World J Surg (2012) 36:864–871 DOI 10.1007/s00268-012-1440-4
Gastrointestinal Stromal Tumors: Case Series of 29 Patients Defining the Role of Imatinib Prior to Surgery Shailesh V. Shrikhande • Sachin S. Marda • Kunal Suradkar Supreeta Arya • Guruprasad S. Shetty • Munita Bal • Parul J. Shukla • Mahesh Goel • K. M. Mohandas
•
Published online: 14 February 2012 Socie´te´ Internationale de Chirurgie 2012
Abstract Background The aim of this study was to assess the role of neoadjuvant imatinib in redefining treatment for gastrointestinal stromal tumors (GISTs). Methods A total of 76 patients were reviewed. Among them, 29 patients who were administered neoadjuvant imatinib for borderline resectable and locally advanced GISTs followed by surgery were analyzed. Adjuvant imatinib was administered based on risk stratification. Results The median age of the neoadjuvant imatinib group was 51 years. The median duration of neoadjuvant imatinib administration was 8.5 months. The response rate with neoadjuvant imatinib was 79.3%. Five patients, initially considered to have locally unresectable lesions, ultimately underwent resection (three R0, two R2). Another three patients, who had M1 disease, underwent R2 resection (due to the presence of metastasis) with complete resection of the primary lesion. In 19 patients, who would S. V. Shrikhande (&) S. S. Marda K. Suradkar G. S. Shetty P. J. Shukla M. Goel Department of Gastrointestinal and HPB Surgical Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel, Mumbai 400012, Maharashtra, India e-mail:
[email protected];
[email protected] S. Arya Department of Radiology, Tata Memorial Hospital, Mumbai, India M. Bal Department of Pathology, Tata Memorial Hospital, Mumbai, India K. M. Mohandas Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai, India
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have originally required extensive surgery, underwent conservative surgery (R0). In two patients, neoadjuvant imatinib did not influence the final procedure. The postoperative complication rate was 13.8%, and there were no postoperative deaths. There was one locoregional recurrence and two cases of distant metastasis. The 1-, 2-, and 3-year overall survivals were each 100%. Conclusions Neoadjuvant imatinib for locally advanced GISTs is a safe concept for downsizing, improving resectability, and aiding organ-preserving surgery. It also improves the chance of long-term survival. Surgery, however, remains the cornerstone of curative treatment of GISTs even after neoadjuvant imatinib.
Introduction As described by Hirota et al. [1, 2], gastrointestinal (GI) soft tissue neoplasms are known as GISTs on the basis of molecular and immunohistologic features. GISTs represent 1% of all primary GI tumors arising from the interstitial cells of Cajal, which are the pacemaker cells of the GI tract [3]. The principal management of GISTs is surgical resection, but not all of these tumors are resectable. During the era before imatinib (preimatinib era), unresectable and metastatic GISTs had a poor overall prognosis, with a median survival of 12–19 months. Response rates to palliative anthracycline-based chemotherapy ranged from 5 to 10% [4–6]. Imatinib mesylate, a tyrosine kinase inhibitor of KIT, PDGFRa, and bcr-abl, has revolutionized the treatment of advanced GISTs. A landmark United States—Finland B 2222 study by Demetri et al. [7] showed a response to treatment in 54% with another 28% achieving prolonged
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stable disease. Imatinib is now regarded as the standard of care for first-line treatment of unresectable or metastatic GISTs. A multicentric Phase III trial has also confirmed its role in the adjuvant setting with significant recurrence-free survival [8]. Our GI and hepatopancreaticobiliary (HPB) surgical oncology department has followed the current standard of diagnosis and treatment with surgery in initially resectable tumors followed by adjuvant imatinib according to risk stratification [9, 10]. Even though the roles of neoadjuvant imatinib in down-staging the tumor and improving resectability are not yet well established, we offered neoadjuvant imatinib to selected patients with those aims in mind. There are various studies on GISTs in the literature, but data from the Indian subcontinent is sparse [11]. Hence, no comparisons can be made with published data.
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Complications were graded according to the Dindo– Clavien classification [14]. All tumors were reviewed by dedicated GI pathologists for confirmation of GIST with evaluation of the morphologic and immunohistochemical characteristics. Pathologic response was noted and adjuvant therapy offered according to risk stratification (very low, low, intermediate, high). Recurrence, metastasis, and patient status were recorded during periodic follow-ups. Statistical analysis All data was entered in SPSS (version 14) software (SPSS, Chicago, IL, USA). The data analysis was based on objectives of overall survival.
