NIH Public Access Author Manuscript Am Surg. Author manuscript; available in PMC 2015 September 01.
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Published in final edited form as: Am Surg. 2014 September ; 80(9): 890–895.
Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy in Sarcomatosis from Gastrointestinal Stromal Tumor MICHELLE L. BRYAN, M.D., Ph.D.*, NORA C. FITZGERALD, M.S.†, EDWARD A. LEVINE, M.D.*, PERRY SHEN, M.D.*, JOHN H. STEWART, M.D.*, and KONSTANTINOS I. VOTANOPOULOS, M.D., Ph.D.* *Surgical
Oncology Service in the Departments of General Surgery, Winston-Salem, North
Carolina †Department
of Biostatistics, Wake Forest Baptist Health, Winston-Salem, North Carolina
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Abstract
NIH-PA Author Manuscript
The role of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) procedures in the management of patients with gastrointestinal stromal tumor (GIST)-induced sarcomatosis that is refractory to tyrosine kinase inhibitors (TKI) is not well defined. A retrospective analysis of a prospective database of 1070 CRS/HIPEC procedures was performed. Demographics, Eastern Cooperative Oncology Group performance status, resection status, morbidity, mortality, perioperative use of targeted therapies, and overall survival were analyzed. Since 1992, 18 CRS/HIPEC procedures were performed for peritoneal dissemination of GIST. Fifty per cent of these cases were performed before the introduction of TKIs. R0/1 resection was achieved in 72 per cent, whereas 63 per cent of patients were treated with neoadjuvant and/or adjuvant targeted therapy. Thirty-day morbidity and mortality were 33.3 and 5.6 per cent, respectively. Median overall survival after CRS/HIPEC was 3.33 years with 3-year survival of 56 per cent. Median survival in those who did not receive targeted therapy was 1.04 versus 7.9 years for those treated with TKI and cytoreduction. Median postsurgical survival for those treated preoperatively with progression on TKI treatment was 1.35 years versus not reached in those on TKI therapy without progression. Primary therapy for patients with disseminated GIST should be TKI therapy. However, in patients with sarcomatosis from GIST, cytoreduction should be considered before developing TKI resistance. Progression on TKI is associated with poor outcomes even after complete cytoreduction. Gastrointestinal stromal tumor (GIST) has the highest incidence and prevalence of gastrointestinal tract sarcomas, accounting for approximately five per cent of all mesenchymal tumors.1 Although the mainstay of GIST treatment remains complete surgical resection, the introduction of tyrosine kinase inhibitors (TKIs) in 2002 has transformed
Address correspondence and reprint requests to Konstantinos I. Votanopoulos, M.D., Ph.D., Surgical Oncology Service, Medical Center Boulevard, Winston-Salem, NC 27157. [email protected].. Presented at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Savannah, GA, February 22–25, 2014.
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GIST from a purely surgical disease to one in which medical therapy significantly increases survival.
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GISTs may result in sarcomatosis that is chemotherapy-resistant, leaving patients with few options in the pre-TKI era. One surgical option that has been offered is cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC). This modality carries a prolonged recovery with morbidity rates approaching 40 per cent. As such, the role of surgery for metastatic GIST in the post-TKI era remains controversial.2 Recently, investigators have described the positive impact of re-section in select patients with metastatic GIST.3, 4 Most often these studies involve isolated peritoneal or liver metastases.5, 6 Patients with peritoneal sarcomatosis represent a small subset of patients with metastasis and therefore are rarely analyzed as a unique cohort. The primary aim of this article was to determine the surgical outcomes of CRS/HIPEC procedures on patients with GIST-induced sarcomatosis. The secondary goal was to define the impact of TKI resistance on overall survival of patients treated with CRS/HIPEC.
Methods NIH-PA Author Manuscript
This is a retrospective analysis of a prospectively maintained database of 1070 CRS/HIPEC procedures performed from 1992 to 2012. Institutional Review Board approval was obtained. Data relevant to our analysis included histologic confirmation of sarcomatosis, demographics, Eastern Cooperative Oncology Group (ECOG) performance status, R status of resection, comorbidities, preoperative or postoperative use of TKIs, volume of peritoneal disease, morbidity, mortality, and survival. Eligibility criteria for CRS/HIPEC were histologic diagnosis of peritoneal dissemination and complete recovery from prior systemic chemotherapy or radiation treatments, resectable or resected primary lesion, debulkable peritoneal disease, and no extra-abdominal disease.
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CRS-HIPEC was conducted as previously described by our group.7 The degree of resection was judged by the surgeon and classified as follows: R0 for complete macroscopic resection with no evidence of involved margins on final pathology and R1 for complete macroscopic resection of gross tumor with positive microscopic margins on final pathology. Cytoreductions with residual macroscopic disease were characterized as R2 and subdivided based on the size of residual disease (R2a 5 mm or less, R2b 2 cm or less, R2c greater than 2 cm). Chemoperfusion was performed at 40°C with 40 mg mitomycin C with or without 10 to 30 mg mitoxantrone for 60 to 120 minutes. All data were collected prospectively and analyzed retrospectively. Patients were typically followed with physical examination and computed tomography imaging every 6 months. We summarized patient characteristics using means/standard deviations or medians/ interquartile range for continuous variables and frequencies for categorical variables. These descriptive statistics were calculated overall, by TKI at any time point (yes/no), and by TKI preoperative progression (yes/no) within TKI at any time point. Significant differences in these groups were assessed using Fisher’s exact test for categorical variables, analysis of variance for approximately normal continuous variables, or Kruskal-Wallis test for non-
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normal continuous variables. Time to death or censorship was defined from the date of the CRS/HIPEC to the date of death or last follow-up. We estimated median overall survival (OS), OS probability, and 3-year survival probability using Kaplan-Meier survival estimators. To compare survival by the pre-operative TKI status and TKI at any time point, we generated Kaplan-Meier survival curves for each group and tested for significant differences in survival using the log-rank test. For those patients who received more than one CRS/HIPEC, survival was determined from the initial procedure. All hypothesis tests performed were two-sided and evaluated at the 0.05 significance level; statistical analysis was performed in SAS Version 9.3 (SAS Institute, Cary, NC).
Results
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One thousand seventy CRS/HIPEC procedures were performed from 1992 to 2012, whereas 18 CRS/HIPEC procedures were performed in 16 patients for GIST-induced sarcomatosis. Clinical characteristics of the cohort are listed in Table 1. Mean age at the time of surgery was 49.7 years (range, 37 to 68 years). Sixty-one per cent of the patients had an ECOG functional status of 0 or 1 at the time of surgery. Mean albumin was 3.8 (range, 1.8 to 4.4), indicating that patients had adequate nutritional reserves at the time of surgery. A complete R0/R1 macroscopic CRS was obtained in 72 per cent (13 of 18). Six patients had a major Clavien III–IV complication, yielding an overall 30-day major morbidity rate of 33.3 per cent. There was one death within 30 days of surgery, yielding a 30-day mortality of 5.6 per cent. Median overall survival after CRS/HIPEC was 3.33 years (range, 0.64 to 11.9 years) for all patients regardless of TKI treatment (Fig. 1). Targeted Therapy with Tyrosine Kinase Inhibitors
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Of 16 patients, six never received targeted therapy, whereas the remaining 10 received targeted therapy either pre- or postoperatively, depending on clinical course and drug availability. Patients who received TKIs had a median survival of 7.89 years versus 1.04 years in those who never received targeted therapy (Fig. 2). As a result of the small numbers, this is statistically underpowered, yielding a P value of 0.3926. Comparison of the two populations showed no difference in age (P = 0.75), resection status (P = 0.60), performance status (P = 0.61), or complications (P = 0.20). Patients who were exposed to TKIs did trend toward a slightly improved nutritional status with a mean albumin of 4.05 versus 3.4 (P = 0.04). As a result of the proven importance of complete CRS on survival, analysis was predominantly focused on the subgroup of patients who underwent R0/1 resection.8 Within patients with an R0/1 resection, those who never received TKI at any point before or after CRS/HIPEC had a median survival of 1.09 years versus median survival was not reached in those who received TKI (P = 0.28). Median survival in patients who progressed on TKI preoperatively was 1.35 years postCRS/HIPEC as compared with a median survival that was not reached in those without progression on TKIs (P = 0.007) (Fig. 3). Those without progression represented patients who received TKI therapy either before or after HIPEC or both. Statistical comparison of the two populations showed no difference in preoperative factors, including age, nutritional status, and performance status (Table 2). In addition, patients with progression on TKI
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therapy had a median hospital stay of 13 days versus six days in those without progression (P = 0.013), possibly an indication of a more infiltrative biologic behavior of disease.
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Discussion TKIs as treatment for GIST were introduced in 2002, a year that represents the midpoint of our institutional experience with CRS/HIPEC procedures. The database analyzed in the current article includes a unique population of those who underwent CRS/HIPEC before and after the introduction of TKIs. In addition, a subset of this population progressed on TKI therapy and was then referred for CRS/HIPEC as a last treatment resort. The primary aim of this article was to determine the surgical outcomes of cytoreduction procedures on patients with GIST-induced sarcomatosis, whereas the secondary aim was to define the impact of TKI resistance on overall survival of patients treated with cytoreduction.
NIH-PA Author Manuscript
In this article, the morbidity and mortality of CRS/HIPEC in patients with GIST-induced sarcomatosis was similar to the morbidity and mortality reported for CRS/HIPEC procedures undertaken for a variety of other primaries of epithelial origin.9, 10 Several centers including ours rarely perform HIPEC after CRS for sarcomatosis given that survival outcomes post-CRS/HIPEC are not different from historically reported outcomes in sarcomatosis patients treated with CRS only.11 Therefore, the morbidity and mortality of CRS might possibly be even lower if HIPEC is not performed. In the current study, the median OS for the entire cohort was 3.33 years post cytoreduction. The patients driving this result were those who achieved a complete macroscopic CRS and were referred before development of resistance to TKI treatment. It is important to mention that complete CRS by itself was not related to improved survival in patients who were either treated before the introduction of TKIs or developed resistance and progressed while on TKI therapy. This underscores the importance of TKIs as the primary treatment for patients with GIST sarcomatosis.
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The presented data indicate that CRS in those who have progressed on preoperative TKIs yields a poor outcome with a median survival of 1.09 years. These patients had a higher chance of obtaining an incomplete CRS, possibly as an indication of a worse biologic behavior and volume of disease. A theoretical role for performing cytoreduction of resistant clones with the hope that residual disease will be TKI-responsive has been proposed. Because retrospective information on the specific topography and possible progression of residual disease before CRS was not available, it is unclear from this study what that role might be. In addition, our analysis was unable to include exon-specific resistance data. Comparison of the cohort with refractory disease to those who underwent CRS before the development of resistance to TKI treatment revealed a statistically significant survival benefit of several years in favor of the TKI-responsive group. This is in agreement with a recent report, which described a median OS of 1.5 years from metastectomy for patients progressing on TKI at the time of surgery.12 Given that the median time to develop TKI resistance is approximately two years and only 20 per cent of patients will not progress at
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five years, we argue that patients not progressing on TKIs should be referred for cytoreduction early within this timeframe.13
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We currently consider offering CRS without HIPEC in patients with GIST sarcomatosis who on preoperative imaging have disease responsive or stable on TKIs. In addition, we guide the extent of the cytoreduction based on morbidity and quality of life criteria and not necessarily by achieving negative microscopic margins, as long as macroscopic margins are obtained while TKIs are continued indefinitely after CRS. In conclusion, primary therapy for patients with GIST sarcomatosis should be a systemic approach with TKIs. Cytoreduction should be considered in highly selected patients before developing TKIs resistance. Progression on TKIs is associated with poor outcomes even after complete cytoreduction.
Acknowledgments We acknowledge the support of the Biostatistics Shared Resources, Comprehensive Cancer Center of Wake Forest University and National Cancer Institute Cancer Center Support Grant P30 CA012197.!
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REFERENCES
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1. Perez EA, Livingstone AS, Franceschi D, et al. Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. J Am Coll Surg. 2006; 202:623–9. [PubMed: 16571433] 2. Fisher SB, Kim SC, Kooby DA, et al. Gastrointestinal stromal tumors: a single institution experience of 176 surgical patients. Am Surg. 2013; 79:657–65. [PubMed: 23815996] 3. Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol. 2007; 14:14–24. [PubMed: 17072676] 4. Zaydfudim V, Okuno SH, Que FG, et al. Role of operative therapy in treatment of metastatic gastrointestinal stromal tumors. J Surg Res. 2012; 177:248–54. [PubMed: 22831567] 5. De la Fuente SG, Deneve JL, Parsons CM, et al. A comparison between patients with gastrointestinal stromal tumours diagnosed with isolated liver metastases and liver metastases plus sarcomatosis. HPB. 2013; 15:655–60. [PubMed: 23458233] 6. Turley RS, Peng PD, Reddy SK, et al. Hepatic resection for metastatic gastrointestinal stromal tumours in the tyrosine kinase inhibitor era. Cancer. 2011; 118:3571–8. [PubMed: 22086856] 7. Levine EA, Stewart JH, Russell GB, et al. Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures. J Am Coll Surg. 2007; 204:943–53. [PubMed: 17481516] 8. Gouveia AM, Pimenta AP, Capelinha AF, et al. Surgical margin status and prognosis of gastrointestinal stromal tumor. World J Surg. 2008; 32:2375–82. [PubMed: 18685890] 9. Bakrin N, Bereder JM, Decullier E, et al. Peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian carcinoma: a French multicentre retrospective cohort study of 566 patients. Eur J Surg Oncol. 2013; 39:1435–43. [PubMed: 24209430] 10. Wagner PL, Austin F, Maduekwe U, et al. Extensive cytoreductive surgery for appendiceal carcinomatosis: morbidity, mortality, and survival. Ann Surg Oncol. 2013; 20:1056–62. [PubMed: 23456385] 11. Randle RW, Swett KR, Shen P, et al. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in peritoneal sarcomatosis. Am Surg. 2013; 79:620–4. [PubMed: 23711273] 12. Bauer S, Rutkowski P, Hohenberger P, et al. Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib—analysis of prognostic factors (EORTCSTBSG collaborative study). Eur J Surg Oncol. 2014; 40:412–9. [PubMed: 24491288]
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13. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard-versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008; 26:620–5. [PubMed: 18235121]
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Fig. 1.
Overall survival post-CRS/HIPEC. Survival was assessed from the date of CRS/HIPEC. For the two patients undergoing a repeat procedure, survival was assessed from the date of the first procedure. CRS/HIPEC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
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Fig. 2.
Survival post-CRS/HIPEC stratified by TKI exposure. Survival was assessed from the date of CRS/HIPEC. CRC/HIPEC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy; TKI, tyrosine kinase inhibitor.
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NIH-PA Author Manuscript NIH-PA Author Manuscript Fig. 3.
Survival post-CRS/HIPEC stratified by progression on TKI. Survival was assessed from the date of CRS/HIPEC. CRC/HIPEC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy; TKI, tyrosine kinase inhibitor.
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Table 1
Patient and Operative Characteristics*
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No. (%) or Median [range] Preoperative Sex Male
8
Female
10
Age at the time of surgery (years): mean (range)
49.7 (37–61)
ECOG at the time of resection: no. (%) 0
5 (27.7)
1
6 (33.3)
2
6 (33.3)
Albumin: mean (range)
3.8 [3.2–4.4]
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Location of primary tumor: no. (percent) Stomach
5 (31.3)
Small intestine
10 (62.5)
Extragastrointestinal
1 (6.3)
Perioperative Resection status R0/1
13 (72.2)
R2
5 (27.8)
Complications: Clavien grade: no. (%) None
3 (16.7)
Minor (I/II)
8 (44.4)
Major (III/IV)
6 (33.3)
Death (V)
1 (5.6)
Length of hospital stay (days)
8 [4–80]
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ECOG, Eastern Cooperative Oncology Group.
*
n = 16 for total patients, n = 18 for total surgeries, which are reported here; two patients underwent repeat hyperthermic intraperitoneal chemotherapy for recurrence.
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Table 2
Comparison of Patient Characteristics with Preoperative Progression on TKI versus TKI
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Exposure without Progression* Progression on TKI Characteristic Age at HIPEC (years)
No Progression on TKI P Value
No. or Mean
Percent or SD
No. or Mean
Percent or SD
47.00
8.40
51.00
12.30
0.55
Albumin
4.02
0.59
4.08
0.34
0.85
Length of stay from HIPEC (median, IQR)
13.00
11, 18
6.00
6, 7
0.013†
Female
2
40
3
50
1
Male
3
60
3
50
0
1
20
3
50
1
1
20
2
33.33
2
3
60
1
16.67
3
0
0
0
0
R0/1
2
40
5
83.33
R2
3
60
1
16.67
Gender
ECOG
0.45
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Resection status 0.24
Complications: Clavien grade None (0)
0
0
3
50
Minor (I/II)
2
40
3
50
Major (III/IV/V)
2
40
0
0
Death (V)
1
20
0
0
0.15
TKI, tyrosine kinase inhibitor; SD, standard deviation; HIPEC, hyperthermic intraperitoneal chemotherapy; IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group.
*
For categorical traits, P value assessed using Fisher’s exact test for small cell counts.
†
P value assessed using Kruskal-Wallis test.
