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Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review T.R. van Oudheusden a, S.W. Nienhuijs a, M.D. Luyer a, G.A. Nieuwenhuijzen a, V.E. Lemmens b, H.J. Rutten a, I.H. de Hingh a,* a

Department of Surgical Oncology, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands b Department of Research, Eindhoven Cancer Registry/Comprehensive Cancer Centre the Netherlands (IKNL), PO Box 213, 5600 AE Eindhoven, The Netherlands Accepted 27 May 2015 Available online - - -

Abstract Introduction: The optimal treatment for peritoneal carcinomatosis (PC) of colorectal origin is a combination of cytoreductive surgery and intraperitoneal chemotherapy (CRS þ IPC). Although 5-year survival rates of up to 40% have been reported, recurrent disease remains common and is estimated to be a strong negative prognostic factor for survival. This systematic review elaborates on the incidence of recurrent disease and the possibilities to prevent and treat recurrence. Methods: Two searches were performed. To identify the magnitude of recurrent the disease, a search was performed in Pubmed and EMBASE until September 2014. A second search was performed in Pubmed to identify treatment of recurrent disease with secondary CRS þ IPC. Results: The first search resulted in 139 and 94 articles in Pubmed and EMBASE respectively. Among those, 28 were included. Overall recurrence rates ranged from 22.5 to 82%. Local, systemic and combined local-systemic recurrence ranged from 6 to 42.5%, 10.4e43% and 5.8e21.5%. Median time to recurrence varied from 9 to 23 months, three-year disease free survival ranged from 14 to 41.5%. The second search resulted in 140 articles among which 17 met the inclusion criteria. A total of 190 patients underwent secondary CRS. Median survival after the second procedure ranged from 18 to 55.7 months. One, two and three-year survival ranged between 66 and 94, 44e50 and 0e66%. Conclusion: Recurrence is very common after cytoreductive surgery and intraperitoneal chemotherapy for PC of colorectal origin. Repeat cytoreductive surgery suggests a potential survival benefit for a highly selected group. Therefore, strategies to prevent recurrence are of the utmost importance. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Peritoneal carcinomatosis; Cytoreductive surgery; Intraperitoneal chemotherapy; Recurrent disease; Colorectal cancer

Introduction * Corresponding author. Catharina Hospital Eindhoven, Department of Oncologic Surgery, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands. Tel.: þ31 40 2399111; fax: þ31 40 2455035. E-mail address: [email protected] (I.H. de Hingh).

To prevent recurrence, radical resection of a malignant tumor is one of the most important targets in surgical oncology. However, for peritoneal carcinomatosis (PC), a disease characterized by widespread dissemination of

http://dx.doi.org/10.1016/j.ejso.2015.05.018 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: van Oudheusden TR, et al., Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.018

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T.R. van Oudheusden et al. / EJSO xx (2015) 1e9

tumor deposits on the peritoneal surface, a microscopic complete resection is illusive. Therefore, after resection of macroscopic disease e commonly referred to as cytoreductive surgery or CRS e intraperitoneal chemotherapy (IPC) is administered in high dosages to destroy remaining tumor cells.1,2 The addition of heat (HIPEC) is thought to further enhance the effect of IPC.3 In the last two decades, this treatment has evolved and in selected patients a 5-year survival rate of up to 40% has been reported.4 The major prognostic factors predicting a good oncological outcome are a low peritoneal tumor burden as measured by the Peritoneal Cancer Index (PCI) and the possibility to achieve a macroscopic complete cytoreduction. Other factors such as a favorable tumor histology and low nodal status are also important.5e7 Comparable to the surgical treatment of liver metastases,8 disease recurrence is a strong negative prognostic factor for survival.9 In PC, even though a macroscopic complete resection is achieved in the majority of patients treated with CRS and IPC, recurrent disease is very common.10 It is postulated that in these patients, too high microscopic tumor burden is left behind to be eliminated by intraperitoneal chemotherapy (surgical failure) or that the chemotherapeutic agent itself was not effective enough to eliminate the tumor cells (chemotherapeutic failure).11 This review elaborates on the incidence of recurrence after CRS and IPC and the possibilities to prevent and treat recurrence. Methods Selection criteria All available studies reporting on recurrence after cytoreductive surgery and intraperitoneal chemotherapy (CRS þ IPC), heated intraperitoneal chemotherapy (HIPEC) or early/sequential postoperative intraperitoneal chemotherapy (EPIC/SPIC) for PC of colorectal origin were included. Studies that reported on other origins then colorectal cancer were excluded. In case of mixed origins, papers were reviewed individually to decide whether or not the proportion of CRC was significant, defined as a minimum of 50% of cases from colorectal origin. Given the different biological behavior of PC from appendiceal adenocarcinoma, appendiceal tumors were not regarded as colorectal. Also, conference abstracts were excluded. There were no language restrictions. Search strategy A search until September 2014 was conducted in PubMed and EMBASE to identify studies reporting on recurrence after CRS þ IPC for PC of colorectal origin and studies reporting the outcome of surgical treatment of these recurrences. The first search strategy was performed in Pubmed using the following search criteria to identify recurrence related