Results Materials and methods
Neoadjuvant imatinib group
Patients
The median age of the neoadjuvant imatinib group was 51 years (range 28–73 years): 21 men, 8 women. The tumors were localized in the stomach (n = 16; 55.2%), duodenum (n = 6; 20.7%), jejunum (n = 3; 10.3%), colon (n = 1; 3.4%), rectum (n = 2; 6.8%), and pancreas (n = 1; 3.4%). The mean size of the tumors was 8.8 cm (range 2.1–25.0 cm). The median duration of neoadjuvant treatment was 8.5 months (range 1–36 months). The objective changes in tumor size (preimatinib to postimatinib—reported by our dedicated GI radiologist) was possible in only 16 patients (for the remaining 13 patients we could not document objective changes in size simply because only hard copies of CT images were available, but no Digital Imaging and Communication in Medicine (DICOM)-compatible digital data for objective assessment). Nevertheless, a joint-clinic decision (also based on previous objective comparison of hard copies of the images of preimatinib and postimatinib CT studies by a GI radiologist) was made for these 13 patients with regard to documentation of tumor response and disease status. Results were as follows: PR in 20 patients (69%); CR in 3 patients (10.3%); SD in 5 (17.2%) patients; PD in 1 (3.4%) patient. Table 1 shows the objective data on preimatinib and postimatinib sums of diameters (SODs) of the target lesions and the response according to the Choi and RECIST criteria. The joint clinical assessment response is also documented in Table 1. Two patients developed periorbital edema on preoperative imatinib administered for over 12 months. Despite that, the neo-adjuvant imatinib succeeded in inducing marked symptomatic and radiologic improvement (Fig. 1).
A total of 76 patients with histologically proven GIST were operated on from March 2006 to February 2011. In all, 29 of the patients were given neoadjuvant imatinib before surgery and were analyzed. The other 47 patients underwent surgery without imatinib. Clinical data were retrieved and recorded from patient hospital files and electronic medical records (EMRs). Radiologic data were retrieved from the hospital picture archiving and communication system (PACS). The information recorded included patient age, sex, CD117 (KIT) status, tumor site, size, mitotic rate, invasion of adjacent structures, recurrence, and presence of metastasis. ‘‘Locally advanced’’ GISTs were defined by size, the need for multivisceral resection of surrounding organs, anatomic proximity with major vessels, and risk of intraoperative spillage. All of these patients (n = 29) were discussed in joint clinics and were offered neoadjuvant imatinib 400 mg/day until their best response. At that point, the surgical management of the patients was discussed again in the joint clinics. The best radiologic response was assessed with computed tomography (CT) every 2–3 months by the radiologist, and the response to therapy was assessed by them and categorized into four responses: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). The radiologic response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria and Choi criteria [12, 13] from CT scans. Various surgical resections were performed depending on the organ of origin, with documentation of blood loss, postoperative hospital stay, and complications.
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Table 1 Objective data on the patients’ tumor size before and after imatinib SOD of target lesions Response No.
Tumor location
Before imatinib
After imatinib
Choi criteria
RECIST criteria
Joint clinic assessment of responsea
1
Stomach
10.8
9.7
PR
SD
PR
2
Stomach
2.6
2.1
PR
SD
PR
3
Stomach
10.8
3.7
PR
PR
PR
4
Stomach
6.9
3.7
PR
PR
PR
5
Stomach
8.4
9.2
SD
SD
SD
6
Stomach
9.8
9.1
SD
SD
SD
7 8
Stomach Stomach
12.0 22.5
6.0 9.3
PR PR
PR PR
PR PR
9
Stomach
3.1
3.6
SD
SD
SD
10
Stomach
13.5
10.5
PR
SD
PR
11
Stomach
13.4
12.5
SD
SD
PR
12
Duodenum
7.2
6.1
PR
SD
PR
13
Duodenum
18.0
9.0
PR
PR
PR
14
Duodenum
6.7
6.0
PR
SD
PR
15
Duodenum
6.5
6.0
SD
SD
SD
16
Jejunum
12.0
14
SD
SD
PR
17
Stomach
NA
NA
NA
NA
CR
18
Stomach
