Abstract
Background/Aim: Intersphincteric resection (ISR) aims to preserve anal function in patients with very low rectal tumors. Here, we analyzed patients who underwent neoadjuvant imatinib therapy followed by ISR for low rectal gastrointestinal stromal tumors (GISTs). Patients and Methods: We retrospectively analyzed patients with low rectal GISTs who underwent neoadjuvant imatinib therapy and ISR between January 2013 and December 2015 at the University of Tokyo hospital. Results: The study included 4 men and 1 woman, with a median age of 67 years (range=45-67). All patients received 400 mg of neoadjuvant imatinib once daily for the median duration of 4 months (range=3-12). Microscopically, R0 resection was performed in 4 patients, and R1, in 1 patient. There was 1 recurrence event during the median follow-up duration of 35 months. Conclusion: Neoadjuvant imatinib therapy and ISR for low rectal GISTs is a challenging, but promising, alternative to achieve complete resection margins and preserve anal function.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and occur in about 10-15 people per million per year (1-3). GISTs have the features of leiomyosarcomas and neural tumors (4-6), appear to be derived from the interstitial cells of Cajal, and harbor activating mutations in the KIT (a receptor tyrosine kinase or RTK, also called CD117) gene (7). GISTs are commonly located in the stomach (50%) and the proximal small intestine (35%), but uncommonly in the rectum (5%) (8). Surgery is the only curative treatment for resectable GISTs. For locally advanced low rectal GISTs, radical excisions are performed with sphincter-sparing procedures, abdominal perineal resections, or more extended surgery, accompanied by the removal of adjacent organs. However, the recurrence rates are moderately high, about 40-60% within 2 years of treatment, despite undergoing complete surgical resections (9).
Currently, imatinib mesylate, a small-molecule inhibitor of the proto-oncogene c-KIT tyrosine kinase, is the first-line treatment for patients with locally advanced or metastatic GISTs, and is proven to improve recurrence-free survivals in adjuvant settings (10-13). Additionally, imatinib also provides a new approach for the treatment of GISTs, in neoadjuvant settings (14-16). In this regard, a few reports have described the efficacy of neoadjuvant imatinib therapy (17-23) and the combination of neoadjuvant imatinib therapy and intersphincteric resection (ISR) for the treatment of low rectal GISTs (22, 23).
The present study included patients who underwent neoadjuvant imatinib therapy followed by ISR for low rectal GISTs, and evaluated the responses of rectal GISTs to imatinib, based on the radiological assessments of tumors, and the outcomes of subsequent surgeries.
Patients and Methods
Patients. We retrospectively analyzed 5 patients with low rectal GISTs who underwent neoadjuvant imatinib therapy followed by ISR, between January 2013 and December 2015, at the University of Tokyo Hospital. Medical records of these patients were retrieved from our registry, and patient demographics, tumor characteristics, radiological findings, surgical outcomes, and postoperative follow-up data were collected. The study protocol was approved by the Ethics Committee of the University of Tokyo.
All patients underwent digital rectal examinations, colonoscopy, and imaging by computed tomography (CT) and magnetic resonance imaging (MRI), for disease evaluation. Additionally, they underwent pre-treatment core needle biopsies to confirm histology, and displayed positive immunostaining for CD117 (c-KIT). CT scans were obtained for staging before initiating treatment, and resectability was assessed based on MRI scans. Maximum tumor diameters were measured based on MRI or CT scans. Colonoscopy, CT, and MRI were performed repeatedly every 3 months to measure tumor responses to imatinib treatment. Patients with favorable responses were offered surgical treatment, whereas those with stable disease or the need for permanent stoma continued neoadjuvant therapy for the next 3 months. Pathology reports were reviewed to identify tumor histopathological characteristics, molecular analysis, and microscopic clearance. Risk classification was determined using the Joensuu classification (24). The disease evaluation was performed per the Response Evaluation Criteria in Solid Tumors (RECIST) (25).
Postoperative follow-up included the following procedures: physical examinations every 3 months, chest and abdominal CT scans every 6 months, and colonoscopy every 12 months. Adjuvant imatinib was administered to 1 selected patient for 3 years. Local and distant recurrences were defined by radiographic and histological findings.