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Published in final edited form as: Am Surg. 2014 September ; 80(9): 890–895.
Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy in Sarcomatosis from Gastrointestinal Stromal Tumor MICHELLE L. BRYAN, M.D., Ph.D.*, NORA C. FITZGERALD, M.S.†, EDWARD A. LEVINE, M.D.*, PERRY SHEN, M.D.*, JOHN H. STEWART, M.D.*, and KONSTANTINOS I. VOTANOPOULOS, M.D., Ph.D.* *Surgical
Oncology Service in the Departments of General Surgery, Winston-Salem, North
Carolina †Department
of Biostatistics, Wake Forest Baptist Health, Winston-Salem, North Carolina
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Abstract
NIH-PA Author Manuscript
The role of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) procedures in the management of patients with gastrointestinal stromal tumor (GIST)-induced sarcomatosis that is refractory to tyrosine kinase inhibitors (TKI) is not well defined. A retrospective analysis of a prospective database of 1070 CRS/HIPEC procedures was performed. Demographics, Eastern Cooperative Oncology Group performance status, resection status, morbidity, mortality, perioperative use of targeted therapies, and overall survival were analyzed. Since 1992, 18 CRS/HIPEC procedures were performed for peritoneal dissemination of GIST. Fifty per cent of these cases were performed before the introduction of TKIs. R0/1 resection was achieved in 72 per cent, whereas 63 per cent of patients were treated with neoadjuvant and/or adjuvant targeted therapy. Thirty-day morbidity and mortality were 33.3 and 5.6 per cent, respectively. Median overall survival after CRS/HIPEC was 3.33 years with 3-year survival of 56 per cent. Median survival in those who did not receive targeted therapy was 1.04 versus 7.9 years for those treated with TKI and cytoreduction. Median postsurgical survival for those treated preoperatively with progression on TKI treatment was 1.35 years versus not reached in those on TKI therapy without progression. Primary therapy for patients with disseminated GIST should be TKI therapy. However, in patients with sarcomatosis from GIST, cytoreduction should be considered before developing TKI resistance. Progression on TKI is associated with poor outcomes even after complete cytoreduction. Gastrointestinal stromal tumor (GIST) has the highest incidence and prevalence of gastrointestinal tract sarcomas, accounting for approximately five per cent of all mesenchymal tumors.1 Although the mainstay of GIST treatment remains complete surgical resection, the introduction of tyrosine kinase inhibitors (TKIs) in 2002 has transformed
Address correspondence and reprint requests to Konstantinos I. Votanopoulos, M.D., Ph.D., Surgical Oncology Service, Medical Center Boulevard, Winston-Salem, NC 27157. [email protected].. Presented at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Savannah, GA, February 22–25, 2014.
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GIST from a purely surgical disease to one in which medical therapy significantly increases survival.
NIH-PA Author Manuscript
GISTs may result in sarcomatosis that is chemotherapy-resistant, leaving patients with few options in the pre-TKI era. One surgical option that has been offered is cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC). This modality carries a prolonged recovery with morbidity rates approaching 40 per cent. As such, the role of surgery for metastatic GIST in the post-TKI era remains controversial.2 Recently, investigators have described the positive impact of re-section in select patients with metastatic GIST.3, 4 Most often these studies involve isolated peritoneal or liver metastases.5, 6 Patients with peritoneal sarcomatosis represent a small subset of patients with metastasis and therefore are rarely analyzed as a unique cohort. The primary aim of this article was to determine the surgical outcomes of CRS/HIPEC procedures on patients with GIST-induced sarcomatosis. The secondary goal was to define the impact of TKI resistance on overall survival of patients treated with CRS/HIPEC.
Methods NIH-PA Author Manuscript
This is a retrospective analysis of a prospectively maintained database of 1070 CRS/HIPEC procedures performed from 1992 to 2012. Institutional Review Board approval was obtained. Data relevant to our analysis included histologic confirmation of sarcomatosis, demographics, Eastern Cooperative Oncology Group (ECOG) performance status, R status of resection, comorbidities, preoperative or postoperative use of TKIs, volume of peritoneal disease, morbidity, mortality, and survival. Eligibility criteria for CRS/HIPEC were histologic diagnosis of peritoneal dissemination and complete recovery from prior systemic chemotherapy or radiation treatments, resectable or resected primary lesion, debulkable peritoneal disease, and no extra-abdominal disease.