NA
NA
NA
NA
CR
19
Stomach
NA
NA
NA
NA
CR
20
Stomach
NA
NA
NA
NA
PR
21
Stomach
NA
NA
NA
NA
PR
22 23
Duodenum Duodenum
NA NA
NA NA
NA NA
NA NA
SD PR
24
Jejunum
NA
NA
NA
NA
PR
25
Jejunum
NA
NA
NA
NA
PR
26
Colon
NA
NA
NA
NA
PD
27
Rectum
NA
NA
NA
NA
PR
28
Rectum
NA
NA
NA
NA
PR
29
Pancreas
NA
NA
NA
NA
PR
SOD sum of diameters, CNA scans were not available in the hospital database for radiology review, PR partial response, CR complete response, SD stable disease, PD progressive disease, RECIST Response Evaluation Criteria in Solid Tumors a
•
•
Joint clinic decision was based on comparison of hard copies of scans (not available later for review)
Unresectable and metastatic disease (n = 8): Five of eight patients initially deemed to have unresectable GISTs (two gastric, two duodenal, one colonic) did undergo resection after neoadjuvant imatinib. Three of the five patients underwent R0 resection; the remaining two (one duodenal, one colonic) underwent primary tumor resection, but metastases were left behind making them R2 resections. The remaining three (of the eight) patients whose tumors were deemed resectable underwent R2 resections due to the presence of peritoneal deposits (two gastric, one jejunal). Locally advanced but resectable disease (n = 21): The remaining 21 patients underwent R0 resections. Among them, eight patients who were originally planned for possible total/proximal/distal gastrectomy, a wedge
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resection of the stomach was performed. Another three patients, all planned for total gastrectomy, underwent proximal, distal, and subtotal gastrectomy, respectively. Four patients, possibly requiring pancreatoduodenectomy for duodenal lesions, underwent pancreas-preserving duodenal resection. Two patients having large jejunal masses underwent single-segment resections. For two patients originally requiring abdominoperineal resection, an ultra low anterior resection was performed in one. The other had the mass removed locally through a transperineal approach. In two patients (planned for total gastrectomy and pancreatoduodenectomy), the treatment plan did not change even after neoadjuvant imatinib. Details of the surgical procedures performed after neoadjuvant imatinib are provided in Table 2.
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(a)
(c)
(b)
(d)
Fig. 1 a Axial computed tomography (CT) of a duodenal gastrointestinal stromal tumor (GIST) before imatinib. b Axial CT image of the duodenal GIST (8 months after imatinib). c Axial CT image
shows a large GIST along the posterior wall of the stomach. d Axial CT image shows the reduced size of the GIST after imatinib
The mean blood loss was 883.3 ml (range 50–5,000 ml), and the median hospital stay was 10 days (range 3–32 days).
were classified into very low-, low-, intermediate-, and high-risk categories, respectively. Adjuvant imatinib
Postoperative complications There were a total of four complications, for an incidence of 13.8%. One patient who underwent lateral wedge duodenectomy developed a minor leak but was managed conservatively. One patient required reexploration because of bleeding from a raw area, with multivisceral resection. One patient had a wound infection. Pathology The mean mitotic index was 6.6 mitoses/50 hpf (range 0–20). In all, 28 of 29 (96.6%) patients were C-kit-positive, and 1 was negative. In this group, 3, 2, 5, and 19 patients
After resection, 25 patients were given adjuvant imatinib, and 3 were not. Data were not available for one patient. Follow-up Postoperatively, the mean follow-up was 10 months (range 2–52 months). There were no deaths. Locoregional recurrence was found in one patient and distant metastasis in two. A few of the patients were lost to follow-up, and data for the remaining patients were analyzed. Six patients were nonresponders (one PD and five SD). The patient with PD had extensive liver metastases and a primary colonic mass and thus underwent R2 resection.
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Table 2 Surgical procedures after neoadjuvant imatinib No.