Statistical analysis. Descriptive statistics are presented as median (range). The parametric two-tailed paired t-test was used to analyze changes in tumor sizes. The reported p-values are two-tailed, and values <0.05 were considered significant. Data were analyzed using EZR v.1.33 for Windows software (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (26).
Results
A total of 4 men (80%) and 1 woman (20%), with a median age of 67 years (range=45-75), were included in this study. Laparoscopic ISR was performed in all patients. The distal resection lines were at the dentate line (partial ISR), in all patients. No patient was lost to follow-up. The median maximum tumor diameter at presentation was 44 mm (range=40-64 mm). The median distance from anal verge to the lower margin of the tumor at surgery was 3 cm (range=2-4). Based on the Joensuu classification, 2 tumors (40%) were classified as high-risk and 3 (60%), as low-risk. All patients exhibited positive immunostaining for KIT. Demographic and clinical data of patients are presented in Table I.
Patient characteristics and treatment outcomes are presented in Table II. All patients were administered neoadjuvant imatinib at 400 mg, once daily, for the median duration of 4 (range=3-12) months. Dermatologic side effects occurred in 3 patients. In 2 of them, neoadjuvant imatinib therapy was ceased 3 or 4 months later, and surgery was performed. The median maximum tumor diameter at the time of surgery decreased significantly to 25 mm (range=18-42 mm) (p<0.01) (Figure 1). All patients experienced tumor reductions (partial responses as classified by RECIST) that allowed sphincter-preserving procedures. Pre- and post-treatment MRI scans for a representative patient with a rectal GIST are shown in Figure 2.
Maximum tumor diameters of rectal gastrointestinal stromal tumors, before and after neoadjuvant imatinib therapy.
Macroscopically, complete resections were achieved in all patients. The median time of surgery was 407 min (range=348-768 min), and the median estimated blood loss was 210 ml (range=50-1,320 ml). There were no intraoperative complications. Microscopically, R0 resection (complete resections with no residual tumors) was performed in 4 patients and R1 (tumor cells present near the resection margin) in 1. There were no deaths within 30 days of surgery. Postoperative complications were as follows: urinary tract infection and small bowel obstruction in 1 patient each, respectively. These complications were treated with conservative therapy. The median duration of postoperative hospital stay was 23 days (range=17-29 days).
The median follow-up period was 35 months (range=26-48 months). Postoperative imatinib was administered to 1 patient who underwent R1 resection, and was treated for 3 years after surgery. One patient experienced lateral pelvic lymph node metastases at 23 months after surgery, and has been treated with imatinib continuously since then. The 4 remaining patients were alive at the end of the follow-up period, without any evidence of local or systemic recurrence. Ileostomies were closed in 4 patients who showed good anal function after 5-10 months and good fecal continence after stoma closure. Stoma closure was postponed in 1 patient because of insufficient anal function. All patients showed good urinary functions.
Demographic and clinical data on patients included in the study.
Patient characteristics and outcomes of treatment.
Discussion
Surgery for rectal GISTs may be difficult because they are often large in size; no standard treatment strategies have been yet established for rectal GISTs because of the small number of such cases (27). The aim of surgery for low rectal GISTs is to achieve both microscopically negative resection margins and anal sphincter preservation. For these purposes, two aspects should be considered, namely, the preoperative use of imatinib, and the surgical procedure.
Treatment with neoadjuvant imatinib for patients with locally advanced or marginally resectable GISTs offers several potential benefits, including tumor down-sizing, preventing the intraoperative rupture of the tumor, providing an opportunity to maintain the functioning of the involved organs, and reducing the risks of recurrence. In fact, treatment with neoadjuvant imatinib successfully downsizes tumors and aids the performance of organ-preserving surgeries in patients with high-risk GIST tumors arising in the gastrointestinal tract (14, 28, 29). Fiore et al. reported that all patients with GISTs of the digestive tract showed a median reduction in tumor size of 34% with tolerable toxicities, following preoperative imatinib therapy, for a median duration of 9 months (14). Previous studies have reported response rates of 73-100% with no evidence of progressive disease following preoperative imatinib therapy in patients with rectal GISTs, for 1-60 months (18, 19, 21, 30). The European Society for Medical Oncology guidelines recommend neoadjuvant imatinib therapy for tumors under the following conditions: if R0 resection is not feasible, if resection could be achieved by less mutilating surgery, or if the surgical procedure could be made safer, for instance, by decreasing the blood loss and the risks of tumor rupture (31). Only a few reports have described the efficacy of neoadjuvant imatinib for rectal GISTs; these studies indicated that patients with rectal GISTs who received neoadjuvant imatinib therapy were associated with higher rates of R0 resections and improved disease-free and overall survivals (17, 18, 30). In the current study, 5 patients were treated with a combination of neoadjuvant imatinib therapy and surgery, and R0 (complete) and R1 resections were performed in 4 and 1 of the patients, respectively. This result was comparable to those of previous studies, where the patients underwent transabdominal resections (R0, 62.5-86.7%; R1, 13.3-37.5%) (20, 30).
