-year failure rates are respectively 56% and 48% among patients treated with 400 mg imatinib once or twice daily, resulting in a median progression-free survival (PFS) of 19 and 24 months, respectively7.

The aim of this study was to evaluate the feasibility and better define the role of secondary surgery following imatinib treatment.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
The medical records of all patients who presented with inoperable GIST treated with imatinib at the Institut Gustave Roussy, Villejuif, France, were identified. All patients had been included in national or international prospective studies. All tumors were reviewed and confirmed to be cKIT positive (cKIT+) GIST by CD117 immunohistochemistry.8 The study focused on patients who underwent surgical exploration after imatinib therapy. Patient data included sex, age, site of the primary tumor and recurrence, the dose of imatinib and the duration of administration, treatment-related surgical complications, indications for surgery, and outcomes.

Radiographic and pathological responses were recorded. Abdominal and pelvic computed tomography (CT) scans were performed and used in the decision-making process with respect to surgical resection. Doppler ultrasound with perfusion software and contrast agent injection9 and PET scan (positron emission tomography) were also performed as predictors of tumor response to imatinib, but they were not used to decide whether surgery should be performed or not. After the initiation of imatinib therapy, CT scans were performed every 2 months during the first 6 months and every 3 months thereafter. Radiological response has been described elsewhere10: a complete radiographic response was defined as the failure to identify a lesion that had previously been depicted. A radiographic response was scored as a partial response (PR) if there was evidence of a decrease in tumor volume, necrosis, or a cystic change in the lesion. The largest lesion was measured and considered to be the target lesion for the purpose of this study. Progression was defined as the appearance of a new lesion or reactivation of any lesion. Overall progression was defined as the progression of all target lesions. Local tumor reactivation after a PR was defined as the progression of only one target or the development of a nodule in the mass while all the other targets were stable.

Indications for surgery have been evolving concomitant with our growing knowledge of imatinib based on 5 years of clinical experience with this new drug. Surgery was part of the treatment in three distinct clinical situations that were identified a posteriori: life-threatening complications due to treatment efficacy; unresectable primary or metastatic tumors becoming amenable to surgery following a good response; reactivated local disease in responders to imatinib. Unresectability of the primary tumor was defined by size, need for resection of surrounding organs, or major vessel involvement. Surgery was systematically discussed in the "sarcoma multidisciplinary team" of our institution as soon as no further improvement was noted between two CT scans, with the exception of emergency cases. In patients with metastases, the extent of sarcomatosis was intraoperatively scored using the Peritoneal Cancer Index (PCI) described by Sugarbaker.11 The lesion size score (LSS) was determined for 13 abdomino-pelvic regions (0 for no tumor, 1, 2, and 3 for tumors measuring ≤ 5 mm, 0.5–5 cm, > 5 cm, respectively). The summation of the LSS score in each of the 13 abdomino-pelvic regions (0–39) is the PCI.

A pathological response was defined as a PR when tumor necrosis or a myxoid change was evident. A complete pathological response was defined as the complete absence of viable tumor cells in the specimen (hematoxylin, eosin and saffranin staining). Survival rates were calculated according to the Kaplan-Meier method.12 Overall survival (OS) was calculated from the date of surgery: the endpoint was date of last follow-up or date of death if the patient died. Progression-free survival (PFS) was calculated from the first day of imatinib administration, and the endpoint was the date of the last follow-up, date of the appearance of a new lesion (after macroscopically complete surgery), or date of reactivation or appearance of any lesion (after macroscopically incomplete surgery or no surgery). PFS of operated patients was retrospectively compared with PFS of the whole group of patients having received imatinib. The aim of this study was not to analyze the entire patient population with locally advanced or meta-static disease who received imatinib in our institution: this analysis has been done elsewhere, and the duration of PFS calculated from the start of imatinib therapy was 19 and 24 months after 400 mg imatinib once or twice daily, respectively.7 We chose the same initial reference point to roughly appraise whether adding surgery after imatinib treatment could affect this variable.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Patient Characteristics
Between February 2001 and October 2004, 180 patients with unresectable cKIT+ GIST were treated with imatinib in our institution. Five of these patients had unresectable primary GIST, and 175 had unresectable metastases. All patients were treated within prospective national or international trials. Of these 180 patients, 22 underwent surgical exploration following imatinib therapy. The initial tumor site was the esophagus (n = 1), stomach (n = 4), small bowel (n = 11), colon and rectum (n = 6).