NIH-PA Author Manuscript
CRS-HIPEC was conducted as previously described by our group.7 The degree of resection was judged by the surgeon and classified as follows: R0 for complete macroscopic resection with no evidence of involved margins on final pathology and R1 for complete macroscopic resection of gross tumor with positive microscopic margins on final pathology. Cytoreductions with residual macroscopic disease were characterized as R2 and subdivided based on the size of residual disease (R2a 5 mm or less, R2b 2 cm or less, R2c greater than 2 cm). Chemoperfusion was performed at 40°C with 40 mg mitomycin C with or without 10 to 30 mg mitoxantrone for 60 to 120 minutes. All data were collected prospectively and analyzed retrospectively. Patients were typically followed with physical examination and computed tomography imaging every 6 months. We summarized patient characteristics using means/standard deviations or medians/ interquartile range for continuous variables and frequencies for categorical variables. These descriptive statistics were calculated overall, by TKI at any time point (yes/no), and by TKI preoperative progression (yes/no) within TKI at any time point. Significant differences in these groups were assessed using Fisher’s exact test for categorical variables, analysis of variance for approximately normal continuous variables, or Kruskal-Wallis test for non-
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normal continuous variables. Time to death or censorship was defined from the date of the CRS/HIPEC to the date of death or last follow-up. We estimated median overall survival (OS), OS probability, and 3-year survival probability using Kaplan-Meier survival estimators. To compare survival by the pre-operative TKI status and TKI at any time point, we generated Kaplan-Meier survival curves for each group and tested for significant differences in survival using the log-rank test. For those patients who received more than one CRS/HIPEC, survival was determined from the initial procedure. All hypothesis tests performed were two-sided and evaluated at the 0.05 significance level; statistical analysis was performed in SAS Version 9.3 (SAS Institute, Cary, NC).
Results
NIH-PA Author Manuscript
One thousand seventy CRS/HIPEC procedures were performed from 1992 to 2012, whereas 18 CRS/HIPEC procedures were performed in 16 patients for GIST-induced sarcomatosis. Clinical characteristics of the cohort are listed in Table 1. Mean age at the time of surgery was 49.7 years (range, 37 to 68 years). Sixty-one per cent of the patients had an ECOG functional status of 0 or 1 at the time of surgery. Mean albumin was 3.8 (range, 1.8 to 4.4), indicating that patients had adequate nutritional reserves at the time of surgery. A complete R0/R1 macroscopic CRS was obtained in 72 per cent (13 of 18). Six patients had a major Clavien III–IV complication, yielding an overall 30-day major morbidity rate of 33.3 per cent. There was one death within 30 days of surgery, yielding a 30-day mortality of 5.6 per cent. Median overall survival after CRS/HIPEC was 3.33 years (range, 0.64 to 11.9 years) for all patients regardless of TKI treatment (Fig. 1). Targeted Therapy with Tyrosine Kinase Inhibitors
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Of 16 patients, six never received targeted therapy, whereas the remaining 10 received targeted therapy either pre- or postoperatively, depending on clinical course and drug availability. Patients who received TKIs had a median survival of 7.89 years versus 1.04 years in those who never received targeted therapy (Fig. 2). As a result of the small numbers, this is statistically underpowered, yielding a P value of 0.3926. Comparison of the two populations showed no difference in age (P = 0.75), resection status (P = 0.60), performance status (P = 0.61), or complications (P = 0.20). Patients who were exposed to TKIs did trend toward a slightly improved nutritional status with a mean albumin of 4.05 versus 3.4 (P = 0.04). As a result of the proven importance of complete CRS on survival, analysis was predominantly focused on the subgroup of patients who underwent R0/1 resection.8 Within patients with an R0/1 resection, those who never received TKI at any point before or after CRS/HIPEC had a median survival of 1.09 years versus median survival was not reached in those who received TKI (P = 0.28). Median survival in patients who progressed on TKI preoperatively was 1.35 years postCRS/HIPEC as compared with a median survival that was not reached in those without progression on TKIs (P = 0.007) (Fig. 3). Those without progression represented patients who received TKI therapy either before or after HIPEC or both. Statistical comparison of the two populations showed no difference in preoperative factors, including age, nutritional status, and performance status (Table 2). In addition, patients with progression on TKI
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therapy had a median hospital stay of 13 days versus six days in those without progression (P = 0.013), possibly an indication of a more infiltrative biologic behavior of disease.