articles: (colorectal neoplasms OR colorectal cancer) AND (peritoneal carcinomatosis OR peritoneal metastases) AND (HIPEC OR EPIC OR SPIC OR intraperitoneal chemotherapy OR hyperthermic intraperitoneal chemotherapy OR early postoperative chemotherapy OR sequential postoperative intraperitoneal chemotherapy) AND (recurrence OR recurrent disease). Following the Pubmed search, the EMBASE database was consulted using the following search terms: ((colorectal cancer or colorectal carcinoma or colorectal neoplasms) and (Peritoneal metastases or peritoneal carcinomatosis) and (intraperitoneal chemotherapy or IPC or hyperthermic intraperitoneal chemotherapy or HIPEC or sequential postoperative intraperitoneal chemotherapy or SPIC or early postoperative intraperitoneal chemotherapy or EPIC) and (Recurrence or recurrent disease)). Data on patient type, operation type, completeness of resection, adjuvant chemotherapy, recurrence, recurrence location, time to recurrence and disease free survival were extracted. A second search was performed to identify articles on treatment of recurrent disease with secondary CRS þ intraperitoneal chemotherapy or surgery only using the following search terms in Pubmed: (Colorectal cancer OR colorectal origin OR colorectal neoplasm) AND (peritoneal carcinomatosis OR peritoneal metastases) AND (cytoreductive surgery OR Surgery) AND (HIPEC OR EPIC OR SPIC OR intraperitoneal chemotherapy OR hyperthermic intraperitoneal chemotherapy OR early postoperative chemotherapy OR sequential postoperative intraperitoneal chemotherapy) AND (iterative OR second procedure OR repeat OR treatment of recurrence). Data on the procedure type, completeness of resection, morbidity/mortality, the interval between first and second procedure and survival were extracted. Furthermore, all references from all relevant articles were analyzed to identify other potential manuscripts. Data was extracted from the included articles independently by TR van Oudheusden and IH de Hingh. In case of disagreement, SW Nienhuijs rechecked the concerning article for definite data extraction. Results Incidence of recurrent disease Search results & provided treatment The search performed in Pubmed resulted in 139 articles and the EMBASE search in 94 articles. After exclusion and analyzing all reference lists, 27 studies met the inclusion criteria. The study flowchart is presented in Fig. 1. A summary of the included studies is provided in Table 1. Data was only provided when given in the original article or deducible from the results section. Patients were either treated with CRS þ HIPEC, EPIC, SPIC or HIPEC þ EPIC. In 23 articles, provided treatment

Please cite this article in press as: van Oudheusden TR, et al., Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.018

T.R. van Oudheusden et al. / EJSO xx (2015) 1e9

3

Figure 1. Study fowchart.

was CRS þ HIPEC in 100% of patients. In the remaining three articles, a part of the patients underwent CRS þ EPIC or SPIC or both. Completeness of cytoreduction varied between 7.1% and 100%. Systemic chemotherapy after surgical intervention was provided in 25.7e67.2% of patients. Incidence of recurrence Overall recurrence ranged from 22.5 to 82%. Local -, systemic- and combined local systemic recurrence ranged from 6 to 42.5%, 10.4e43% and 5.8e21.5% respectively. Disease free survival Reported median time to recurrence varied from 9 to 23 months. Three-year disease free survival ranged from 15 to 41.5%. Detection of recurrence Seven studies specifically described the follow up schedule of included patients. Follow up in these studies included 3 monthly CEA and CA 19.9 measurements and abdominal-thoracic computed tomography every 3e6 months for the first 2 years. Two studies mentioned that in case of elevated tumor markers, PET scans were routinely performed. In one group, routine colonoscopy was performed after 2e3 years in every patient.

Treatment of locoregional recurrent disease Search results & provided treatment The second search performed in Pubmed concerning the treatment of recurrent disease resulted in 140 articles. After exclusion and hand searching reference lists, 17 studies met the inclusion criteria. A total of 190 patients underwent secondary CRS, of whom 25 with no further intraperitoneal treatment. CRS was combined with HIPEC, EPIC, SPIC or HIPEC þ EPIC in 139, 8, 4 and 6 patients respectively. Treatment type was unknown in 13 patients. In 7 patients, a tertiary CRS procedure was performed. The interval between primary and secondary intervention ranged from less then 12 monthse22 months. Results are given in Table 2. Data was only provided when given in the original article or deducible from the results section. Survival Median survival after the second surgical procedure ranged from 18 to 55.7 months. One -, two e and threeyear survival ranged between 66 and 94%, 44e50% and 0e66%. Selection criteria for redo CRS Criteria used to determine eligibility for redo CRS are listed in Table 3 when mentioned.

Please cite this article in press as: van Oudheusden TR, et al., Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.018

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T.R. van Oudheusden et al. / EJSO xx (2015) 1e9

Table 1 Incidence of recurrent disease after CRS þ IPC for PC of colorectal origin. Local þ systemic (%)

MTTR (m)

DFS (m)

14.3

11.4

e

e

e

e

e

e

e

e

82

42.5 6c

20.5 12c

15.1

e e

23 (CC0 only) 10.9 15% e 3 yr e e

e

e

e

e

e

e

22% e 3 yr

51.5

82

21.5

21.5

e

19% e 3 yr

e

e

e

e

e

15 (PFS)

e

48

19.2

7.5

e

e

e

e

e

e

e

e CC0/1 90.9%

e 31.8

e 18.2

e 54.5

e 18.2

e e

22 48

e e

Np 62.5

e 55 (CC0/1 only) e e

30 (HIPEC þ EPIC) 19 (HIPEC) 20 (EPIC) 3.6% 5-yr 24

e e

e e

e e

e 19.8

2012

151

CC0 64.2%

25.7

22.5

13.2

e

19.3

Cashin56

2011

32

R1 100%

37.5

12 (in resurgery group) 7 (in palliative group) 22.8 (HIPEC group) 13.0 (SPIC group)

Quenet57 Mulsow58

2011 2011

146 31

Np 52.8

70.6 74

21.2 29.0

Cavaliere59

2011

146

e

e

e

e

e

e

26% e 3 yr

Bretcha60

2011

20

e

50

e

e

e

e

30% e 5yr

Elias61 Akaishi62

2010 2009

523 21a

CC0 90.4% R0/R1 100% CC0 85.1% CC1 7.5% CC0 75% CC1 5% CC2 20% CC0 84% e

47 e

e 42

e 14

e e

e e

e e

Hagendoorn63 Bijelic11

2009 2007

49 70

e

44.9 70

40

e 14.3

e 14.3

12 9

15% 3 yr 16 35% e 3yr e e

Elias20

2006

30

>50

73

36.7

e

e

14

Author

Year

N

CCR (%)

Adjuvant treatment (%)

Overall recurrence (%)

Local recurrence (%)

Braam9

2014

287

e

46

19.9

Nikolic47

2014

61

67.2

e

e

Rivard48

2014

68

R0/R1 100% 93.4% CC0 6.6% CC1/2 CC0 100%

48.5

e

Kuijpers5 Ceelen49

2014 2014

e CC0 47.5% CC1 39.8%

43.8 50

Gervais50

2013

73b 166 (152 CRC)a 25

Goere32

2013

107

Kuijpers51

2013

Konigsrainer15

2013

660 (598 CRC)a 52

CC0 40% CC1 60% CC0 94.8% CC1 5.2% R1 80% R2a/b 19%

Chua14

2013

98

Teo52 Duraj53

2013 2013

28 22

Tan54 Hompes55

2012 2012

Cashin13

CC0 60% CC1 40% CC0/1100%

R0/R1 92% CC0 7.1% CC1 92.9% CC0 100%

Systemic recurrence (%) 11.8

43 e

21.2

35.6 29.0

5.8

13.7 16.1

27.7% 3 yr 65.8% e 1 yr 45.5% e 2 yr 15 (HIPEC) 10 (SPIC) 32% 5yr (HIPEC) 12% 5yr (SPIC)

15.7

41.5% 3yr 34% 5 yr

(continued on next page)

Please cite this article in press as: van Oudheusden TR, et al., Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.018

T.R. van Oudheusden et al. / EJSO xx (2015) 1e9

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Table 1 (continued ) Author

Year

N

CCR (%)

Adjuvant treatment (%)

Overall recurrence (%)

Local recurrence (%)

Verwaal10

2004

106a

e

65.7

36.8b

Glehen12

2004

506

CC0-1 85.8% CC0 271 CC1 106

40

73.3

31.2

a b c

Systemic recurrence (%) 10.4b

Local þ systemic (%) 6.6b

e

e

MTTR (m)

DFS (m)

10.9

e

e

e

Included other primary tumors (mainly appendiceal, sometimes PMP, mesothelioma). Only lymph node positive patients. Among patients alive at time of analyses.

Discussion Although CRS þ IPC generally results in prolonged survival, many patients suffer from recurrent disease after initial treatment. The second largest study in literature reports recurrence rates of up to 73.3%.12 In a more recent study performed by Braam and colleagues, a 46% recurrence rate was detected even though only patients with CCR 0e1 were included in this analyses.9 Similar results were observed in other groups included in this review.9e15

Although it is clear that recurrence is common, it cannot be deduced from these numbers whether it is more prevalent as local or systemic recurrent disease since the percentages vary greatly in the reviewed articles. Moreover, no elaboration can be made to determine which type of recurrence comes first. Since locoregional recurrence, systemic recurrence and the combination of both are all prevalent, one must assume that both the primary extensive procedure including surgery and intraperitoneal chemotherapy but also the systemic adjuvant chemotherapy fail to adequately

Table 2 Secondary procedures for local recurrent disease. Author

Year

Number of re-CRS

Number of re-re-CRS

Secondary procedure type

CCR0

Morbidity/ mortality (%)

Interval

MS survival after secondary procedure

Braam9

2014

18

3

e

e

e

42.9 vs. 11.8a

Klaver64

2013

18b (13 CRC)

e

22

1 yr ¼ 72% 2 yr ¼ 50%

2013

11

e

CC0 13 CC2 2 CC3 3 e

16.7% (III/IV)/0%

Chua19

58.8% reCRS only 41.2% reCRS þ HIPEC 14 reCRS þ HIPEC 3 reCRS þ EPIC 1 reCRS þ HIPEC þ EPIC 100% reCRS þ HIPEC

e

e

Williams27

2013

18

e

Tabrizian25 Cashin13

2013 2012

15 8

e e

Golse21 Votanopoulos26 Quenet57

2012 2012 2011

30b (8 CRC) 4 Undeterminable

2 e e

Bretcha60

2010

2

Brouquet18 Elias20 Kianmanesh22 Bijelic11

2009 2006 2007 2007

20b (4 CRC) 2 11 26

3 e e e

Glehen12 Portilla23

2004 1999

26 18

1 e

a b c

16.7% (III/IV)/0%

16.2

e e

e e

e e

23 1 yr ¼ 3 yr ¼ 22.6 1 yr ¼ 2 yr ¼ 3 yr ¼ 3 yr ¼ 23

e e e

e e e

e e e

e 55.7 e

e

e

e

e e e CC0 69.2%

e e e e

e e e e

Patient 1: 19m DFS Patient 2: 18 months e e e 42c

e CC0 11 CC1 7

e Np/0%

e 51yr

1 reCRS 5 reCRS þ EPIC 7 reCRS þ HIPEC 5 reCRS þ HIPEC þ EPIC 100% reCRS þ HIPEC 50% CRS þ HIPEC 50% CRS þ SPIC 100% reCRS þ HIPEC 100% ReCRS þ HIPEC Unknown reCRS 3 HIPEC CRS þ HIPEC þ EPIC

CC0 100%

100% ReCRS þ HIPEC or EPIC 2 reCRS 100% reCRS þ HIPEC 46.2% reCRS only 53.8% reCRS-HIPEC 100% reCRS þ HIPEC 100% reCRS þ HIPEC

90% 0% 94% 48% 12% 66.5%

57.6% 20 1 yr ¼ 66% 2yr ¼ 44%

Median survival after initial operation comparing surgical intervention to palliative treatment for intra-abdominal recurrence. Appendiceal þ Colorectal mix. Excluding incomplete reCRS.

Please cite this article in press as: van Oudheusden TR, et al., Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.018

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T.R. van Oudheusden et al. / EJSO xx (2015) 1e9

Table 3 Criteria for second cytoreductive surgery with or without additional intraperitoneal chemotherapy. Author

Year

Klaver

2013

Chua

2013

Williams

2013

Golse

2012

Votanopoulos

2012

Inclusion Age

Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review.

The optimal treatment for peritoneal carcinomatosis (PC) of colorectal origin is a combination of cytoreductive surgery and intraperitoneal chemothera...
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