Preoperative tyrosine kinase inhibitors risk bowel anastomotic healing of advanced primary and recurrent/ metastatic gastrointestinal stromal tumors Jin-Chiao Lee1, Chun-Han Chen2, Tse-Ching Chen3, Chun-Yi Tsai1, Keng-Hao Liu1, Jun-Te Hsu1, Chun-Nan Yeh1, Ta-Sen Yeh1, Tsann-Long Hwang1, Yi-Yin Jan1, Min-Fu Chen1 Departments of Surgery,1 and Pathology,3 Chang Gung Memorial Hospital at LinKou, Chang Gung University Medical College, Taoyuan, Taiwan Departments of Surgery,2 Chang Gung Memorial Hospital at Chia-Yi, Taiwan

Background Surgery was the only effective treatment for gastrointestinal stromal tumor (GIST) before 2001 Dramatic improvement in GIST management was achieved with the use of tyrosine kinase inhibitors (TKI) For GIST, surgery was the only effective treatment before 2001 because of the limited response to chemotherapy and radiotherapy Until the use of tyrosine kinase inhibitors , including imatinib (IM), sunitinib (SU) and regorafenib, the outcome of GIST had dramatic improvement

Surgery after TKI Cytoreduction surgery in advanced GIST Recurrent GIST after adjuvant therapy Oncologic emergency during TKI treatment Resection after neoadjuvant TKI treatment Because of the wide-spread use of TKI, many patients underwent surgery after TKI treatment. There are four common surgical indications, including resection of recurrent GIST after adjuvant therapy, cytoreduction surgery in advanced GIST, Oncologic emergency during TKI treatment, such as bleeding, obstruction or perforation, and the last one is noeadjuvant TKI.

Postoperative complications Postoperative complication rate was high after use of TKI 58% after imatinib (DeMatteo R.P et al. Ann of Surg. 2007) 54% complications and 15.3% major complications after sunitinib (Raut C.P. et al. Ann Surg Oncol. 2010) (Yeh C.N. et al. Int J surg 2017) Despite the TKI and cytoreduction surgery gave patients better survival outcome, the postoperative complication rate was extremely high after use of TKI. Dr Dematteo reported the complications up to 58% after imatinib in 2007. and Dr Raut and Dr Yeh found 54% of the patients had complications and 15.3% of the patient had major complications after use of preoperative sunitinib. These reported complication rates were obviously higher than other elective surgery.

Aim Evaluate the effect of preoperative tyrosine kinase inhibitors on postoperative complications Our aim was to evaluate the effect of preoperative TKI on postoperative complications.

Patients and method

Patients Cohort From March 1991 to June 2017 Inclusion Criteria Patients who underwent surgery for pathologic proven GIST in CGMH – Linkou branch Exclusion Criteria Surgery for previous complications Patients without complete data Our patient cohort was from March 1991 ot June 2017. The inclusion criteria was the patient who underwent surgery for pathologic proved GIST in Linkou CGMH, and the surgery for previous complications or incomplete data were excluded from our study.

Method Patients were classified by use of preoperative TKI or not into 2 groups Postoperative complications were recorded according to the Clavien-Dindo classification We further classified the patients in to 2 group by use of pre-operative TKI or not. The postoperative complications was recorded according to Clavien-Dindo classification.

Results

Before Matching After Matching   Before Matching After Matching Factors Pre-OP TKI p value Yes (n=108) No (n=108) No (n=505) Age (years) <60 60 (55.6) 258 (51.1) 0.399 58 (53.7) 0.785 >60 48 (44.4) 247 (48.9) 50 (46.3) Sex 0.002 0.662 Male 72 (66.7) 253 (50.1) 75 (69.4) Female 36 (33.3) 252 (49.9) 33 (30.6) CCI 7 (6.5) 48 (9.5) 0.245 11 (10.2) 0.459 1-2 45 (41.7) 171 (33.9) 38 (35.2) >3 56 (51.9) 286 (56.6) 59 (54.6) Surgery with anastomosis <0.0001 0.561 Yes 71 (65.7) 461 (91.3) No 37 (34.3) 44 (8.7) Primary Site 0.018 0.676 Stomach 44 (40.7) 269 (53.3) 41 (38.0) Other 64 (59.3) 236 (46.7) 67 (62.0) Size 8.5 + 5.1 6.6 + 4.9 <0.001 8.5 + 5.3 0.976 Risk 0.300 None 3 (2.8) 57 (11.3) 6 (5.6) Very Low 3 (3.2) 94 (18.6) Low 21 (19.8) 85 (16.8) 12 (11.1) Medium 19 (18.6) 83 (16.4) 19 (17.6) High Unknown 3 (3.0) There were 613 patients who underwent surgery for GIST. 108 patients had preoperative use of TKI, we called them TKI group, and 505 patient had no use of TKI, we called them non-TKI group. We can see that there are several significant difference between two groups, including sex, surgery with anastomosis or not, primary site, size and risk. So we try to even out the bias between two groups. We did the propensity score matching, and there are 108 patients in each groups after matching. All the difference between two groups are even out. Then we check our primary outcome.

Post-operative complications   Before Matching After Matching Factors Pre-OP TKI p value P Yes (n=108) No (n=505) No (n=108) Post-OP complication <0.0001 Yes 37 (34.3) 35 (6.9) 11 (10.2) No 71 (65.7) 470 (93.1) 97 (89.8) Grade of post-OP complication 473 (93.1) 1-2 19 (17.6) 27 (5.3) 8 (7.4) 3-5 18 (16.7) 8 (1.6) 3 (2.8) Anastomosis related complications 0.032 13 (18.3) 13 (2.8) 5 (6.7) 58 (81.7) 448 (97.2) 70 (93.3) Our primary outcome was postoperative complications. The TKI groups had significant higher postoperative complications rate compared with non TKI group. The complications rate was 34.3% in TKI group and 6.9% in non-TKI group, p value was less than 0.0001. The anastomosis related complications was also significantly higher in TKI groups, with 18.3% versus 2.8% in nonTKI group. Then we did the propensity score matching to even out the demographic bias, and the difference of postoperative complications was still signicant after propensity score matching in both complications and anastomosis related complications.

Univariant and Multivariant analysis – major complications Factors Odds ratio 95% C.I. P value p value Age (years)   >60/<60 1.481 0.702-3.122 0.303 Sex Male/Female 1.093 0.520-2.296 0.815 CCI >3/<3 1.383 0.644-2.968 0.406 Pre-OP TKI Yes/No 7.482 3.344-16.739 <0.001 6.256 2.224-17.599 0.001 Repeat Surgery Yes/ No 5.573 2.611-11.891 2.234 0.959-5.205 0.062 Primary Site Stomach/Other 2.060 0.926-4.583 0.077 Size >10cm/<10cm 1.441 0.644-3.223 0.374 Risk High/None-Medium 3.361 1.509-7.490 0.003 1.470 0.539-4.010 0.452

Discussion

TKI impairs wound healing A number of currently approved TKIs are suspected or have been reported to impair wound healing There have been no formal clinical trials to evaluate the extent of the risk (Shah D.R et al. Drug Saf. 2014)

TKI impairs wound healing (Shah D.R et al. Drug Saf. 2014) Some of the TKIs were labelled to have the risk of impairing wound healing, and were suggested to be stopped before the elective surgery based on its half-life.

Imatinib impairs wound healing through PDGFR Fibroblast migration and proliferation Collagen Type I Biosynthesis Angiogenesis during wound healing (Rajkumar et al. AJP 2006) Dr Rajkumar in 2006 used animal studies and laboratory experiments to find that imatinib impairs fibroblast migration and proliferation, Collagen Type I biosynthesis and angiogenesis during wound healing. The picture showed the healing of punch wound on mice was obviously impaired after used of imatinib.

Pre-OP use of TKI increased postoperative complications Patient with pre-operative use of TKI had significantly higher postoperative complications compared to those without the use of TKI. 34.3% versus 6.9%, p < 0.001 34.3 % versus 10.2%, p < 0.001, after propensity score matching Anastomosis insufficiency 18.3% versus 2.8%, p < 0.001 18.3% versus 6.7%, p = 0.032, after propensity score matching Back to our clinical data, the preoperative use of TKI increased the rate of postoperative complications and anastomosis insufficiency, and the findings were significant even after propensity score matching.

Conclusion Preoperative use of TKI significantly increased the rate of postoperative complication and anastomosis insufficiency.

Conclusion Discontinuation of the TKI medication based on its half-life is suggested before elective surgery. The anastomosis of GI tract has a high risk of insufficiency after use of TKI, and thus requires a more meticulous technique and close postoperative monitoring.

Thanks for your attention!

TKI in adjuvant therapy Adjuvant imatinib following complete resection prolonged recurrence-free survival in patients with higher risk. Tumor size > 10 cm or high mitotic rate 2 years RFS improved from <50% to over 70% (DeMatteo R.P et al, Lancet 2009) The TKI can be used as adjuvant therapy. Adjuvant imatinib following complete resection was proved to prolong recurrence-free survival in patients with high risk GIST based on tumor size and mitotic count. 2 years RFS improved from <50% to over 70%

TKI in advanced GIST Improve median PFS and OS Pre-imatinib: both <12 months With imatinib: 18 months and 55 months 22 months and 69% at 2yrs 37.6 months and 71.0 months (Blanke CD et al. J Clin Oncol. 2008) (Verweij J et al. Lancet 2009) (Yeh C.N. et al. Transl. Oncol. 2011) For advanced GIST, including metastatic, locally advanced and unresectable disease, TKI can improve PFS and OS from both less than 1 year to 3 years and over 5 years.

Cytoreduction Surgery Benefit of cytoreduction surgery in metastatic GIST after imatinib has no been proved by randomized controlled trial. Patient whosed disease responds to imatinib benefit more from surgery than those with disease progression After use of TKI, cytoreduction surgery started to be use as part of the treatment for GIST. No phase III RCT can prove the benefit of cytoreduction surgery in advanced GIST. But if the patient had stable or partial response to TKI, they benefit more from cytoreduction surgery than those with progression disease.

Cytoreduction Surgery Surgery should be considered in Stable or responsive to TKI therapy Limited disease progression (Keung E.Z et al. Surg Clin N Am, 2017) So, cytoreduction surgery should be considered in patients with stable or partial response disease after TKI therapy, or at least limited progressed disease.

Propensity Score Matching Sex Size Risk Surgery with anastomosis Primary site And we did the propensity score matching to even out the demographic bias between two groups. We matched 5 factors, including sex, size, risk, surgery with anastomosis or not, and primary site of the GIST

Imatinib impairs wound healing through PDGFR (Rajkumar et al. AJP 2006) Staining of sections with Masson’s trichrome confirmed that granulation tissue in treated animals was poorly formed and relatively hypocellular (I, arrows) compared with control animals (H, arrows). Granulation tissue in control animals was characterized by the formation of small blood vessels (H, inset, arrowhead), which were not present in imatinib-treated wounds (I, inset, arrowhead).