Treatment option before imatinib
Duration (months)
1
Proximal/total gastrectomy in presence of liver metastases
9
2
Proximal/total gastrectomy in presence of liver metastases
36
Wedge resection of stomach
R0
No
3
8
Wedge resection of stomach
R0
No
4
Proximal gastrectomy in a previously resected GIST at the same site Proximal gastrectomy in presence of omental metastasis
12
Wedge resection of stomach
R2
Yes
5
Proximal gastrectomy
4
Wedge resection of stomach
R0
No
6
Proximal/total gastrectomy
12
Wedge resection of stomach
R0
No
7
Distal gastrectomy
3
Wedge resection of stomach
R0
No
8
Distal gastrectomy
7
Wedge resection of stomach
R0
No
9
Total gastrectomy
4
Distal gastrectomy
R0
No
10
Total gastrectomy
11
Total gastrectomy ? left hepatectomy
12
Total gastrectomy
13
Gastrectomy with distal pancreatosplenectomy
24
14 15
Unresectable gastric mass Unresectable gastric mass
16
Borderline resectable left hypochondrial mass extending up to left lumbar region in presence of generalized metastatic nodules
17
4
Surgical procedure after imiatinib
R status
Metastasis
Wedge resection of stomach
R0
No
Proximal gastrectomy
R0
No
Subtotal gastrectomy with left lateral segment wedge resection of liver
R0
No
Total gastrectomy
R0
No
Wedge resection of stomach
R0
No
14 8
Wedge resection of stomach Wedge resection of stomach
R0 R0
No No
18
Wedge resection of stomach with splenectomy and diaphragm resection
R2
Yes
Unresectable duodenal mass with liver infiltration
7
R2
Yes
18
Large jejunal mass involving bowel loops requiring multiple segmental resections
7
Distal gastrectomy with R2 resection of mass with cholecystectomy Single small bowel resection and anastomosis
R0
No
19
Large jejunal mass involving bowel loops requiring multiple segmental resections
6
Single small bowel resection and anastomosis
R0
No
20
3
Yes
25
Single small bowel resection and anastomosis Pancreas-preserving duodenal resection
R2
21
Jejunal mass resection in presence of peritoneal and mesenteric deposits Unresectable duodenal mass
R0
No
22
Pancreatoduodenectomy
12
Pancreas-preserving duodenal resection with Roux-en-Y gastrojejunostomy
R0
No
23
Pancreatoduodenectomy
9
R0
No
24
Pancreatoduodenectomy in presence of suspicious liver lesions
22
Pancreas-preserving duodenal resection with cholecystectomy and gastrojejunostomy Pancreas-preserving duodenal resection
R0
No
25
Pancreatoduodenectomy
6
Pancreas-preserving duodenal resection
R0
No
26
Pancreatoduodenectomy
10
Pylorus-preserving pancreatoduodenectomy
R0
No
27
Abdominoperineal resection
11
28
Abdominoperineal resection
3
29
Unresectable colonic and pelvic mass
36 8
36
Ultra-low anterior resection
R0
No
Local excision via transperineal approach
R0
No
Segmental resection anastomosis of colon with R2 resection of mass
R2
Yes
GIST gastrointestinal stromal tumor
This patient was lost to follow-up 1 year after surgery. The five patients with SD underwent R0 resection. Two of these patients were operated on in March 2011 and are without disease recurrence as of this writing. The
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remaining three patients are alive with no evidence of disease and have been followed up for 15, 27, and 52 months, respectively. The details of patient follow-up are provided in Table 3.
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Table 3 Patient follow-up Patient status
Mean follow-up period
Neoadjuvant imatinib group (no.)
Alive without disease
10 Months (range 2–52)
26
Alive with disease
16 Months (range 5–24)
3
Locoregional recurrence
One recurrence during third year
1
Distant metastasis (liver, peritoneum, lung, bone)
7.5 Months (range 5–10)
2
Lost to follow-up
2 Months (range 0–3)
4
Death
None
0
Overall survival
1 Year
25 (100%)
2 Years
11 (100%)
3 Years
6 (100%)
Discussion For some GISTs, owing to their large size and proximity to other vital structures, resection becomes difficult or incomplete with expected increased risk of tumor spillage and/or hemorrhage with major functional morbidity. Large proximal stomach GISTs often are subjected to total or proximal gastrectomy. Additionally, multivisceral resection may be needed. These are major procedures with considerable morbidity and even mortality. Similarly, duodenal GISTs (especially on the medial wall or they are large tumors) make surgical decision-making difficult owing to the peculiar anatomy of the pancreatoduodenal region. In the above-mentioned scenarios, all patients were counseled for possible major resections, including pancreatoduodenectomy and abdominal perineal resection. By offering neoadjuvant imatinib in such situations, we observed objective downsizing, enabling more conservative resections with increased safety. A study in 16 Egyptian patients showed considerable tumor shrinkage after 6 months of neoadjuvant imatinib. The authors concluded that neoadjuvant imatinib is safe for increasing resectability and improving the prognosis for locally advanced and unresectable GISTs [15]. With regard to quality of life issues, very low rectal GISTs run the risk of an abdominoperineal resection with a permanent colostomy. In our experience, the administration of neoadjuvant imatinib enabled sphincter conservation and the potential risk of neurologic dysfunction in these situations. Raut et al. [16], in a study of 69 patients, showed that although surgery may extend the benefits of neoadjuvant imatinib in patients with SD or limited PD surgery has no
