TREATMENT OF PERITONEAL COLORECTAL CARCINOMATOSIS

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1 TREATMENT OF PERITONEAL COLORECTAL CARCINOMATOSIS Anna Lepistö, MD, PhD Department of Colorectal Surgery, Abdominal Center, Helsinki University Hospital

2 Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer J. Segelman1,*, F. Granath2, T. Holm1, M. Machado3, H. Mahteme4, A. Martling1 British Journal of Surgery 2012; 99: patients 8.3 % had synchronous or metachronous peritoneal carcinomatosis 4.3 % had synchronous PC 4.8 % cumulative incidence of metachronous PC in 4.8 % PC was the first and only localization of metastases

3 Effect of systemic chemotherapy on colorectal peritoneal carcinomatosis lack of data especially concerning PC as the only localization of metastases median survival of 6 months in unselected patients with older chemotherapies -> 5-year OS 5 % median survival less than 24 months in highly selected patients with modern chemotherapies -> 5-year OS 13 %

4 Franko J, Shi Q, Goldman CD et al. 20;30(3):263-67, OVERALL SURVIVAL OF PATIENTS WITH PC OF CRC ORIGIN pccrc median OS 14 months 5-year survival 4.1 % (A) leucovorin, fluorouracil, oxaliplatin (B) irinotecan, leucovorin, fluorouracil (C) irinotecan and oxaliplatin

5 Philosophy of CytoReductive Surgery (CRS) and Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) Peritoneum can be considered as an organ itself and as the third route of spreading of metastases in addition to hematogenous and lymphatic metastases. Thus, in selected patients, when peritoneal afficions can be technically removed, total cure is possible to achieve.

6 Cytoreduction and HIPEC in the Netherlands: NationwideLong-term Outcome Following the Dutch Protocol A. M. J. Kuijpers et al. Ann Surg Oncol 2013 OS overall survival PFS progression-free survival CRC median PFS 15 months median OS 33 months 3-y survival 46 % 5-y survival 31 % PMP median PFS 53 months median OS 130 months 3-y survival 77 % 5-y survival 65 %

7 Jan Franko MD, PhD, Zuhaib Ibrahim MD, Niraj J. Gusani MD, et. al,cancer 2010; 116: median survival 34.7 months vs months presence of liver metastases was negative predictor of survival (HR 2.13) Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis control group inclusion criteria: 1) asymptomatic PC 2) aggressive chemotherapy 3) primary tumor removed

8 Goere D, Malka D, Tzanis D et al. 2013, 257(6): CURATION RATE AFTER CRS AND HIPEC FOR PC OF COLORECTAL ORIGIN 107 patients years year survival 35 % 10-year survival 15% 16 % disease-free after 5 years

9 ... Selected patients with colorectal carcinomatosis have 5- year survival of 25 to 30 %. Compare to 30-40% 5-year survival and 17% cure after resection of colorectal cancer liver metastases or 18 % 5-year survival after radical surgery for pancreatic cancer

10 Carefully selected patients with peritoneal carcinomatosis from colorectal origin benefit from cytoreductive surgery combined with intraperitoneal chemotherapy. Questions: How do we select the right patients considering 0-18 % mortality and % morbidity rate associated with CRS and HIPEC? How do we find the right patients?

11 Prognostic factors affecting survival after CRS and HIPEC in patients with colorectal PC PCI CC-rate number of involved areas small bowel involvement liver metastases (number of?) progression during neoadjuvant chemotherapy adjuvant chemotherapy tumor differentiation, tumor histology serum tumor markers

12 Impact of tumor mass on survival after radical surgery Limited peritoneal cancer index ( <9, <10, <12?) or limited peritoneal cancer score are positive predictors of survival. Benizri E et al. World J Surg Oncol 2012: 10: 56-. Yonemura Y et al. ScientificWorldJournal 2013 Maggiori L et al. Ann Surg 2013; 258: Verwaal VJ et al. Br J Surg 2004; 91: PCI is reliable tool of measuring the extent of PC, because inter-surgeon concordance (> 90 %) before and after surgery is high. Elias D et al. EJSO ;

13 adopted by Paul Sugarbaker

14 Goere D, Malka D, Tzanis D et al. 2013, 257(6): Overall survival in 107 patients after CRS and IPC according to peritoneal cancer index. median PCI: 4 (3-16) in cured 12 (2-36) in noncured

15 Number of affected regions Age Sex Verwaal VJ et al. 2004; 91: Location (app / colon) Location (rectum / colon) Recurrence or primary Differentiation Signet cell or non-signet cell No of affected regions

16 Small bowel involvement Yonemura Y et al. ScientificWorldJournal 2013

17 Surgical radicality: CC-0 vs. CC-1 CCR-O: 5-y survival 20% CCR-1: 5-year survival 9.9% Yonemura Y et al. ScientificWorldJournal 2013 Benizri E et al. World J Surg Oncol 2012; 10:56

