Oncology/Genetics Peritoneal metastases from small bowel cancer: Results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in The Netherlands Thijs R. van Oudheusden, MD,a Valery E. Lemmens, PhD,b Hidde J. Braam, MD,c Bert van Ramshorst, MD, PhD,c Jeroen Meijerink, MD,d Eline A. te Velde, MD, PhD,d Akash M. Mehta, MD,e Vic J. Verwaal, MD, PhD,e and Ignace H. de Hingh, MD, PhD,a Eindhoven and Amsterdam, The Netherlands
Introduction. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered the standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer. CRS + HIPEC has also been suggested as a potential treatment option in PM of the much rarer small bowel cancer. Therefore, the current study was undertaken to investigate the results of CRS + HIPEC in all HIPEC centers in The Netherlands. Methods. From the 4 tertiary referral centers for peritoneal surface malignancies in The Netherlands, data from all patients with peritoneally metastasized small bowel carcinoma intended to undergo CRS and HIPEC were collected between January 2005 and July 2014. Primary tumor characteristics, operative details, and survival outcomes were collected. Results. Sixteen of 19 patients (84.2%) who underwent explorative laparotomy underwent CRS + HIPEC. Of these patients, 81.3% were female, and primary tumors were mainly located in the ileum (50%). A complete macroscopic resection was achieved in 93.8%. Serious adverse events requiring re-intervention occurred in 25%, and no in-hospital mortality was observed. Recurrent disease was observed in 50% of patients and median survival after CRS and HIPEC was 31 months. Conclusion. In a select group of patients in whom a complete macroscopic resection can be achieved, survival rates comparable with those in colorectal PM are attainable with acceptable morbidity. The role of adjuvant chemotherapy needs further research. (Surgery 2015;157:1023-7.) From the Department of Surgical Oncology,a Catharina Hospital, and the Department of Research,b Eindhoven Cancer Registry/Comprehensive Cancer Centre The Netherlands (IKNL), Eindhoven; the Department of Surgical Oncology,c St. Antonius Hospital, Nieuwegein, the Department of Surgical Oncology,d VU University Medical Center Amsterdam, and the Department of Surgical Oncology,e The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands
CYTOREDUCTIVE SURGERY and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered to be standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer in many countries.1 This treatment is currently under Accepted for publication January 29, 2015. Reprint requests: Ignace H. de Hingh, MD, PhD, Catharina Hospital Eindhoven, Department of Surgical Oncology, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2015.01.021
clinical investigation for other frequently occurring cancers known to develop PM in many patients, such as gastric or ovarian cancer. However, some peritoneal cancer manifestations are very rare, including that originating from small bowel cancer (SBC). SBC accounts for only 3% of all gastrointestinal malignancies. As a result, little has been reported on its treatment and oncologic outcomes.2,3 Although operative resection has been established as the treatment of choice in the absence of metastases for several decades, overall survival is considered poor and has not improved significantly over the last 20 years.4 PM of SBC (PMSBC) are present in up to onequarter of patients and the peritoneal cavity is a SURGERY 1023
1024 van Oudheusden et al
common site of recurrence after curative surgery.2,5 With the achieved results in colorectal cancer in mind, CRS + HIPEC has been suggested as a potential treatment option to increase survival in this otherwise ill-fated group. Given the rarity of PMSBC, support for this treatment will not come from randomized clinical trials. Therefore, the current study was undertaken to investigate the results of CRS and HIPEC in several HIPEC centers in The Netherlands. METHODS Patients. From the 4 tertiary centers for peritoneal surface malignancies in The Netherlands (Catharina Hospital Eindhoven, St. Antonius Hospital Nieuwegein, VU University Medical Centre Amsterdam and The Netherlands Cancer Institute Amsterdam), all patients with peritoneally metastasized small bowel adenocarcinoma intended to undergo CRS + HIPEC between January 2005 and July 2014 were identified and data on primary tumor characteristics, operative details, and survival outcomes were collected. The local medical ethics committee approved this study. CRS and HIPEC. All patients undergoing CRS and HIPEC were treated according to the Dutch nationwide protocol for HIPEC procedures.6 Before surgery, all patients underwent CT to assess disease burden, primary tumor resectability, and the presence of systemic metastases. Cases were discussed in a multidisciplinary tumor board. After initial exploratory laparotomy, CRS