The sex ratio was 16 males: 6 females. The median age at initiation of imatinib was 53 years (range: 18–76 years). Seventeen patients had metastases: peritoneal seeding (sarcomatosis) (n = 11), multiple hepatic metastases (n = 1), or both (n = 5). Five patients had an unresectable primary tumor that became amenable to surgery following imatinib: one had invaded the stomach, spleen, and colon, one had developed on the mesentery, small bowel, and right colon, and three had developed on the rectum. The median Sugarbaker’s PCI for the 16 sarcomatosis was 12 (range: 4–26). All hepatic metastases were multiple and bilateral.

Preoperative Treatment
Nineteen patients received imatinib at a dose of 400 mg, three received 800 mg (with a dose reduction before surgery in two of them because of toxicity). The median duration of preoperative treatment was 12 months (range: 1–30 months).

Radiological Response
No patient with overall progression was operated on, even in emergency cases. As shown in Table 1Go, one patient with metastatic disease exhibited a complete radiological response, 19 exhibited a partial radiological response, and one had stable disease. The latter patient was operated on for reactivated local disease after an initial PR. The initial median target size was 92 mm (range: 11–240 mm), and the median size after imatinib therapy at the time of surgery was 54 mm (range: 0–200).


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  		TABLE 1. Surgery post Imatinib
 
Indications for Surgery
At the beginning of our clinical experience with imatinib, five patients with metastases (PR in four and no radiological change in one) underwent emergency surgery after a median treatment duration of 4 months (range: 1–6 months). Three of these patients experienced a hemorrhage due to imatinib-related rupture of large necrotic masses [liver metastasis (n = 1) and intraperitoneal masses (2)] (Fig. 1Go), one had a perforated digestive tract due to an unresected primary tumor situated on the duodenum with synchronous hepatic metastases, and one had an enterocutaneous fistula complicating a huge local recurrence.


Figure 1
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  		FIG. 1. Spontaneous rupture of a huge necrotic mass.

 
Twelve other patients with metastases were operated on, two in order to prevent expected complications when massive evolving necrosis appeared, independently of size (see Fig. 2Go). Of the 180 patients treated with imatinib, three other patients developed large necrotic masses responsible for their death, but these were not operated on because of extensive metastatic disease. Nine metastatic patients were operated on to await a macroscopically complete resection (n = 9) performed by a surgeon well versed in surgery for extensive peritoneal seeding. The criteria used to assess whether resection could be macroscopically complete were based on the volume and topography of the residual lesions and on an estimation of what would be left following these cumulative resections, based on the last CT scan. One patient with metastases was operated on for a reactivated lesion located on the first jejunal loop (n = 1) after an initial PR; the other responding targets were deliberately left in place. The mean number of visceral resections due to tumor involvement was three (range: 1–5). Many nodules were resected without the need to perform visceral resection.


Figure 2
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  		FIG. 2. Planned surgery for a large necrotic mass.

 
All five patients with an unresectable primary tumor that became amenable to surgery with imatinib were partial responders with at least a 50% shrinkage of the tumor prior to resection. This tumor shrinkage was a specific change brought by imatinib which allowed surgery (see Fig. 3Go).


Figure 3
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  		FIG. 3. Unresectable primary rectal GIST pretreated with imatinib. The tumor was amenable to surgery after 8 months under imatinib (anterior resection with posterior colpectomy and colo-anal anastomosis).

 
Results of Surgery
Three of the five patients who underwent emergency surgery died shortly thereafter (on Day 1 and Day 2, respectively due to persistent hemorrhage, and on Day 14 due to sepsis), whereas none of the 17 patients for whom surgery had been planned died during the postoperative period, and no surgical complications required operative re-intervention. No patient had anastomotic leak.

All patients with a primary tumor that became amenable to surgery (5/5) and ten of the 17 patients operated on for either peritoneal or hepatic recurrences had a macroscopically complete resection. The five patients who underwent emergency surgery had a macroscopically incomplete resection. Of the 17 patients (88%) for whom surgery had been planned, 15 had a complete resection. In the two scheduled resections that were incomplete, responding targets were deliberately left in place because the objective was to remove a reactivated lesion in one case and to remove a necrotic mass in order to avoid spontaneous rupture in the other case.

The pathological review of the operative specimen revealed that two patients had achieved a CR: a primary rectal GIST (n = 1/5) and a metastasis (n = 1/17). Seventeen patients had achieved a PR, and in three patients, no treatment effect was evidenced within the resected lesions.

Postoperative Treatment
Of the 19 patients who were alive after surgery, 18 received adjuvant imatinib at a dose of 400 mg, with the imatinib therapy commencing as soon as patients were able to eat. The only patient for whom imatinib was stopped after a complete surgery of a primary GIST developed hepatic metastasis 9 months later.

Survival
The median follow-up calculated from the time of surgery was 32 months (range: 4–44 months). OS at 2 years after surgery was 62% (Fig. 4Go). Among the 22 patients operated on, the median duration of PFS calculated from the start of imatinib therapy was 18.7 months (Fig. 5Go). The median duration of PFS was 23.4 months, taking into account exclusively the 17 patients who underwent planned surgery. Patients who developed a recurrence after surgery received imatinib at a higher dose or another drug under development. No patient underwent surgery twice. The patient operated on for a reactivated localized GIST had radiofrequency ablation (RFA) 18 months later for two hepatic metastases and, at the time this article was being written, has been free of progression for 12 months.


Figure 4
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  		FIG. 4. Overall survival after surgery.

 

Figure 5
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  		FIG. 5. PFS of operated patients (calculated from the start of imatinib).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Since its introduction in August 2000, imatinib has revolutionized the management of GIST, which up to that time were notoriously resistant to chemotherapy, and surgery was the only potentially curative treatment.13 The low resectability rate for recurrences and the fact that isolated local recurrences concerned only one third of all patients14 prompted clinicians to use imatinib as a first-line treatment in these situations. At the beginning of its use, patients enrolled in successive trials had tumors that unquestionably prohibited surgery. The rates of response to imatinib were impressive, but CRs were rare (5%), as observed in the European and US studies.4,5 Moreover, it is now known that 2-year failure rates are 56% and 48% among patients treated with 400 mg imatinib once or twice daily, respectively, resulting in a median PFS of 19 and 24 months.7 Therefore, in an attempt to achieve complete clinical remission, secondary surgery was systematically discussed for patients with an initial good response to imatinib followed by stabilization (no additional response observed on the CT scan), except in emergency cases.

In our study, patients were operated on after a median treatment duration of 12 months with imatinib, as reported by others.15 These patients were all responders. Excluding the emergency surgeries, patients were deemed operable if no radiographic evidence of ongoing regression was observed on two successive CT scans and if resection or sub-optimal resection seemed feasible with no evidence of non-resectability criteria. When these criteria were applied, few responders underwent surgery. The proportion of operated patients (12% in our study) is similar to that found at other institutions. At the MD Anderson Cancer Center, 17 of 126 patients with unresectable or metastatic GIST previously treated with imatinib were operated on, and resection was complete in 16.15 In the EORTC phase III trial, the median time to the best response was 4 months, but optimal responses were still obtained at 12 months, after which a plateau was observed.7 Thus, for the best outcome, planned surgery should be scheduled when an optimal response has been obtained, as evidenced on by CT scan (after 4 months)4,5 when there has been no additional regression between two successive CT scans, and before the possible occurrence of secondary resistance.7 Surgery should then be considered after 6–12 months of imatinib among responders.