18 Surgical radicality: CC-0 vs. CC-1 Passot G et al. Ann Surg 2012; 256:

19 Synchronous liver metastases and PC Maggiori L et. al. 2013;258: patients with PC + LM, 61 patients with PC 3-year overall and disease-free survival: 40 % and 6 % in PC + LM group 60% and 27 % in PC only group

20 Synchronous liver metastases and PC Maggiori L et. al. 2013;258: Median survival: PCI < 12 and no LM 76 months PCI < 12 and 1-2 LMs 40 months PCI >= 12 and > 2 LMs 27 months

21 Progression of PC during neoadjuvant chemotherapy Passot G et al. Ann Surg 2012; 256(1): Progression during neoadjuvant chemotherapy was not a negative predictor of survival after CRS and HIPEC. p = 0.475

22 Effect of adjuvant chemotherapy Passot G et al. Ann Surg 2012; 256(1): p = 0.049

23 Tumor differentiation Age Sex Verwaal VJ et al. 2004; 91: Location (app / colon) Location (rectum / colon) Recurrence or primary Differentiation Signet cell or non-signet cell No of affected regions

24 Effect of tumor differentiation and histology Median and 5-year survival after CRS and HIPEC: 25.9 months and 24.6 % in differentiated 10.7 months and 0 % in poorly differentiated Yonemura Y et al. The Scientific World Journal Volume 2013 (2013), Article ID , 7 pages

25 Patients at risk for colorectal PC previous synchronous PC ovarian metastases tumor perforation liver metastases venous and perineural invasion right-sided colonic cancer T3-T4 N1-N2 fewer than 12 LNs examined emergency procedures non-radical resection

26 Synchronous ovarian metastases with primary tumor without synchronous PC do occur in % of all colorectal cancers -> PC in 62 % of patients at second-look after 12 months -> PC in 56 % of patients in imaging studies after surgery level of evidence 3b to 4 (case-control study,case series) Honore C et al.2013; 20:

27 Synchronous PC with the primary tumor in about 4.8 % of patients scheduled for curative surgery -> PC in second-look after 12 months in 54% of patients with completely resected synchronous PC level of evidence 3b to 4 (case-control study,case series) Honore C et al. 2013; 20:

28 Perforated primary tumor Overall tumor perforation rate is about 1 to 8 %. -> PC in 27 % of patients having second-look after 12 months of primary operation with tumor perforation. Honore C et al.2013; 20:

29 Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer J. Segelman1,*, F. Granath2, T. Holm1, M. Machado3, H. Mahteme4, A. Martling1 British Journal of Surgery 2012; 99: patients operated in Stockholm County followed until 2010 metachronous PC in 447 (4.2 %) diagnosis of metacronous PC after median of 16 ( ) months

30 Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer J. Segelman1 et al. British Journal of Surgery 2012; 99: Statistically significant risk factors for metachronous PC: colon cancer (especially right-sided) advaced tumor, T3-4 advanced node status (N 1-2) less than 12 investigated nodes emergency surgery non-radical resection

31 Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer J. Segelman et al. British Journal of Surgery 2012; 99: patients had PC as the sole site of metastases after resection of Stage I-III primary tumor. -> about half of these could be candidates for radical surgery only 1 % of Stage I-III patients would benefit from second-look

32 Laparoscopy in evaluating PC of colorectal origin Iversen LH et al. BJS 2013;100: Laparoscopy succeeded technically in all 26 patients with CRC originated PC. 45 patients 14 synchronous PC with CRC 12 metachronous PC after CRC 19 other than CRC originated CRC patients selected for CRS and HIPEC on the basis of laparoscopy: 7 patients with metachronous PC and 8 patients with synchronous PC

33 Laparoscopy in evaluating PC of colorectal origin CRS and HIPEC was not possible Iversen LH et al. BJS 2013;100: in 1 of 8 synchronous PCs in 5 of 7 metachronous PCs Laparoscopy most often failed to recognize retroperitoneal and hepatic pedicle carcinomatosis.

34 Conclusions Carefully selected patients with colorectal carcinomatosis benefit from CRS and HIPEC and can achieve about 30 % 5-year survival and 16 % 5-year disease-free survival. In order to prevent unnecessary suffering of patients and use of limited health care resources, we should limit CRS and HIPEC to patients with good prognostic factors and true possibility of CC-0 surgery.

35 Conclusions A second look (within 6 to 12 months?) laparotomy/scopy should be considered in patients with synchronous ovarian metastases, synchronous peritoneal carcinomatosis or tumor perforation. Patients with peritoneal progression during neoadjuvant treatment or with 1 to 2 liver metastases should not be automatically excluded from CRS and HIPEC. Patients possibly benefit from adjuvant chemotherapy after CRS and HIPEC.