NIH-PA Author Manuscript
Discussion TKIs as treatment for GIST were introduced in 2002, a year that represents the midpoint of our institutional experience with CRS/HIPEC procedures. The database analyzed in the current article includes a unique population of those who underwent CRS/HIPEC before and after the introduction of TKIs. In addition, a subset of this population progressed on TKI therapy and was then referred for CRS/HIPEC as a last treatment resort. The primary aim of this article was to determine the surgical outcomes of cytoreduction procedures on patients with GIST-induced sarcomatosis, whereas the secondary aim was to define the impact of TKI resistance on overall survival of patients treated with cytoreduction.
NIH-PA Author Manuscript
In this article, the morbidity and mortality of CRS/HIPEC in patients with GIST-induced sarcomatosis was similar to the morbidity and mortality reported for CRS/HIPEC procedures undertaken for a variety of other primaries of epithelial origin.9, 10 Several centers including ours rarely perform HIPEC after CRS for sarcomatosis given that survival outcomes post-CRS/HIPEC are not different from historically reported outcomes in sarcomatosis patients treated with CRS only.11 Therefore, the morbidity and mortality of CRS might possibly be even lower if HIPEC is not performed. In the current study, the median OS for the entire cohort was 3.33 years post cytoreduction. The patients driving this result were those who achieved a complete macroscopic CRS and were referred before development of resistance to TKI treatment. It is important to mention that complete CRS by itself was not related to improved survival in patients who were either treated before the introduction of TKIs or developed resistance and progressed while on TKI therapy. This underscores the importance of TKIs as the primary treatment for patients with GIST sarcomatosis.
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The presented data indicate that CRS in those who have progressed on preoperative TKIs yields a poor outcome with a median survival of 1.09 years. These patients had a higher chance of obtaining an incomplete CRS, possibly as an indication of a worse biologic behavior and volume of disease. A theoretical role for performing cytoreduction of resistant clones with the hope that residual disease will be TKI-responsive has been proposed. Because retrospective information on the specific topography and possible progression of residual disease before CRS was not available, it is unclear from this study what that role might be. In addition, our analysis was unable to include exon-specific resistance data. Comparison of the cohort with refractory disease to those who underwent CRS before the development of resistance to TKI treatment revealed a statistically significant survival benefit of several years in favor of the TKI-responsive group. This is in agreement with a recent report, which described a median OS of 1.5 years from metastectomy for patients progressing on TKI at the time of surgery.12 Given that the median time to develop TKI resistance is approximately two years and only 20 per cent of patients will not progress at
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five years, we argue that patients not progressing on TKIs should be referred for cytoreduction early within this timeframe.13
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We currently consider offering CRS without HIPEC in patients with GIST sarcomatosis who on preoperative imaging have disease responsive or stable on TKIs. In addition, we guide the extent of the cytoreduction based on morbidity and quality of life criteria and not necessarily by achieving negative microscopic margins, as long as macroscopic margins are obtained while TKIs are continued indefinitely after CRS. In conclusion, primary therapy for patients with GIST sarcomatosis should be a systemic approach with TKIs. Cytoreduction should be considered in highly selected patients before developing TKIs resistance. Progression on TKIs is associated with poor outcomes even after complete cytoreduction.
Acknowledgments We acknowledge the support of the Biostatistics Shared Resources, Comprehensive Cancer Center of Wake Forest University and National Cancer Institute Cancer Center Support Grant P30 CA012197.!
