crs and hipec for colorectal cancer · divided, a single entry into the peritoneal cavity in the...

  CRS and HIPEC for Colorectal Cancer

Rajesh Nair, MD UF Health Cancer Center-Orlando Health March 11, 2017

  Peritoneal Carcinomatosis from CRC •  Historically, a devastating

problem•  Extreme morbidity from

disease and from treatment•  Obstruction

•  Prior to “modern chemotherapy,” survival was very limited

Zhu et al. J Gastrointest Oncol 2013; 4(1): 62-71.

  Colorectal Cancer

•  True incidence of PC in CRC hard to estimate•  In various series, the peritoneal surface is the initial site of

failure in 10%-20% of patients after curative colon resection•  It is also involved in 40%-70% of patients who present with

advanced disease•  In ~ 5%-10% of all patients with colon cancer and in

10%-35% of all patients with recurrent disease, tumor recurrences are confined to the peritoneal surface only

Khatri. J Clin Oncol 2010; 28(1): 5-7.

  Multi-step process

•  The pathophysiology of PC is complex and incompletely defined

•  Likely includes:•  Exfoliated tumor cells with direct communication to the peritoneal

surface•  Exfoliated cells delivered by the lymphatic system into the peritoneal

cavity and sub-mesothelial spaces•  Growth factors, angiogenic factors and implantation factors either

embedded in mucin or secreted directly into the peritoneal cavity

Sugarbaker PH (ed): Peritoneal Carcinomatosis: Principles of Management. Kluwer: Boston, p79, 1996

  CRS and HIPEC

•  Goal: Complete cytoreduction followed by perfusion•  Applications

•  Appendiceal•  Mesothelioma•  Colorectal•  Small bowel

  Why even consider HIPEC?

•  Systemic chemotherapy for advanced colorectal cancer has improved with longer median survival times

•  Recent trials in advanced colorectal cancer with intensified systemic chemotherapy (both oxaliplatin and irinotecan treatment) including a biologic monoclonal antibody have demonstrated 30+ month median OS and a 12+ month PFS

Loupakis et al. N Engl J Med 2014; 371: pp. 1609-1618.

Cashin et al. Eur J Cancer 2016. 53:155-62.

•  However, long-term survival is still poor with 5-year projected survival < 10%

•  The complete response rate is ± 4.8% and systemic chemotherapy alone has in spite of the improvements, basically no curative potential

  The peritoneum

•  Single layer of mesothelial cells overlying several layers of connective tissues

•  Total thickness of ∼90 μm

•  There are very few blood vessels within the peritoneum, and those that exist are ∼40 μm from the surface

Flessner et al. American Journal of Physiology - Renal Physiology 2005; 288 (3).

  The peritoneum

•  The mesothelial cells play a major role in the secretion of lubricant solutions made of primarily phospholipids and glycosaminoglycans

•  This ensures a smooth sliding surface between the visceral and parietal peritoneum which is important for gut motility

Flessner et al. American Journal of Physiology - Renal Physiology 2005; 288 (3).

  Something perhaps a little better…

•  High drug concentrations in contact with floating tumor cells and at-risk lining surfaces

•  Limited drug absorption, thereby enhancing tumor drug exposure but limiting systemic toxicity

•  With mitomycin C, peak IP concentrations about 50-fold higher than peak serum levels have been demonstrated

Intraperitoneal chemotherapy gives high response rates within the abdomen because the peritoneal space to plasma barrier provides dose intensive therapy (1). Figure 1 shows that large molecular weight substances, such as mitomycin C. are confined to the abdominal cavity for long time periods (2). This means that the exposure of peritoneal surfaces to pharmacologically active molecules can be increased considerably by giving the drugs via the intraperitoneal as opposed to intravenous route.

Sugarbaker PH et al. Cancer Res 1990; 50: 5790-5794.

  Rationale for hyperthermia

•  Heat has anti-tumor effects by itself•  Heat increases drug penetration into tissue•  Heat increases the cytotoxicity of selected chemotherapy

agents•  Heat at the peritoneal surface causes increased cytotoxicity of

systemic chemotherapy to small cancer nodules

  Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy •  A retrospective, multicenter cohort study performed in

French-speaking institutions to evaluate toxicity and principal prognostic factors after CRS and HIPEC and/or early postoperative intraperitoneal chemotherapy (EPIC) for PC from nongynecologic malignancies

Glehen et al. Cancer 2010; 116(24): 5608–5618.

  Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy •  Included 1290 patients from 25 institutions who underwent

1344 procedures between February 1989 and December 2007•  Overall morbidity rate: 33.6%•  Overall mortality rate: 4.1%


  Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy

•  Overall median survival:•  PMP: not reached•  Appendiceal adenoCA: 77

months•  Mesothelioma: 41 months•  CRC: 30 months•  Gastric cancer: 9 months


  Origin of Carcinomatosis in Patients Who Underwent Cytoreductive Surgery Combined With Perioperative Intraperitoneal Chemotherapy

Etiology No. of Patients % Colorectal cancer 523 40.5

Pseudomyxoma peritonei 301 23.3

Gastric cancer 159 12.3

Peritoneal mesothelioma 88 6.8

Appendiceal adenocarcinoma 50 3.9

Small bowel adenocarcinoma 45 3.5

Primary peritoneal serous carcinoma 30 2.3

Peritoneal sarcomatosis 28 2.2

Others 66 5.1


From Esquivel J. Sugarbaker PH: Elective surgery in recurrent colon cancer with peritoneal seeding: When to and when not to proceed. Cancer Therapeutics, Nov, l998.

  Completeness of cytoreduction

From Esquivel J. Sugarbaker PH: Elective surgery in recurrent colon cancer with peritoneal seeding: When to and when not to proceed. Cancer Therapeutics, Nov, l998.

•  In high-grade malignancy, complete cytoreduction may require a CC-0 score

•  In less invasive malignancy such as pseudomyxoma peritonei, a complete cytoreduction may include CC-0 and CC-1 cytoreduction

  Imaging Challenges

•  Disease underestimation

  Imaging Challenges

Kyriazi et al. Nature Reviews Clinical Oncology 2010; 7: 381-393.

Diagram highlighting the common 'blind spots' on conventional imaging owing to the low contrast of metastases against adjacent structures

  Steps/Areas of Inspection •  Abdominal incision•  Abdominal peritoneum•  Greater omentum•  Lesser omentum•  Right hemidiaphragm•  Left hemidiaphragm•  Liver surface•  Spleen•  Pancreas surface•  Stomach•  Small bowel•  Large bowel•  Right paracolic gutter•  Left paracolic gutter•  Right pelvic sidewall•  Left pelvic sidewall•  Bladder•  Vagina & internal genitalia•  Cul-de-sac of Douglas•  Retroperitoneum•  Kidneys

  Assessment of the parietal peritoneum

•  After the linea alba has been divided, a single entry into the peritoneal cavity in the upper portion of the incision (peritoneal window) allows the surgeon to assess the requirement for a complete parietal peritonectomy

•  If cancer nodules are palpated on the parietal peritoneum, a decision regarding a complete parietal peritonectomy should occur

•  Except for the small defect in the peritoneum required for this peritoneal exploration, the remainder of the peritoneum is maintained intact

From De Lima Vazquez V, Sugarbaker PH: Total anterior parietal peritonectomy. J Surg Oncol 83:261-263, 2003.

From Sugarbaker PH: Peritonectomy procedures. Surg Oncol Clin N Am 12:703-727, 2003.