Patients clearly benefiting from surgery are those with an unresectable primary tumor that becomes amenable to surgery following imatinib therapy.16,17 In this group, the resectability rates after imatinib were better than those observed among patients with metastases. Thus, surgical resection should always be considered and discussed, even among the rare complete responders, owing to the risk of secondary resistance. Imatinib does not release the surgeon from performing optimal initial surgery for primary resectable GIST–complete surgery without rupture being the objective18–as acquired resistance to the agent may develop in the case of recurrence. Nevertheless, results obtained in unresectable primary GIST show that indications for neoadjuvant imatinib may be extended, especially when a functional benefit can be expected through tumor shrinkage, particularly in rectal and esophageal tumors. In these cases, a rapid treatment response assessment by PET or CT should be performed to be sure that there is no primary resistance,19 with the subsequent decision being taken in a multidisciplinary discussion.

Clearly, a further benefit of surgery is the prevention of expected complications in life-threatening situations.20 In this study, 3% of the patients treated with imatinib developed complications, particularly in relation to the rupture of large tumor masses that became necrotic under treatment.21 Given the high operative mortality rates in emergency settings and the lower rates of macroscopically complete resection obtained, it is preferable to schedule patients for surgery who develop large necrotic masses (Fig. 2Go). Considering the number of patients we treated with imatinib, these complications were rare, and are comparable to those reported in the literature.22

In the present study, no patient with extensive progression (primary resistance) or overall re-progression (secondary resistance) underwent surgery. It is known that the results of such operations in this patient population are poor23 and that it is therefore preferable either to increase the dose of imatinib or to use new compounds under development in these patients. An extensive progression throughout the whole abdomen should be differentiated from that limited to a single target. This "localized" progression may correspond to partial resistance through the acquisition of new monoclonal mutations that are resistant to imatinib.24 At the time of our study, only one patient had surgery and RFA for this type of progression. These selected approaches for treating "localized" progressive nodules are used in various American and European centers, while they continue to treat the other unresectable targets with imatinib.25

Currently, no consensus exists as to which therapeutic approach is the most appropriate for residual metastatic solid lesions (as opposed to necrotic lesions). Whether located in the liver or disseminated throughout the abdominal cavity, these lesions can become resectable, but the benefit of surgery in terms of survival remains to be evaluated. Macroscopically complete resections are rare when you consider the number of patients treated with imatinib, and the majority of patients continue to have active residual masses, as shown in our study or other reports.15 In the present study, PFS from the start of imatinib was 18.7 months for all the operated patients (including operative mortality of emergency surgeries) and 23.4 months for patients in whom surgery was discussed and planned.

Obviously, the first patients who were ever operated on after receiving imatinib therapy had huge tumors as they were the first to receive this new drug, and this may have contributed to the poor results. However, observed survival is not very different from that reported for all patients treated with imatinib in European or American studies, most of whom did not undergo surgery.7,26 Although our study was not randomized, the results study suggest that secondary surgery after imatinib warrants further research in this category of patients. Moreover, imatinib should always be pursued after surgery.27 Surgery should therefore be randomly evaluated in the future, especially for residual metastatic solid lesions (liver and peritoneal).


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Metastatic and/or unresectable recurrences should be treated with imatinib as first-line therapy. Surgery could be considered for maximal responses (between 6 and 12 months) as soon as no further improvement is visualized between two successive CT scans. Approximately 15% of all patients can undergo secondary surgery. For the majority of residual lesions, the benefit of this secondary surgery should be randomly evaluated in the future since the PFS is similar to that reported among non-operated patients. However, the benefit of surgery is observed for primary tumors that become amenable to surgery following imatinib therapy, evolving necrosis and reactivated localized disease (to avoid life-threatening complications).


   ACKNOWLEDGMENTS
 
The authors thank Mrs. Lorna Saint-Ange for editing.

Received for publication April 21, 2005. Accepted for publication February 26, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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