and HIPEC was performed when a complete macroscopic resection was believed to be possible and no distant metastases were present. The amount of peritoneal cancer was assessed by the ‘‘7-region score,’’ during which the presence of peritoneal cancer is scored in 7 welldefined abdominal regions. This scoring system was proven to be equally adequate compared with more complex scoring systems such as the Peritoneal Cancer Index to predict the outcome and prognosis of peritoneal cancer patients after HIPEC and is most commonly used in The Netherlands.7 Exclusion criteria to continue with CRS and HIPEC after exploration were a region score of >5, an unresectable primary tumor, extensive small bowel involvement resulting in short bowel syndrome if resected, and/or intraoperative discovery of unresectable liver metastases. HIPEC procedures were performed by using the open colosseum technique and mitomycin C (MMC; 35 mg/m2 at 41–428C) as the intraperitoneal chemotherapy regimen for 90 minutes. Completeness of cytoreduction was assessed using the R-score. In case no macroscopic tumor is left
Surgery June 2015
behind, the result of cytoreduction is scored as ‘‘R1.’’ When there was remnant macroscopic tumor, the score is ‘‘R2a’’ when the tumor is 1 year. Eight patients
N
7-Region count I 3 II 2 III 1 IV 5 V 1 VI 1 VII 1 Unknown 2 Median blood loss (mL) 900 (225–3,300) Mean operation time (min) 339.0 (275.6–402.4) R score R1 15 R2a 0 R2b 1 Hospital stay (d) 11 (5–46) Serious adverse event >3 4 Hospital mortality 0 Adjuvant chemotherapy Yes 9 No 6 Unknown 1 Recurrent disease 8 Location of recurrent disease Local/PC 7 Lung 1
% 18.8 12.5 6.3 31.3 6.3 6.3 6.3 12.5
93.8 0 6.3 25.0 0 56.3 37.5 6.3 50 87.5 12.5
PC, Peritoneal carcinomatosis.
(50%) developed a recurrence during follow-up. These were mainly intraperitoneal recurrences (87.5%) with lung metastases occurring in 1 patient (12.5%). The patient treated with HIPEC after an R2b resection status died after 3.5 months. DISCUSSION Peritoneally metastasized small bowel carcinoma is a rare disease, with only 16 patients treated with CRS + HIPEC over a period of almost 9 years in The Netherlands. With limited postoperative morbidity and no postoperative mortality, the achieved median survival of 31 months may be regarded as promising. Between 2005 and 2012, 281 patients were diagnosed with PMSBC in The Netherlands, which currently has 16.8 million inhabitants (Dutch National Cancer Registry). In this period, 5% of these patients were considered for CRS + HIPEC. In the literature, only 3 case series address the surgical treatment of PMSBC. The first series is by Marchettini et al,9 who reported 6 patients all undergoing CRS + HIPEC + early postoperative intraperitoneal chemotherapy (EPIC) treatment. For HIPEC, MMC was used during 90 minutes using the open colloseum technique. After the procedure,
1026 van Oudheusden et al
Figure. Kaplan–Meier curve of patients undergoing Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases of small bowel cancer.
all patients received EPIC using 5-flurouracil. Median survival was 12 months, and 4 out of 6 patients (66.7%) died owing to progression or recurrent systemic disease. Chua et al10 described 7 patients who underwent CRS combined with either HIPEC with MMC, EPIC with 5-flurouracil, or both. Overall median survival was 25 months and all 7 patients developed intraabdominal recurrence (100%) of whom 6 ultimately had died at time of analysis. The largest case series is published by Sun et al,11 which also incorporated a prior case series from the same institution, previously reported by Jacks et al.12 Seventeen patients underwent 20 CRS + HIPEC with MMC using the closed technique over 120 minutes, attaining a median survival of 18.4 months. Fifteen out of 17 patients (88.2%) died of progressive intraabdominal disease. In our current series, median survival was 31 months. Although 6 patients were treated 1 year and 5 among them of >2 years. The difference in survival compared with previously published articles is most likely owing to a stricter patient referral and selection. A recent commentary by the American Society of Peritoneal Surface Malignancies recommends HIPEC centers to strive for $30-month median survival in colorectal cancer patients undergoing CRS + HIPEC.13 The result of 31 months in SBC in the current series meets this recommendation. Overall 5-year survival in all small bowel adenocarcinoma patients is 37%.5 Metastasized SBC has a median survival of not >13 months, with high recurrence rates mainly in the first year.14 Colorectal peritoneal carcinomatosis, a disease
Surgery June 2015
considered to have a poor survival, has a 5-year survival of #30% when treated with CRS + HIPEC, which is similar to overall 5-year survival of small bowel adenocarcinoma.15 These poor outcomes can to a certain extent be explained by 3 facts. First, presentation of SBC is often late and nonspecific, owing to its relatively asymptomatic early evolution in the first stages of disease. For example, time between onset of symptoms and surgery was not
Introduction. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered the standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer. CRS + HIPEC has also been suggested as a potential treatment option in PM of the much rarer small bowel cancer. Therefore, the current study was undertaken to investigate the results of CRS + HIPEC in all HIPEC centers in The Netherlands. Methods. From the 4 tertiary referral centers for peritoneal surface malignancies in The Netherlands, data from all patients with peritoneally metastasized small bowel carcinoma intended to undergo CRS and HIPEC were collected between January 2005 and July 2014. Primary tumor characteristics, operative details, and survival outcomes were collected. Results. Sixteen of 19 patients (84.2%) who underwent explorative laparotomy underwent CRS + HIPEC. Of these patients, 81.3% were female, and primary tumors were mainly located in the ileum (50%). A complete macroscopic resection was achieved in 93.8%. Serious adverse events requiring re-intervention occurred in 25%, and no in-hospital mortality was observed. Recurrent disease was observed in 50% of patients and median survival after CRS and HIPEC was 31 months. Conclusion. In a select group of patients in whom a complete macroscopic resection can be achieved, survival rates comparable with those in colorectal PM are attainable with acceptable morbidity. The role of adjuvant chemotherapy needs further research. (Surgery 2015;157:1023-7.) From the Department of Surgical Oncology,a Catharina Hospital, and the Department of Research,b Eindhoven Cancer Registry/Comprehensive Cancer Centre The Netherlands (IKNL), Eindhoven; the Department of Surgical Oncology,c St. Antonius Hospital, Nieuwegein, the Department of Surgical Oncology,d VU University Medical Center Amsterdam, and the Department of Surgical Oncology,e The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands
CYTOREDUCTIVE SURGERY and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered to be standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer in many countries.1 This treatment is currently under Accepted for publication January 29, 2015. Reprint requests: Ignace H. de Hingh, MD, PhD, Catharina Hospital Eindhoven, Department of Surgical Oncology, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2015.01.021
clinical investigation for other frequently occurring cancers known to develop PM in many patients, such as gastric or ovarian cancer. However, some peritoneal cancer manifestations are very rare, including that originating from small bowel cancer (SBC). SBC accounts for only 3% of all gastrointestinal malignancies. As a result, little has been reported on its treatment and oncologic outcomes.2,3 Although operative resection has been established as the treatment of choice in the absence of metastases for several decades, overall survival is considered poor and has not improved significantly over the last 20 years.4 PM of SBC (PMSBC) are present in up to onequarter of patients and the peritoneal cavity is a SURGERY 1023
1024 van Oudheusden et al
common site of recurrence after curative surgery.2,5 With the achieved results in colorectal cancer in mind, CRS + HIPEC has been suggested as a potential treatment option to increase survival in this otherwise ill-fated group. Given the rarity of PMSBC, support for this treatment will not come from randomized clinical trials. Therefore, the current study was undertaken to investigate the results of CRS and HIPEC in several HIPEC centers in The Netherlands. METHODS Patients. From the 4 tertiary centers for peritoneal surface malignancies in The Netherlands (Catharina Hospital Eindhoven, St. Antonius Hospital Nieuwegein, VU University Medical Centre Amsterdam and The Netherlands Cancer Institute Amsterdam), all patients with peritoneally metastasized small bowel adenocarcinoma intended to undergo CRS + HIPEC between January 2005 and July 2014 were identified and data on primary tumor characteristics, operative details, and survival outcomes were collected. The local medical ethics committee approved this study. CRS and HIPEC. All patients undergoing CRS and HIPEC were treated according to the Dutch nationwide protocol for HIPEC procedures.6 Before surgery, all patients underwent CT to assess disease burden, primary tumor resectability, and the presence of systemic metastases. Cases were discussed in a multidisciplinary tumor board. After initial exploratory laparotomy, CRS and HIPEC was performed when a complete macroscopic resection was believed to be possible and no distant metastases were present. The amount of peritoneal cancer was assessed by the ‘‘7-region score,’’ during which the presence of peritoneal cancer is scored in 7 welldefined abdominal regions. This scoring system was proven to be equally adequate compared with more complex scoring systems such as the Peritoneal Cancer Index to predict the outcome and prognosis of peritoneal cancer patients after HIPEC and is most commonly used in The Netherlands.7 Exclusion criteria to continue with CRS and HIPEC after exploration were a region score of >5, an unresectable primary tumor, extensive small bowel involvement resulting in short bowel syndrome if resected, and/or intraoperative discovery of unresectable liver metastases. HIPEC procedures were performed by using the open colosseum technique and mitomycin C (MMC; 35 mg/m2 at 41–428C) as the intraperitoneal chemotherapy regimen for 90 minutes. Completeness of cytoreduction was assessed using the R-score. In case no macroscopic tumor is left
Surgery June 2015
behind, the result of cytoreduction is scored as ‘‘R1.’’ When there was remnant macroscopic tumor, the score is ‘‘R2a’’ when the tumor is 1 year. Eight patients
N
7-Region count I 3 II 2 III 1 IV 5 V 1 VI 1 VII 1 Unknown 2 Median blood loss (mL) 900 (225–3,300) Mean operation time (min) 339.0 (275.6–402.4) R score R1 15 R2a 0 R2b 1 Hospital stay (d) 11 (5–46) Serious adverse event >3 4 Hospital mortality 0 Adjuvant chemotherapy Yes 9 No 6 Unknown 1 Recurrent disease 8 Location of recurrent disease Local/PC 7 Lung 1
% 18.8 12.5 6.3 31.3 6.3 6.3 6.3 12.5
93.8 0 6.3 25.0 0 56.3 37.5 6.3 50 87.5 12.5
PC, Peritoneal carcinomatosis.
(50%) developed a recurrence during follow-up. These were mainly intraperitoneal recurrences (87.5%) with lung metastases occurring in 1 patient (12.5%). The patient treated with HIPEC after an R2b resection status died after 3.5 months. DISCUSSION Peritoneally metastasized small bowel carcinoma is a rare disease, with only 16 patients treated with CRS + HIPEC over a period of almost 9 years in The Netherlands. With limited postoperative morbidity and no postoperative mortality, the achieved median survival of 31 months may be regarded as promising. Between 2005 and 2012, 281 patients were diagnosed with PMSBC in The Netherlands, which currently has 16.8 million inhabitants (Dutch National Cancer Registry). In this period, 5% of these patients were considered for CRS + HIPEC. In the literature, only 3 case series address the surgical treatment of PMSBC. The first series is by Marchettini et al,9 who reported 6 patients all undergoing CRS + HIPEC + early postoperative intraperitoneal chemotherapy (EPIC) treatment. For HIPEC, MMC was used during 90 minutes using the open colloseum technique. After the procedure,
1026 van Oudheusden et al
Figure. Kaplan–Meier curve of patients undergoing Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases of small bowel cancer.
all patients received EPIC using 5-flurouracil. Median survival was 12 months, and 4 out of 6 patients (66.7%) died owing to progression or recurrent systemic disease. Chua et al10 described 7 patients who underwent CRS combined with either HIPEC with MMC, EPIC with 5-flurouracil, or both. Overall median survival was 25 months and all 7 patients developed intraabdominal recurrence (100%) of whom 6 ultimately had died at time of analysis. The largest case series is published by Sun et al,11 which also incorporated a prior case series from the same institution, previously reported by Jacks et al.12 Seventeen patients underwent 20 CRS + HIPEC with MMC using the closed technique over 120 minutes, attaining a median survival of 18.4 months. Fifteen out of 17 patients (88.2%) died of progressive intraabdominal disease. In our current series, median survival was 31 months. Although 6 patients were treated 1 year and 5 among them of >2 years. The difference in survival compared with previously published articles is most likely owing to a stricter patient referral and selection. A recent commentary by the American Society of Peritoneal Surface Malignancies recommends HIPEC centers to strive for $30-month median survival in colorectal cancer patients undergoing CRS + HIPEC.13 The result of 31 months in SBC in the current series meets this recommendation. Overall 5-year survival in all small bowel adenocarcinoma patients is 37%.5 Metastasized SBC has a median survival of not >13 months, with high recurrence rates mainly in the first year.14 Colorectal peritoneal carcinomatosis, a disease
Surgery June 2015
considered to have a poor survival, has a 5-year survival of #30% when treated with CRS + HIPEC, which is similar to overall 5-year survival of small bowel adenocarcinoma.15 These poor outcomes can to a certain extent be explained by 3 facts. First, presentation of SBC is often late and nonspecific, owing to its relatively asymptomatic early evolution in the first stages of disease. For example, time between onset of symptoms and surgery was not