•  All adhesions must be lysed to allow for even/complete drug distribution

http://surgicaloncology.com/gpmhiic.htm

  Major Complications (Grade 3/4 According to the National Cancer Institute Common Toxicity Criteria)


Type of Complication No. of Patients %

Grade 3-4 complications 422 33.6

Reoperations 178 14

Neutropenia 161 13.3

Digestive fistula 123 9.7

Pneumonia 115 9.1

Postoperative bleeding 95 7.7

Intra-abdominal abscess 90 7

Systemic sepsis 32 2.3

Bowel obstruction 20 1.5

Renal insufficiency 14 1

  Morbidity and mortality after treatment for peritoneal surface malignancies

N Morbidity Mortality Ref CRS, HIIC, and EPIC 356 68 (19%) 7 (2%) Sugarbaker et al. Ann Surg Oncol 2004. CRS and DIC 14 5 (36%) 0 (0%) Sugarbaker et al. Dis Colon Rectum 1987.

CRS and EPIC 181 31 (17%) 4 (2%) Sugarbaker et al. Ann Surg 1995.

CRS, HIIC, and EPIC 60 21 (35%) 3 (5%) Jacquet et al. Cancer 1996.

CRS, HIIC, and EPIC 200 54 (27%) 4 (2%) Stephens et al. Ann Surg Oncol 1999.

CRS and HIIC 64 35 (55%) 6 (9%) Elias et al. Cancer 2001.

CRS and EPIC 13 7 (54%) 1 (8%) Butterworth et al. Am J Surg 2002.

CRS and HIIC 216 54 (25%) 6 (3%) Glehen et al. Ann Surg Oncol 2003.

CRS and HIIC 34 12 (35%) 0 (0%) Pilati et al. Ann Surg Oncol 2003.

CRS and HIIC 77 23 (30%) 9 (12%) Shen et al. Ann Surg Oncol 2004.

CRS and HIIC 33 9 (27%) 0 (0%) Ahmad et al. Ann Surg Oncol 2004.

CRS and HIIC 102 36 (35%) 8 (8%) Verwaal et al. J Surg Oncol 2004.

CRS and HIIC 67 23 (34%) 3 (4%) Schmidt et al. Eur J Surg Oncol 2005.

CRS and HIIC 209 25 (12%) 2 (1%) Kusamura et al. Ann Surg Oncol 2004.

  Quality Metrics

•  Mortality•  Morbidity•  Completeness of cytoreduction•  Survival•  Quality of life

  Pre-2003 Nonrandomized Data on Patients With Peritoneal Carcinomatosis from CRC Treated by Cytoreduction and Intraoperative Hyperthermic Chemotherapy

Study Year No. of Patients Median Survival (months) Survival Duration (years) % of Patients

Shen et al 2002 109 16 3 33

Piso et al 2001 17 39 4 75

Elias et al 2001 64 36 5 27

Witkamp et al 2001 29 NA 2 45

Beaujard et al 2000 21 12 1 50

Cavaliere et al 2000 14 NR 2 64

2000 22 31 2 52

Loggie et al 38 15 2 39

Rey et al 2000 26 NA 2 12

Sugarbaker and Chang 1999 161 NA 5 30

Fujimara et al 1999 14 10 2 21

Schneebaum et al 1996 15 6 NA

Verwaal et al. J Clin Oncol 2003; 21(20): 3737-3743.

  Randomized Trial - The Netherlands Cancer Institute •  Initially published in 2003 and reviewed in 2008

.

Verwaal V J et al. JCO 2003;21:3737-3743

©2003 by American Society of Clinical Oncology

.



Median survival in the standard arm was 12.6 months, compared with 22.4 months in the HIPEC arm (P = .032)

.



  Follow-up at 8 years. DSS

Verwaal et al. Ann Surg Oncol 2008; 15(9): 2426–2432.

Disease-specific survival was 12.6 months in the standard arm and 22.2 months in the experimental arm (P = 0.028)

  PFS

•  The progression-free survival was 7.7 months in the standard arm and 12.6 months in the experimental arm (P = 0.020)

Verwaal et al. Ann Surg Oncol 2008; 15(9): 2426–2432.

  JCO 2004 Retrospective multiinstitutional study of 506 patients

Variable No. of Patients Median Survival (months) P

Sex

Male 233 16.8 0.003

Female 273 21.6

Age, years

< 65 442 20.4 0.04

≥ 65 64 15.6

Location

Right colon 200 16.8 0.62

Sigmoid 145 24

Left colon 63 20.4

Rectum 40 19.2

Transverse colon 36 19.2

Lymph node involvement

Positive 363 18 0.003

Negative 98 31.2

Tumor differentiation

Well 122 30 < .0001

Moderately 188 20.4

Poor 122 14.4

Unknown 74 18

Glehen et al. J Clin Oncol 2004; 22(16): 3284-3292.


Extent of carcinomatosis

Limited 171 34.8 < .0001

Extended 329 14.4

Preoperative systemic chemotherapy

Yes 275 19.2 0.35

No 231 20.4

Resection of concomitant liver metastasis

Yes 61 16.8 0.008

No 445 20.4

Synchronous resection of primary tumor

Yes 99 19.2 0.27

No 407 19.2

Completeness of cytoreduction

CCR-0 271 32.4 < .0001

CCR-1 106 24

CCR-2 129 8.4





Perioperative intraperitoneal chemotherapy

IPCH 383 19.2 0.61

EPIC 235 19.2

IPCH + EPIC 112 21.6

Postoperative systemic chemotherapy

Yes 204 25.2 0.021

No 302 15.6

Second procedure

Yes 26 57.6 < .001

No 480 18


.

Glehen O et al. JCO 2004;22:3284-3292


With a median follow-up of 53 months (range, 5 to 192 months), the overall 1-year, 3-year, and 5-year actuarial survival rates were 72%, 39%, and 19%, respectively. The overall 1-year, 3-year, and 5-year disease-free survival rates were 40%, 16%, and 10%, respectively

  Morbidity and Mortality

Type of Complication No. % Digestive fistula 42 8.3

Hematologic toxicity 12 2.4

Systemic sepsis 10 2

Postoperative bleeding 9 1.8

Intra-abdominal abscess 9 1.8

Respiratory distress 8 1.6

Pneumonia 8 1.6

Urinary fistula 5 1

Line sepsis 5 1

Bowel obstruction 5 1

Pulmonary embolism 2 0.4

Peritonitis 2 0.4

Other 6 1.2

Combined morbidity 116 22.9

Mortality 20 4


  Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial)

•  Four expert institutions•  1:1 allocation•  Study closed early due to poor accrual as patients

increasingly opted for HIPEC•  Open-label study with no masking•  Randomisation was performed by telefax to an external

secretariat•  The random sequence was computer generated and stratified

on primary tumour colon/rectum versus appendix



•  Exclusion criteria were:•  Extra-abdominal or liver metastases•  Para-aortic or other non-resectable lymph-node metastases•  Need of emergency surgery (obstruction, bleeding or peritonitis)•  Prior treatment with systemic chemotherapy except adjuvant therapy

ending at least 6 months prior to evaluation or previous cytoreductive surgery with intraperitoneal chemotherapy

•  Clinical or histological appearance of pseudomyxoma peritonei•  Age >80 years•  Ongoing infection



Surgical Arm•  After surgery, the patients

received intraperitoneal chemotherapy within 3 h after completion of surgery through an abdominal port-a-cath and continued daily for a total of six infusions (6 days)

Systemic Arm•  Patients in the systemic

chemotherapy arm received FOLFOX-6

•  If oxaliplatin was contraindicated, irinotecan was administered

•  Treatment was given every fortnight for a planned number of 12 cycles or for about 6 months



Surgical Arm•  The regimen consisted of 5-

fluorouracil via the port-a-cath combined with IV leucovorin given as a bolus dose 1 h after start of the intraperitoneal infusion







Surgical Arm•  Further 6-day infusion series

was administered with the same dosage every 4–5 weeks for a total of 6 treatments spanning over a 6-month postoperative period

•  These patients did not receive any systemic chemotherapy







•  The completion rates for chemotherapy cycles in both arms were low, 33% (intraperitoneal chemotherapy) versus 58% (systemic chemotherapy)



•  Actuarial OS after 2 years was 54% in the surgery arm compared to 38% in the systemic chemotherapy arm (p = 0.04)

•  OS after 5 years was 33% (n = 8) and 4% (n = 1), respectively (p = 0.02)



•  Median OS in the surgery arm was 25 months versus 18 months for the systemic chemotherapy arm with a hazard ratio between the arms of 0.51 (95% CI: 0.27–0.96, p = 0.04)



•  Actuarial PFS in the surgery arm was 12 months versus 11 months in the systemic chemotherapy arm ( p = 0.16)

•  Despite this, curves demonstrate that a curative potential exists with the surgical approach but not for systemic chemotherapy only



•  20 patients were labelled “resectable”•  18/24 were resectable at

surgical exploration as well as 2/13 who crossed over from the chemotherapy arm

•  Patients with resectable disease had 40% 5-year OS with 40 months median OS

•  In multivariate analysis, it was demonstrated that surgical resectability was the main independent determinant of OS


  HIPEC timing

•  Prolonged systemic chemotherapy prior to surgery and intraperitoneal chemotherapy is of uncertain benefit

•  In this study, the proportion of patients with resectable disease was clearly smaller after 6 months of chemotherapy (patients that crossed over) compared with those undergoing up-front surgery (15% versus 79%, p < 0.001), albeit not based upon randomisation


Overall survival of group receiving cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic treatment versus those receiving standard treatment.

Elias D et al. JCO 2009;27:681-685


  The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery

•  Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months

•  32.7 months for the MMC group vs. 31.4 months for the Oxaliplatin group (P = 0.925)

•  However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs. 28.2 months in those receiving oxaliplatin (P = 0.012)

•  In PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs. 30.4 months in those receiving Oxaliplatin (P = 0.427)

Prada-Villaverde et al. J. Surg. Oncol., 110: 779–785.

  Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Peritoneal Surface Malignancies of Colonic Origin: A Consensus Statement J. Esquivel1 , R. Sticca2, P. Sugarbaker3, E. Levine4, T. D. Yan3, R. Alexander5, D. Baratti6, D. Bartlett7, R. Barone8, P. Barrios9, S. Bieligk10, P. Bretcha-Boix11, C. K. Chang12, F. Chu13, Q. Chu14, S. Daniel13, E. de Bree15, M. Deraco6, L. Dominguez-Parra16, D. Elias17, R. Flynn10, J. Foster18, A. Garofalo19, F. N. Gilly20, O. Glehen20, A. Gomez-Portilla21, L. Gonzalez-Bayon22, S. Gonzalez-Moreno23, M. Goodman24, V. Gushchin25, N. Hanna5, J. Hartmann26, L. Harrison27, R. Hoefer28, J. Kane29, D. Kecmanovic30, S. Kelley31, J. Kuhn32, J. LaMont32, J. Lange33, B. Li14, B. Loggie18, H. Mahteme34, G. Mann35, R. Martin36, R. A. Misih37, B. Moran38, D. Morris13, L. Onate-Ocana39, N. Petrelli37, G. Philippe40, J. Pingpank41, A. Pitroff1, P. Piso42, M. Quinones43, L. Riley44, L. Rutstein45, S. Saha46, S. Alrawi29, A. Sardi25, S. Schneebaum47, P. Shen4, D. Shibata31, J. Spellman48, A. Stojadinovic49, J. Stewart4, J. Torres-Melero50, T. Tuttle51, V. Verwaal52, J. Villar53, N. Wilkinson54, R. Younan6, H. Zeh7, F. Zoetmulder52 and G. Sebbag55

•  Reasonable expectation of achieving a complete removal of all tumor greater than 2.5 mm and:

•  (1) ECOG performance status two or less•  (2) no evidence of extra-abdominal disease•  (3) up to 3 small, resectable parenchymal hepatic metastases•  (4) no evidence of biliary obstruction•  (5) no evidence of ureteral obstruction•  (6) no evidence of intestinal obstruction at more than one site•  (7) small bowel involvement: no evidence of gross disease in the

mesentery with several segmental sites of partial obstruction•  (8) small volume disease in the gastro-hepatic ligament

Ann Surg Oncol 2007;14(1): 128-33.

  USMCI 8214 / Z6091

•  Phase III Randomized Pilot Study of Standard Systemic Therapy With Versus Without Cytoreduction Surgery and Hyperthermic Intraperitoneal Mitomycin C in Patients With Advanced Limited Peritoneal Dissemination of Colon Adenocarcinoma

•  Expected Enrollment: 340•  Primary Outcome(s)

•  Overall survival (OS)•  Secondary Outcome(s)

•  Progression-free survival (PFS)•  Quality of life•  Toxicity burden •  Circulating tumor cells �

  USMCI 8214 / Z6091

•  Closed due to poor accrual�

  Controversies

•  Timing:•  Intraop vs. Periop vs. both

•  No differences in outcomes

Spratt et al. Cancer Res 1980; 40: 256–60. Sugarbaker et al. Cancer Res 1990; 50: 5790–4. Sugarbaker et al. Ann Surg Oncol 1999; 6: 727–31. Yan et al. Ann Surg Oncol 2007; 14: 484–92. Yan et al. J Clin Oncol 2009; 27: 6237–42. Elias et al. J Clin Oncol 2010; 28: 63–8. da Silva et al. J Am Coll Surg 2006; 203: 878–86. Elias et al. Int J Surg Invest 2000; 1: 431–9. Verwaal et al. Ann Surg Oncol 2005; 12: 65–71. Quenet et al. Ann Surg. 2011 (in press).

  Controversies

•  Open vs. Closed•  No differences in outcome


  Controversies

•  Different drug regimens:•  e.g. Oxaliplatin vs. MMC vs. Bidirectional

•  No differences in outcome


  Controversies

•  Different temperatures, durations and carrier solutions:•  No differences in outcome


  Does chemo really add anything to complete CRS?

•  The main conclusion that can be drawn from these data is that perhaps IP chemotherapy is bereft of efficacy because the results are identical whatever the modalities used

•  Randomized multicenter trial in humans comparing HIPEC versus no HIPEC after CCRS is ongoing in France (Prodige 7) and has already randomized more than half of the 260 patients planned for accrual

  Peritoneal and organ mets

  Better imaging

  PCI and location for PC from CRC

Elias et al. Eur J Surg Oncol. 2014 Nov;40(11):1467-73.

Elias et al. Eur J Surg Oncol. 2014 Nov;40(11):1467-73.

  Better delineation of timing

  Optimal regimens

•  Drugs•  Bidirectional•  Carriers•  Timing

  American Society of Peritoneal Surface Malignancies standardized HIPEC delivery in patients with colorectal cancer with peritoneal dissemination

Turaga et al. Ann Surg Oncol (2014) 21: 1501.

•  A survey was conducted of all cancer centers performing HIPEC in the United States

•  Attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters

  American Society of Peritoneal Surface Malignancies standardized HIPEC delivery in patients with colorectal cancer with peritoneal dissemination

HIPEC method Closed

Drug Mitomycin C

Dosage 40 mg

Timing of drug delivery 30 mg at time 0; 10 mg at 60 min

Volume of perfusate 3 L

Inflow temperature 42 °C

Duration of perfusion 90 min

Turaga et al. Ann Surg Oncol (2014) 21: 1501.

  Future Uses for prophylaxis/Second Look Operations

  Ascites mitigation

crs and hipec for colorectal cancer · divided, a single entry into the peritoneal cavity in the...

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