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REFERENCES
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1. Perez EA, Livingstone AS, Franceschi D, et al. Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. J Am Coll Surg. 2006; 202:623–9. [PubMed: 16571433] 2. Fisher SB, Kim SC, Kooby DA, et al. Gastrointestinal stromal tumors: a single institution experience of 176 surgical patients. Am Surg. 2013; 79:657–65. [PubMed: 23815996] 3. Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol. 2007; 14:14–24. [PubMed: 17072676] 4. Zaydfudim V, Okuno SH, Que FG, et al. Role of operative therapy in treatment of metastatic gastrointestinal stromal tumors. J Surg Res. 2012; 177:248–54. [PubMed: 22831567] 5. De la Fuente SG, Deneve JL, Parsons CM, et al. A comparison between patients with gastrointestinal stromal tumours diagnosed with isolated liver metastases and liver metastases plus sarcomatosis. HPB. 2013; 15:655–60. [PubMed: 23458233] 6. Turley RS, Peng PD, Reddy SK, et al. Hepatic resection for metastatic gastrointestinal stromal tumours in the tyrosine kinase inhibitor era. Cancer. 2011; 118:3571–8. [PubMed: 22086856] 7. Levine EA, Stewart JH, Russell GB, et al. Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures. J Am Coll Surg. 2007; 204:943–53. [PubMed: 17481516] 8. Gouveia AM, Pimenta AP, Capelinha AF, et al. Surgical margin status and prognosis of gastrointestinal stromal tumor. World J Surg. 2008; 32:2375–82. [PubMed: 18685890] 9. Bakrin N, Bereder JM, Decullier E, et al. Peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian carcinoma: a French multicentre retrospective cohort study of 566 patients. Eur J Surg Oncol. 2013; 39:1435–43. [PubMed: 24209430] 10. Wagner PL, Austin F, Maduekwe U, et al. Extensive cytoreductive surgery for appendiceal carcinomatosis: morbidity, mortality, and survival. Ann Surg Oncol. 2013; 20:1056–62. [PubMed: 23456385] 11. Randle RW, Swett KR, Shen P, et al. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in peritoneal sarcomatosis. Am Surg. 2013; 79:620–4. [PubMed: 23711273] 12. Bauer S, Rutkowski P, Hohenberger P, et al. Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib—analysis of prognostic factors (EORTCSTBSG collaborative study). Eur J Surg Oncol. 2014; 40:412–9. [PubMed: 24491288]
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13. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard-versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008; 26:620–5. [PubMed: 18235121]
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Fig. 1.
Overall survival post-CRS/HIPEC. Survival was assessed from the date of CRS/HIPEC. For the two patients undergoing a repeat procedure, survival was assessed from the date of the first procedure. CRS/HIPEC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
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Fig. 2.
Survival post-CRS/HIPEC stratified by TKI exposure. Survival was assessed from the date of CRS/HIPEC. CRC/HIPEC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy; TKI, tyrosine kinase inhibitor.
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NIH-PA Author Manuscript NIH-PA Author Manuscript Fig. 3.
Survival post-CRS/HIPEC stratified by progression on TKI. Survival was assessed from the date of CRS/HIPEC. CRC/HIPEC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy; TKI, tyrosine kinase inhibitor.
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Table 1
Patient and Operative Characteristics*
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No. (%) or Median [range] Preoperative Sex Male
8
Female
10
Age at the time of surgery (years): mean (range)
49.7 (37–61)
ECOG at the time of resection: no. (%) 0
5 (27.7)
1
6 (33.3)
2
6 (33.3)
Albumin: mean (range)
3.8 [3.2–4.4]
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Location of primary tumor: no. (percent) Stomach
5 (31.3)
Small intestine
10 (62.5)
Extragastrointestinal
1 (6.3)
Perioperative Resection status R0/1
13 (72.2)
R2
5 (27.8)
Complications: Clavien grade: no. (%) None
3 (16.7)
Minor (I/II)
8 (44.4)
Major (III/IV)
6 (33.3)
Death (V)
1 (5.6)
Length of hospital stay (days)
8 [4–80]
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ECOG, Eastern Cooperative Oncology Group.
*
n = 16 for total patients, n = 18 for total surgeries, which are reported here; two patients underwent repeat hyperthermic intraperitoneal chemotherapy for recurrence.
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Table 2
Comparison of Patient Characteristics with Preoperative Progression on TKI versus TKI
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Exposure without Progression* Progression on TKI Characteristic Age at HIPEC (years)
No Progression on TKI P Value
No. or Mean
Percent or SD
No. or Mean
Percent or SD
47.00
8.40
51.00
12.30
0.55
Albumin
4.02
0.59
4.08
0.34
0.85
Length of stay from HIPEC (median, IQR)
13.00
11, 18
6.00
6, 7
0.013†
Female
2
40
3
50
1
Male
3
60
3
50
0
1
20
3
50
1
1
20
2
33.33
2
3
60
1
16.67
3
0
0
0
0
R0/1
2
40
5
83.33
R2
3
60
1
16.67
Gender
ECOG
0.45
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Resection status 0.24
Complications: Clavien grade None (0)
0
0
3
50
Minor (I/II)
2
40
3
50
Major (III/IV/V)
2
40
0
0
Death (V)
1
20
0
0
0.15
TKI, tyrosine kinase inhibitor; SD, standard deviation; HIPEC, hyperthermic intraperitoneal chemotherapy; IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group.
*
For categorical traits, P value assessed using Fisher’s exact test for small cell counts.
†
P value assessed using Kruskal-Wallis test.
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