Management of Peritoneal Carcinomatosis in Colorectal

CancerDr. Chan Kwan Kit

Queen Mary Hospital

Colorectal Cancer (CRC)

High incidence with significant morbidity and mortality

Metastasis on presentation or as recurrent disease commonly encountered

Liver and peritoneal surface are the most frequent sites of metastasis

Treatment of colorectal liver metastases well established

Peritoneal Carcinomatosis (PC)

“Death sentence” Median survival: 6 – 9 months Treatment of palliative intent

systemic chemotherapy symptomatic relief emergency operation for

complications e.g. intestinal obstruction/ perforation

Chu DZ et al. Cancer 1989;63:364–7Sadeghi B et al. Cancer 2000; 88: 358-63

Jayne DG et al. British Journal of Surgery 2002; 89:1545–50

Pathophysiology of PC

Consequence of full thickness invasion of bowel wall by invasive carcinoma

“Iatrogenic” during primary surgery dissected lymphatics/ bowel lumen blood spillage from the surgical field

Breakthrough?

Jayne et al.: 58% of all patients with synchronous PC had no other systemic metastasis

Sugarbaker et al.: peritoneal cavity is the only metastatic site in 25% of patients with recurrent CRC

Hypothesis: PC as a locoregional disease still susceptible to treatment of curative intent

Dr Paul H Sugarbaker

Washington Hospital Centre Pioneer of the combined

treatment “Sugarbaker’s protocol”

Cytoreductive surgery Perioperative intraperitoneal

chemotherapy

Cytoreductive Surgery

Removal of macroscopic tumour on visceral and parietal peritoneum

Significant involvement of visceral peritoneum may necessitate organ resections

Significant involvement of parietal peritoneum may necessitate formal peritonectomy procedures

Cytoreductive Surgery

Prognostic indicators: Prior Surgical Score (PSS) Peritoneal Cancer Index (PCI) Completeness of cytoreduction score (CCS)

Prior Surgical Score

PSS-0: biopsy only PSS-1: 1 region PSS-2: 2-5 regions PSS-3: >5 regions

Higher PSS associated with reduced survival

Peritoneal Cancer Index (PCI)

Summary of lesion size and distribution of lesions

Correlates with outcome for peritoneal metastases in CRC

Sugarbaker et al. Cancer therapeutics 1998; 1: 213-325

0-39

Peritoneal Cancer Index

Sugarbaker in 1999: PCI < 10: 50% five-year survival PCI 11-20: 20% five-year survival PCI > 20: 0% five-year survival

Pestieau SR, Sugerbaker PH. Dis Colon Rectum 2000; 43:1341–1348

Not applicable when tumour deposit at crucial anatomical site not amenable for resection

Completeness of Cytoreduction Score

Size of persisting tumour after cytoreduction CCS-0: no visible tumour CCS-1: tumours <2.5mm CCS-2: tumours 2.5mm - 2.5cm CCS-3: tumours >2.5cm

Principle prognostic indicator – helps intraoperative decision making

Role of diagnostic laparoscopy

Allows more accurate “staging” with minimal surgical trauma

Reliable prediction of cytoreduction index

Perioperative Intraperitoneal Chemotherapy

Hyperthermic intraperitoneal chemotherapy (HIPEC)

Intraoperative/ early postoperative – no standard protocol as yet

Aim: eradication of microscopic residual disease for curative intent

HIPEC - advantages

Intraperitoneal Increases exposure of tumour to

pharmacologically active molecules

Hyperthermia enhances cytotoxicity improves drug penetration heat has anti-tumour effect itself

HIPEC - advantages

Large volume removes tissue debris and blood products

Diminishes the promotion of tumour growth associated with wound healing process through elimination of platelets/ neutrophils/ monocytes

Surgeon manipulates all viscera to minimize adherence of

peritoneal surfaces and allow uniform distribution of drugs

Duration: 30-90 minutes Continuous irrigation Temperature monitoring

at inflow catheters and within peritoneal cavity - maintained at 42.5ºC

Chemotherapeutic agent

Varies with centres e.g. mitomycin C, oxaliplatin

Mitomycin C being the commonest choice – large molecular weight substance confining to peritoneal cavity for long time periods

Results – the risks

Mortality 2-10% and morbidity 25-45%, predominantly determined by surgery-related factors extent of surgery number of anastomoses volume of blood loss

Results – the risks

Common complication: bowel perforation anastomotic leakage prolonged ileus/ bowel fistulation/

intraabdominal bleeding/ pancreatitis/ haematological toxicity

Results - survival benefit?

Glehen et al.: multi-institutional retrospective study median survival 19.2 months, irrespective of

cytoreduction extent 19% 5-year survival

Glehen et al. J Clin Oncol 2004; 22: 3284-92

Elias et al. & Verwaal VJ et al.: the only two randomized, prospective studies Elias: 60% survival at two years Verwaal: median survival 22.2 months

Elias et al. Ann Surg Oncol 2004; 11: 518-21Verwaal VJ et al. Ann Surg Oncol 2005; 12: 65-71

Results - survival benefit?

With complete macroscopic cytoreduction (CCS-0) average survival from 32.4 – 60 months

Glehen et al. J Clin Oncol 2004; 22: 3284-92

Elias et al. Ann Surg Oncol 2004; 11: 518-21

Verwaal VJ et al. Ann Surg Oncol 2005; 12: 65-71

Sugarbaker PH. Tech Coloproctol 2005; 9: 95-103

Gomez Patilla A. et al. Rev Esp Enferm Dig 2009 Feb;101(2):97-102, 103-6

Patient selection

No survival benefit for patients with synchronous metastases to other organs

Aggressive treatment of large volume, high grade cancer is unlikely to translate into long-term benefit

Prognostic factors

Peritoneal cancer index Completeness of cytoreduction Presence of lymph node involvement Age and performance status

Validation?

Reported trials are of significant heterogeneity

No standard protocol e.g. timing of chemotherapy/ use of hyperthermia

Only two randomized trials published – relatively small scale

Conclusion

Peritoneal carcinomatosis from colorectal origin carries dismal prognosis with conventional treatment

“Combined treatment” - cytoreductive surgery with intraperitoneal chemotherapy may represent a new option of care in peritoneal-only metastatic disease

Conclusion

Significant procedural morbidity/ mortality mandates careful selection

Large scale, randomized, prospective studies needed for clarification of the role of this aggressive approach

HIPEC

Disadvantages Removal of white cells due to chemotherapy

and heat leaves the patient vulnerable to intra-

abdominal infection limited tissue penetration 3-5mm

Postoperative care

Expected prolonged bowel rest prolonged ileus due to extensive surgery allowing more time for healing total parenteral nutrition

Peritonectomy

Peritoneum divided into 6 parts greater omentectomy and splenectomy left upper quadrant peritonectomy right upper quadrant peritonectomy lesser omentectomy and cholecystectomy pelvic peritonectomy and resection of

rectosigmoid colon antrectomy/ gastrectomy

Hyperthermic intraperitoneal chemotherapy (HIPEC)

Setting up: After completion of cytoreductive surgery Catheters are inserted to dependent positions Temperatures at the inflow/ outflow/

intraperitoneal cavity continuously monitored Temporary abdominal skin closure Intraperitoneal temperature maintained 42.5℃

Intraoperative chemotherapy

Reconstructive part of surgery follows No anastomosis is constructed until after the

intraoperative chemotherapy perfusion is completed

Early postoperative intraperitoneal chemotherapy

5-fluorouracil is utilized usually Commenced on day 1 after operation

Infusion via Tenckhoff catheter Chemotherapy agent dwells in the abdomen

for 23 hours and drain for 1 hour Duration: 4-5 days

Counter-argument

Peritoneal carcinomatosis with low PCI and CCS may represent more favourable tumour biology

Opinions vary widely and no consensus could be reached

Genetics study? Molecular features of tumour?