Magnetic resonance imaging scans taken before (A1, A2) and after (B1, B2) neoadjuvant imatinib therapy for Case 4. The patient was administered 400 mg of neoadjuvant imatinib, once daily, for 4 months. The maximum tumor diameter decreased from 64 mm before imatinib treatment to 42 mm at the time of surgery (arrows), and R0 resection was achieved.
The optimal duration of preoperative imatinib therapy for patients with rectal GISTs has not yet been established. Surgery is performed following the maximal tumor responses to imatinib therapy, and prior to the occurrence of secondary mutations, which may occur generally after 6-12 months (31, 32). In the current study, surgery was performed after 3-12 months of treatment.
The decision of the appropriate surgical approach depends on several factors, including tumor size, location, and the presence of local invasion. There are mainly two types of surgeries: transanal local excision and transabdominal resection. The latter includes abdominoperineal resection, pelvic exenteration, anterior resection, and, recently, ISR (22). For small GISTs located close to the anal verge, transanal excision is the treatment of choice (20). However, this treatment is unsuitable for large GISTs because it is difficult to secure clear resection margins with transanal local excisions, when GISTs come in contact with adjacent organs, such as the prostate or vagina (22). A recent study including 39 patients with rectal GISTs reported that the local removal of tumors resulted in 11 of 21 (52%) R0, 9 of 21 (43%) R1, 1 of 21 (5%) R2 resections (30). For large GISTs situated in the lower rectum, abdominoperineal resections are often necessary to accomplish oncological complete resections.
ISR aims to preserve anal function in patients with very low rectal cancers (33). A recent study on treatment with laparoscopic ISR following imatinib treatment for low rectal GISTs, reported that laparoscopic ISR was found to be safe and feasible for downsized low rectal GISTs (22). During laparoscopic ISR, the reaching to the level of intersphincteric plane via the abdomen, and resection of distal margins can be performed under a direct view, thus potentially obtaining better safety margins than those obtained by the transanal approach and preserving the function of the anal sphincter, and hence, avoiding a permanent stoma. Laparoscopic surgery has been widely accepted as a minimally invasive surgical procedure. Although laparoscopic rectal surgery is challenging, a magnified view provides more precise images of the anatomy and the accuracy of the performed surgery. Dissecting tissue between the tumor and the seminal vesicles, prostate, or vagina to the level of the intersphincteric groove is difficult by laparotomy, but may be more feasible by laparoscopic surgery. There were no intraoperative complications, but minor postoperative complications were noted. During the follow-up period, recurrence was observed in only 1 patient, and the others were alive without evidence of local or systemic recurrence. Based on our results, we propose that laparoscopic or robotic assisted laparoscopic ISR is a promising alternative for low rectal GISTs.
This study is limited by its retrospective design and small sample size, and was carried out at a single institution. Therefore, additional studies with larger populations are required to confirm our findings.
In conclusion, this study demonstrated that a reduction in tumor size after preoperative imatinib therapy aided the performance of the sphincter-preserving procedure. A combination of neoadjuvant imatinib therapy and laparoscopic or robotic ISR for low rectal GISTs is a challenging, but promising, alternative to achieve complete resection margins, and preserve anal sphincter function.
Acknowledgements
This research is supported by Grants-in-Aid for Scientific Research (A: grant number, 16H02672; C: grant number, 16K07143; C: grant number, 16K07161; C: grant number, 17K10620; C: grant number, 17K10621; and C: grant number, 17K10623) from Japan Society for the promotion of Science. Additionally, this research is supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE, grant number: 16cm0106502h0001) from the Japan Agency for Medical Research and Development (AMED).
- Received June 29, 2017.
- Revision received July 9, 2017.
- Accepted July 10, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved