Recent Advancements in the Treatment of Rectal Gastrointestinal Stromal Tumor: In Era of Imatinib.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, with an annual incidence of 10-15 cases per million. However, rectal GIST has a low incidence, accounting for approximately 0.1% of all rectal tumors. The treatment of rectal GISTs is still controversial and the relative unified guidelines and consensus opinions are inadequate. Treatment is based primarily on the clinical experience of the physician. The widespread application of neoadjuvant imatinib therapy allows diversification of treatment, especially in the choice of surgical methods. Herein, we reviewed the most recent literature and summarized the new progress in rectal tumor treatment, with the aim of providing patients with more systematic and individualized therapeutic strategies.

Introduction

Gastrointestinal stromal tumor (GIST), as the most common mesenchymal tumor of the gastrointestina tract, the annual incidence is 10–15 cases per million.1 GISTs are believed to originate from the pacemaker cells in the intestinal tract called Cajal interstitial cells. Activating mutations of KIT or PDGFRA oncogenes are considered the key molecular drivers of GIST pathogenesis.2 Most GISTs originate in the stomach (50–60%), followed by the small intestine (20–30%), the colon or rectum (5–10%), the esophagus (<5%), and occasionally outside the gastrointestinal tract.3 Rectal GISTs are very rare with a low incidence, accounting for approximately 0.1% of all rectal tumors.4 Given the anatomical characteristics, including a narrow, deep pelvis and the vicinity to the sphincter or invasions of other organs, these factors make surgery difficult. Surgical resection without lymph nodes resection is still the most standard method treatment for local rectal GISTs. The selection of surgical methods for rectal GIST remains controversial. Laparoscopic surgery and minimally invasive surgery for rectal GIST are both safe and feasible, not only for improving prognosis but also for preserving the patient’s quality of life. Recent studies have also focused on the efficacy of combined treatment for rectal GIST, including perioperative treatment with imatinib mesylate (IM). This article reviews the current treatment of rectal GIST.

Treatment of Rectal GISTs

Local Rectal GISTs

Resectable Rectal GISTs: Surgery

As in any other GISTs, surgical resection without lymph nodes resection is the most standard treatment method for GISTs. The achievement of histologically negative margins in the surgical management has been confirmed beneficial for resectable rectal GIST.5 Complete resection, as the key procedure in the treatment of rectal GIST, can ensure total tumor resection and avoid tumor rupture.6 However, the choice of the surgical procedure remains controversial. Low rectal GISTs are a particular challenge because radical resection is associated with significant morbidity, and when the sphincter or pelvic floor muscles become involved, abdominal perineal resection and permanent colostomy are required. Given that local GIST does not require lymph node removal and that radical excision beyond the mesentery for local GIST is associated with more complications, there is growing enthusiasm for local excision of these lesions. Several studies have also compared local resection (LR) with residual section (RE) and found the superiority of LR with a shorter operative time, less bleeding, and a rapid recovery, while oncology outcomes are similar. LR is an effective procedure for rectal GIST resection and warrants clinical endorsement.7,8 Various surgical techniques for LR have been widely described for the therapy of rectal GIST, including traditional transanal, transanal minimally invasive endoscopy,9 transacral, the perineal resection, and the transvaginal approach.

Transanal (TA) resection was first described by Parks as an alternative treatment for some rectal tumors in 1970.10 An early study revealed that traditional transanal (TA) resection can preserve anal function to the maximum extent possible in low- and mid-rectal lesions with a negative margin.11 The study compared transanal with none transanal in the treatment of rectal GIST. TA resection has a minimally invasive effect, fewer postoperative complications, a high anal sphincter preservation rate, an R0 resection rate, and a better prognosis.12 Given that local recurrence rates are high due to poor excision quality and tumor fragmentation of tumor,13 the transanal minimally invasive endoscopic excisions may lead to improved outcomes. The superiority of minimally invasive endoscopic transanal resection includes transanal minimally invasive surgery (TAMIS), transanal endoscopic microsurgery (TEM), with transanal endoscopic operation (TEO) receiving increasing attention.14

Transanal endoscopic microsurgery (TEM) is widely used in the treatment of local rectal lesions and helps avoid radical surgery. One study reported the results of 7 cases with TEM and only 1 patient experienced recurrence. Two of the 7 patients presented slight complications after surgery.15 A recent study16 reported that among 42 patients that had undergone a TEM procedure only 4 cases experienced recurrence or metastasis. Four patients presented complications after surgery and all patients recovered smoothly after conservative treatment. We summarized three larger retrospective studies in Table 1 and confirmed that the TEM is a feasible procedure for rectal GIST to maintain anal function fewer recurrences or metastases. However, TEM has been slow to become widely adopted by surgeons, and due to the high cost of highly specialized instruments.17 TAMIS, a hybrid between TEM and single-port laparoscopy, was reported in 2010 by Atallah et al. The authors concluded that TAMIS is a viable alternative to TEM at a much lower cost.18 We reviewed three larger retrospective studies of 7 cases without recurrence or metastasis, and confirmed that the TAMIS is a practicable approach for rectal GIST to preserve anal function with less recurrence or metastasis. In another approach to transanal endoscopic operation (TEO), only 1 study has reported the results of retrospective studies in detail (Table 1). The tumors of 2 patients were located in the anterior wall of the rectum and were treated with TEO. Two patients were followed up for 14 and 8 months, respectively, and no metastasis or recurrence was found. The transsacral approach (TSC) of preserving anal function can obtain a good oncological result and is particularly suitable for exogenous mid- and low-rectal GISTs. Two reports19,20 described 3 patients with transsacral procedures and neither complications no recurrence/metastasis after surgery. The adoption of the transsacral approach was considered as the treatment of choice for a rectal GIST. However, a recent study described the outcomes of 17 patients with TSC. Although all patients have a good oncological prognosis, 7 of the 17 patients experienced postoperative complications.21 Anastomotic leakage was found in 5 cases and poor wound healing in 2 cases. Two patients with anastomotic leakage recovered after conservative treatment, including without forced drainage and lavage, and one patient underwent sigmoidostomy. The TSC needs to be validated by further large-scale studies. Para-sacral approaches have also been applied in the therapy of rectal GISTs. Tokunaga et al22 showed that the para-sacral approach is simple and minimally invasive for local rectal GISTs. Matsumi23 et al showed that the para-sacral approach is effective for patients with tumors located between the urethra and the anterior wall of the low rectum in a recent study. To date, few large-scale reports demonstrate the superiority of this approach. Transsacral and transanal resection is beneficial for tumors located in the posterior wall, the areas of the middle or upper rectum.6,20 Although transanal resection is minimally invasive, tumors larger than 4 cm may be difficult to remove through the anus. When the tumor is located in the lower rectal region and is enclosed by the vaginal-rectal septum, the transvaginal approach is an alternative to a low or ultralow anterior resection surgery. However, enucleation without fragmentation may increase the risk of recurrence. We review the 4 studies associated with the transvaginal approach. Table 1 shows all of these patients had tumors of at least 5cm in size. There were no postoperative complications or tumor recurrence or metastasis at the follow-up date. The transvaginal approach is safe and feasible, especially if the tumor is large and is located in the anterior wall of the lower rectum. The perineal approach, which allows safe and effective excision of a tumor without disturbing the rectal anterior wall.24 The 4 cases included in our table were successfully resected with no perioperative complications, including metastasis or recurrence. GIST near the anterior wall of the rectum, anal sphincter, prostate, or urethra, but not invasive tumors can achieve safely and organ-preserving radical resection using the perineal approach. Robotic surgery has also been reported to have feasible and safe advantages, without morbidity or mortality, and that ISR provides bowel continuity and no need for colostomy.25 However, due to the high requirements of robotic surgery for surgical space, the difficulty of pelvic surgery has increased significantly, although there are few relevant studies in the literature.

Table 1

Local Resection for Rectal GISTs

Surgical Method	Year	Author	N. Patients	Rates of nIM	Duration of nIM (Month)	Tumor Size (cm)	Complication	Metastasis /Recurrence	Postop Imatanib	Distance from AV (cm)	Location
Transvaginal	2006	Hellan26	1	N	N	8	N	N	N	3	A
	2012	Hara27	1	N	N	5	N	N	N	6	A
	2019	Wang28	2	N	NA	5	N	N	Y	3	A
				N	NA	4	N	N	Y	5	A
	2021	Marta29	1	N	NA	5.1	N	N	N	2.9	A
Transsacral	2014	Sun30	2	Y	7	5/3.3#	1	N	N	5	A
				Y	3	4.5/3.0#	0	N	N	NA	A
	2007	Matsushima19	2	N	NA	4.1	N	N	N	5	NA
				N	NA	5.5	N	N	N	NA	A
	2008	Gervaz20	1	N	NA	6	N	N	N	NA	P
	2021	Qin21	17	Y:15$	7	4.2	7	1	Y:14	3.3	NA
Para-sacral	2021	Matsumi23	2	Y	5	3.7/1.9#	0	N	NA	3	A
				Y	5	9/6.4#	1	N	NA	NA	A
	2018	Tokunaga22	2	N	N	5	N	N	NA	NA	A
				N	N	4.1	N	N	NA	NA	P
Transperineal	2010	Yanovskiy31	1	N	N	NA	N	N	NA	NA	A
	2008	Madoka32	1	Y	3	3/1.2#	N	N	N	N	A
	2014	Kinoshita33	1	N	N	2	N	N	N	4	A
	2019	Inna24	1	N	N	NA	N	N	Y	NA	A
TAMIS	2021	Kanesada34	1	Y	3	5/3.5#	NA	N	N	NA	NA
	2019	Spinelli35	1	Y	7	2.0/1.5#	N	N	Y	2	NA
	2018	Spinelli9	1	N	N	4.5	N	N	Y	7	P
	2016	Pintor11	3	N	N	2.0*	N	N	N	8	NA
				N	N		N	N	N	9	NA
				N	N		N	N	N	12	NA
TEM	2021	Bai16	42	16	NA	4.41/2.46#	4	4	Y:15$	NA	All
	2021	Punnen15	7	N	NA	2*	2	1	Y	3.9*	All
	2018	Wu36	35	Y:12$	6	3.1/2.6#	NA	N	NA	4*	NA
	2017	Liu37	1	Y	12	1.9/1.5#	N	N	Y	4	NA
	2017	Han38	25	Y:8$	6	1.85*	N	N	Y:8$	4.52*	All
	2019	Christopher39	1	Y	5	5.8/NA#	N	N	Y	3	NA
TEO	2017	D’Hondt40	2	1	4	8/1.5#	0	N	Y	2	A
				2	N	5	1	N	Y	4	A
Open surgery via anus	2020	Sun41	11	Y	7	4.0/2.0#	1	N	N	N	NA

Notes: *Mean; #Tumor size after neoadjuvant imatinib; $Number of patient with imatinib.

Abbreviations: TEO, transanal endoscopic operation; TAMIS, transanal minimally invasive surgery; TEM, transanal endoscopic microsurgery; N, no; Y, yes; NA, unknown; A, anterior; P, posterior.

Several recent approaches of endoscopic resection for rectal GISTs including the submucosal tunneling endoscopic resection (STER) technique, endoscopic submucosal dissection (ESD), and laparoscopic and endoscopic cooperative surgery (LECS) have been reported as the treatment of choice for local GISTs. Ishida et al described 88-year-old anemic woman with a 5 cm rectal submucosal tumor, the tumor was successfully resected by ESD with a negative margin.26 The STER technique successfully removed a 1.5-cm tumor arising from the inherent muscularis layer.27 LECS for rectal GI stromal tumors in patients with GISTs originating in the upper rectum may be a feasible procedure that achieves R0 resection while preserving the rectal function.28 Therefore, endoscopic resection for patients with rectal GIST is also a suitable method and worthy of further investigation.

Local Advanced GISTs: Neoadjuvant Imatinib Therapy with Surgery

IM, a specific tyrosine kinase receptor inhibitor (TKI), was approved by the US Food and Drug Administration (FDA) as the first-line treatment for advanced GIST in February 2002.29 IM is also the only TKI currently available for neoadjuvant therapy (nIM), and the standard dose is 400 mg/day.30,31 However, a case report also showed that sunitinib was selected for neoadjuvant therapy for gastrointestinal stromal tumors firstly. First-line neoadjuvant therapy with sunitinib produced good clinical outcomes in 2 patients with very large rectal GISTs adjacent to the prostate and bladder.32 The inclusion criteria for neoadjuvant therapy remain not well defined. Some studies have suggested a tumor size cut-off of 5 cm to start nIM while other studies recommend starting treatment in high-risk tumors.5,33–35 The European Society for Medical Oncology (ESMO) guidelines suggested that when R0 resection is not feasible, or the tumor can be removed with minor surgery through reduced cells,36 nIM will help reduce tumor size before surgery, preserving the sphincter in most cases. Rutkowski et al collected 161 local advanced GIST patients treated with nIM and showed nIM combining surgery with a good long-term result.37 Neoadjuvant treatment of rectal GISTs with IM was first reported in 2005 to achieve negative resection margins and preservation of the anal sphincter.38 When considering neoadjuvant therapy, diagnosis by biopsy is generally standard practice. One study39 suggested that for larger locally advanced lesions, a biopsy should be performed, preferably with an endoscope-guided fine needle puncture, to confirm the diagnosis before neoadjuvant therapy. When nIM is considered for GISTs, a molecular analysis should also be performed at the same time. However, we should avoid using nIM for wild-type GISTs.40 Most GISTs had a KIT mutation, including exon 11 (90%) or exon 9 (8%) and, less in exon 13 or exon 17.41 The mutant genotype of the rectal stromal tumor is unknown. Kameyama et al described several studies and found a proportion (59–100%) with exon 11 mutations in rectal GISTs.42 We have summarized all published studies including gene analyses since the article was published, all results in Table 2. The gene mutations of rectal GIST include KIT exon 11, KIT exon 9, KIT exon 13, PDGFR-a12, and wild type. We identified a higher proportion (71–90%) of rectal GISTs carrying c-KIT exon 11 mutations. Therefore, the exon mutations of rectal GISTs are similar to GISTs in other sites. For rectal GIST with exon 11 mutations, IM also obtained good therapeutic results. Heinrich et al43 showed that the ratio of objective response is 71.7% for rectal GIST with exon 11 mutations after nIM therapy. Yang et al44 also found the benefits which partial response occurred in 23 of 25 patients with c-KIT exon 11 after nIM therapy.

Table 2

Larger Scale Genotypes in Rectal GISTs

Year	2021	2021	2020	2020	2020	2019
Author	Yang60	Yong61	Sun41	Guo7	Nikki62	Emelia63
Number of patients	31	13	11	10	156	26
Exon11	25	11	9	9	110	23
Exon9	4	2	2	0	21	2
Exon13	0	0	0	0	5	1
PDGFR-a 12	0	0	0	1	1	0
Wild type	2	1	0	0	19	0

Abbreviation: GIST, gastrointestinal stromal tumor.

IM, as a first-line nIM of rectal GISTs, was widely accepted. Similarly, the dose of IM with 400mg/d is most effective for patients with rectal GISTs. However, the optimal duration of nIM is still controversial. If the maximal response appears in the GISTs, IM should be discontinued. The maximal response is considered that when the tumor does not shrink further after two sequential computed tomography scans. The guidelines of the National Comprehensive Cancer Network (NCCN) guidelines suggested that the duration of maximum response may be at least 6 months.45 However, a recent larger study reported that treatment for GISTs located in the rectum seemed to have a longer median duration of 10.0 months.46

In locally advanced or unresectable cases, nIM can improve resectability or may reduce the incidence of complications and improve relapse-free survival.34 The study reported that recurrence rate after surgery was >25%, and the average survival time was less than 34 months.47 Neoadjuvant therapy generally prevents local recurrence and improves overall survival (OS), regardless of tumor size and risk stratification. Yong et al48 compared the patients receiving neoadjuvant therapy with patients undergoing surgery alone. They concluded the conclusion that neoadjuvant TKI has the benefit of downsizing unresectable rectal GIST to benefit from the sphincter-sparing procedure and also confers protection against local recurrence and improves OS. The application of nIM significantly decreased tumor size in large localized rectal GIST, allowing LR to preserve the sphincter and has maintained satisfactory anal function. Bai et al, reported that 16 patients were treated with nIM, resulted in 16 patients undergoing sphincter-sparing surgery that would otherwise require abdominal peritonectomy or pelvic tumor removal.16 However, another study reported LR for 7 patients without nIM and 4 cases of 7 patients with a positive margin. Previous studies have also confirmed that tumor size reduction by preoperative neoadjuvant IM was significantly reduced and improved the preservation rate of the anus. After IM treatment, the anal retention rate increased from 14.2% to 33.0–94.9%.42 Laparoscopic surgery with the advantage of adequate visualization for deep pelvic lesions has been used successfully in rectal GISTs.49–51 The effectiveness of nIM combining laparoscopic surgery has been described in several recent articles with an advanced and larger tumor.52,53 Although there are limited data on the treatment of rectal stromal tumors by laparoscopic surgery, this approach appears to be feasible, especially for locally advanced tumors. We summarized the laparoscopic resection of rectal GISTs nearly 10 years of articles in Table 3. From the results, we determined that most of the patients selected preoperative neoadjuvant therapy because they refused permanent stoma or serious invasive surgery. Neoadjuvant therapy was found to reduce tumor size in most tumors, complete R0 resection, and provided patients with the opportunity to choose surgery to preserve anal function. Furthermore, no recurrence or metastasis was found in all patients counted by the follow-up date. Although the rate of local recurrence of laparoscopic surgery is low, most patients are treated with laparoscopic surgery plus temporary transverse colostomy, which may affect patient quality of life and increase the possibility of ostomy complications. Further studies are needed. These results provide strong evidence that laparoscopic surgery is effective and safe for patients with rectal GISTs.

Table 3

Laparoscopic Surgery for Rectal GIST

Year	Author	Patients	Rates of nIM	Duration of nIM (Month)	Tumor Size (cm)	Complications	Metastatic or Recurrence (Yes or No)	Postopimatanib?	Distance from AV (cm)	Operation Method	Margin
2021	Nagakari70	1	Y	7	7.3/5.0#	N	N	Y	NA	LA+ colostomy	R0
2021	Matsuzuka71	1	Y	6	NA	N	N	Y	NA	NA	R0
2020	Emoto72	1	Y	7	5.5/3.8#	N	N	NA	2	LA+ colostomy	R0
2020	Nagano69	1	Y	8	10/7.8#	N	N	NA	NA	LA+ colostomy	R0
2016	Somu73	1	N	N	6.7	N	N	NA	3	LA+ colostomy	NA
2016	Wachter74	1	NA	NA	10	N	N	Y	NA	LA+ colostomy	R0
2016	Kyo68	1	Y	6	8/3.7#	N	N	NA	NA	LA+ colostomy	R0
2015	Ueki75	3	Y	NA	9/5.1#	Y	N	NA	3	LA +colostomy	R0
			Y	NA	4.8/3.9#	Y	N	NA	3	LA +colostomy	R0
			Y	NA	11/6.9#	Y	N	NA	3	LA +colostomy	R0
2014	Nozawa76	1	Y	12	4.5/2.4#	N	N	NA	2	NA	R0
2014	Yoshiya77	5	Y	NA	4.8*	N	N	NA	3.4*	LA+ colostomy	R0
2014	Piessen78	3	Y	NA	3.1/2.4#	N	N	NA	3	NA	R0
2012	Nakamura79	1	Y	3	8/5#	N	N	NA	NA	LA+ colostomy	R0

Note: #Tumor size after neoadjuvant imatinib.

Abbreviations: GIST, gastrointestinal stromal tumor; N, no; Y, yes; NA, unknown; LA, laparoscopic surgery; AV, anal verge; nIM, neoadjuvant imatinib.

Adjuvant IM After Surgery

The 15 years of recurrence-free survival (RFS) and overall survival (OS) time were found to be 59.9% and 12.4 years with surgery alone respectively.3 Although R0 resection was complete, nearly one-third of the patients experienced relapse after surgery.33 Therefore, for patients at high risk of recurrence, it is necessary to use adjuvant IM after surgery. In a Phase III trial, patients with primary GIST who had a complete resection of at least 3 cm were randomized to receive placebo or IM for 1 year after surgery. The 12-month IM group had significantly better RFS than the placebo group. Based on these data, IM has been approved by the US Food and Drug Administration (FDA) as a postoperative adjuvant therapy. The SSG XVIII trial also included tumors at high risk of recurrence, with 36 months of adjuvant IM significantly improving RFS compared to 12 months of adjuvant therapy. Furthermore, the guidelines recommend that adjuvant therapy should continue for three years in high-risk patients. For intermediate-risk patients, there is still controversy. The consensus in China suggests that patients with moderate risk of small bowel or rectal stromal tumor should receive adjuvant IM for 3 years, while patients with moderate risk of gastric stromal tumor only need 1 year of adjuvant therapy.54,55 Recent studies have confirmed that approximately 50% of deaths during the first 10 years of postoperative follow-up can be avoided in high-risk patients who are treated with adjuvant IM for a longer period of time.56 Therefore, long-term adjuvant IM therapy is recommended for patients at high risk of recurrence.

Treatment for Advanced/Metastatic Rectal GIST

Conventional Medical Therapy

IM was approved by the FDA as a first-line treatment for advanced GIST in February 2002.29 Two-phase III trials determined that 400 mg daily was the optimal dose of IM in advanced GIST. In the trials of S0033 and phase III European Cancer Research and Treatment Group 62,005 trials, both trials demonstrated a significant clinical benefit of IM 400mg/ day. This result was first reported in the B222257 study, which also reported longer progression-free survival (PFS) with IM 800mg/ day, but no difference in OS. Based on these data, the standard dose of adjuvant IM is 400mg/ day.29,58 The BFR1459 trial evaluated patients with advanced GIST whose tumors responded to IM or were in a stable state. At 1, 3, or 5 years after discontinuing IM treatment, patients who stopped treatment had shorter PFS compared to those who continued treatment. No significant differences were found in OS time when treatment resumed. Therefore, in the event of metastasis/recurrence of the disease, the medication should be continued indefinitely.

Second-line sunitinib malate therapy is typically initiated for advanced GIST in which the disease progresses or is not tolerated after first-line IM therapy. A phase III trial also showed significant improvements in PFS and OS in patients treated with sunitinib compared to those treated with placebo.59 Based on these data, sunitinib was approved by US FDA as a second-line treatment for advanced GIST.60

A Phase III study (GRID study)61 in patients with metastatic and/or unresectable GIST who progressed after IM and sunitinib treatment showed that regorafenib significantly improved median disease-free survival, but no statistically significant differences were found in the median survival between the two groups. Regorafenib is approved to treat patients with GIST who had previously failed treatment with IM and sunitinib.61,62 Regorafenib has a similar effect to sunitinib, benefiting mutations in KIT exons 11 or 9 in patients with primary tumors.

A report published in September 2020 revealed that all patients who received ripretinib as second-, third-, or fourth-line therapy significantly prolonged PFS by increasing the dose of ripretinib. The subsequent INVICTUS III study63 confirmed 6.3 and 1.0 months of m PFS, 15.1 and 6.6 months of m OS, respectively, compared to ripretinib and placebo. Based on these results, in May 2020, the US FDA approved ripretinib inclusion as the standard fourth-line treatment for advanced GIST patients who have failed three lines of TKI therapy, including IM. A Phase III trial is currently underway to test the efficacy of lapatinib versus sunitinib in advanced GIST patients who progress in a second-line setting or are intolerant to IM.64

The use of ripretinib for advanced rectal GIST was firstly presented in China.65 The tumor size did not improve further after the initial first to third-line treatments. However, tumors started to shrink after 3 courses of ripretinib treatment. Therefore, the use of mutation inhibitors at an early stage may be more precise and rational.

Of the exon 18 mutations, D842Y was sensitive to IM but resistant to sunitinib,66 most of the mutations, especially D842V, were not sensitive to IM. A Phase II trial reported that a GIST patient harboring a D842V mutation had a good response to dasatinib. Due to these initial therapeutic results, the NCCN added dasatinib to the treatment list of this molecular subtype.67 In a recent NAVIGATOR68 study of 56 advanced patients with the D842V mutation, avapritinib reduced tumors in the majority (98%) of patients. Thus, in January 2020, the US FDA approved avapritinib for the treatment of advanced or metastatic GISTs carrying PDGFRA exon 18 mutations. Avapritinib also received approval from the European Medicines Agency (EMA) on 24 September 2020.69 However, more cognition-related and intracranial hemorrhage adverse events should be closely monitored in clinical application. Therefore, patients with PDGFRA exon 18 mutations must receive avapritinib as first-line therapy.

Other Medicines Treatment

Selective TKIs of targeting secondary KIT mutations, including PLX3397, PLX9486, and AZD3229 are being studied. The integral combination treatment with PLX9486 with sunitinib, improving the median PFS for 2 months.70,71 AZD3229, a pan-KIT/PDGFRα inhibitor, showed good preclinical activity in gastrointestinal stromal tumor models and was deemed worthy of a clinical study. Preclinical studies have confirmed the effects of immune agents on KIT-mutated GIST. Balachandran et al verified the combination of IM and ipilimumab in animal models with KIT-mutated GIST. Compared to treatment alone, combination therapy exhibited synergistic effects and significantly reduced tumor size.72 ETV1 may also be the key to the resistance observed to IM treatment inherent in GIST, KIT-independent stem cell/progenitor cell survival and maintenance, demonstrated that this may be a potential therapeutic target to be considered in wild-type GIST.71 The study showed the benefits of the combination of IM and pinitinib for patients with advanced GIST with all genotypes. In particular, for 9 patients who have an unresectable tumor, the percentage of patients who switched to excision was 88.9%.73 These results confirm the advantages of the combination treatment compared to IM alone. Sirolimus has also been shown to be safe when added to sorafenib or sunitinib in the treatment of advanced tumor.74

Treatment Beyond Medicines: Radiotherapy

Palliative surgery is not considered necessary for recurrent or metastatic GISTs.75,76 However, radiotherapy is usually well-tolerated and the use of IM enhances sensitivity to radiotherapy.77 This limited use can be attributed to GIST’s shifting pattern and radiotherapy has been imposed restrictions on palliative intent.78,79 Radiotherapy can be an effective treatment for patients who cannot tolerate TKIs, are resistant to TKI, or exhibit unresectable tumors. Radiotherapy for rectal GIST alone is very rare. Pollock at al. reported a case rectal GIST with radiotherapy and reported a total treatment plan, treatment field in rectal GIST radiotherapy.80

Conclusions

The treatment of rectal stromal tumors is still dominated by surgery, and the specific surgical method is still controversial. The use of neoadjuvant IM provides better treatment feasibility. Local resection, including transanal, transacral, parasacral, perineal, and transvaginal resection can obtain a good oncological outcome and prevent the appearance of genitourinary and anal dysfunction. Laparoscopic surgery is a safe surgical technique that prevents the appearance of genitourinary and anal dysfunctions and completely resects the tumor, and is especially useful for advanced and larger tumors. Endoscopic resection for rectal GISTs arising from the inherent muscularis layer is also a suitable method and worthy of further investigation.