benefit in patients with generalized PD. In our study, 80% patients had PR or CR, which enabled successful resection of borderline resectable and locally advanced tumors after neoadjuvant treatment with imatinib. Even in the remaining 20%—the nonresponders—the patient with PD did well for 1 year after surgery but was lost to follow-up thereafter. More encouragingly, the remaining five nonresponders underwent R0 resection after neoadjuvant imatinib. Two of these patients were operated on recently (in 2011) and are without disease recurrence to date. The remaining three are alive with no evidence of disease at 15, 27, and 52 months, respectively. Compared to the study of DeMatteo et al. [17], wherein a satisfactory response was achieved after 15 months of neoadjuvant imatinib, our series observed a satisfactory response after a median of 8.5 months, which is more in keeping with the recent French trial where the median duration of neoadjuvant imatinib was 7.3 months [18]. The optimal duration of neoadjuvant imatinib remains unknown. In a Phase III European Organization for Research and Treatment of Cancer (EORTC) trial, the median time to best response was 4 months, but some responses were also documented later [19]. National Comprehensive Cancer Network (NCCN) [9] guidelines recommend neoadjuvant imatinib in unresectable GISTs for 3–6 months with close observation and should undergo surgery as soon as R0 resection is a possibility. Imatinib can then be restarted later, after resection. DeMatteo et al. [17] observed that after resection 20 patients with imatinib-responsive disease had a 2-year overall survival (OS) of 100% compared with 36% in 13 patients who were imatinib-resistant. Similarly, Gronchi et al. [20] showed that patients with advanced or metastatic GIST responsive to imatinib had a postsurgery 2-year disease-free survival (DFS) of 100% and a 1-year progression-free survival (PFS) of 96% compared with 60 and 0% in patients with disease progression at median followup visits of 29 and 12 months, respectively. Furthermore, the French trial reported 3-year PFS and OS rates of 67 and 89%, respectively [18]. The RTOG 0132/ACRIN 6664 trial allocated patients who had taken imatinib for 8–12 weeks preoperatively into two groups: patients with primary GIST and those with operable metastatic GIST. After surgery both groups were given adjuvant imatinib for 2 years. Early results showed that the 2-year PFS rates were 82.7 and 77.3%, respectively. The OS rates were 93.3 and 90.9%, respectively, for the primary and metastatic GIST groups at a median follow-up of 3 years [21]. Edema, particularly periorbital edema, and liver dysfunction were reported as important side effects of imatinib administration [7, 22]. In our series, two patients developed periorbital edema on preoperative imatinib administered for [12 months. The real concern with this regimen is the
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possibility of developing resistance to imatinib, especially in adjuvant and metastatic cases. The optimal strategy after imatinib resistance on standard-dose therapy has not been established. Options would include dose escalation to 400 or 800 mg/day or to proceed to a second-line multitargeted tyrosine kinase inhibitor (e.g., sunitinib). The EORTC 62005 study of 946 patients with high-dose imatinib showed no difference in PFS with their longer median follow-up of 40 months. Some studies have suggested a clinical benefit in about 30% of patients from a higher dose of imatinib, albeit with a concomitant increase in the side effects profile [20, 23]. There have also been promising data from a randomized controlled trial of sunitinib that have shown a median time to progression of 27.3 versus 6.4 weeks with placebo (hazard ratio 0.33, p \ 0.0001) in patients who had failed imatinib or who could not tolerant it [24]. However, until more dose– response studies become available, surgeons who want to adopt this regimen should use the lowest effective dose for the shortest possible duration. We found that 400 mg daily for 3–8 months was most likely the optimal regimen, given our encouraging findings in this small series. At this juncture, it is important to mention that in our series patients were reevaluated every 8 weeks in our joint clinics and neoadjuvant imatinib therapy was individually tailored based on a combination of objective tests: radiologic response, alleviation of symptoms, and the feasibility of offering surgery (based on patient willingness to undergo surgery, fitness for anesthesia, and the hospital wait list). A multidisciplinary approach in the management GISTs is crucial for optimizing patient management and improving outcomes. Surgical resection remains the cornerstone of treatment, and the completeness of the primary resection (R0 vs. R1 or R2) influences the prognosis of patients with a GIST [25]. Surgery should thus aim at complete tumor removal and preservation of function without compromising the completeness of resection, as seen from the results of studies conducted by DeMatteo et al. [26, 27].
Conclusions Preoperative imatinib for locally advanced or borderline resectable GISTs is crucial not only to downsize and reduce the magnitude of major surgery but also reduce functional loss. Until evidence-based guidelines are available, a daily dose of 400 mg for 3–8 months before surgery may be valid option. Based on our experience, however, we believe that imatinib therapy should be tailored according to individual patient response for improving resectability potential with organ and function preservation. Surgery remains the best treatment option for resectable GIST and
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is performed with a low complication rate even in patients treated with neoadjuvant imatinib. For intermediate- and high-grade GISTs, adjuvant imatinib ensures disease control and aids in long-term survival. Conflicts of Interest
The authors declare no conflicts of interest.
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