Surgical Grand Rounds

Cytoreductive Surgery andIntraperitoneal Chemotherapy

Phillip D. Smith, MD4.28.8

HistoryHistory

Cytoreductive surgery alone does not increase survival Adjuvant therapy needed to

decrease microscopic tumor burden peri-operatively Paul Sugarbaker, MD at

Washington Cancer Center 25 years ago

TheoryTheory

Peritoneal seeding occurs via lymphatics and intra-operatively during resectionBlood clots containing viable cancer cells Spread during blunt dissection Fibrin entrapment of cancer cells on

traumatized peritoneal surfacesTumor progression due to biochemical

environment of wound healing

TheoryTheory

Theory Large molecular weight molecules are

sequestered at the site when instilled into the peritoneal cavity Chemotherapeutics will be

bioavailable for both surgically seeded tumor deposits and raw surfaces of incomplete surgical resection

Cytoreductive Surgery for Peritoneal CarcinomatosisCytoreductive Surgery for

Peritoneal Carcinomatosis Excision of all macroscopic tumor

within the abdomen Peritonectomy Often includes splenectomy,

cholecystectomy, partial/total gastrectomy, greater omentectomy, hysterectomy, multiple small bowel resections, and sigmoid colectomy Alimentary tract reconstruction

CytoreductionCytoreduction

Chemotherapy is infused after cytoreduction and before alimentary tract reconstruction Prevents tumor cells from being

trapped in suture lines and decreases local recurrence

Hyperthermic Intraperitoneal Chemotherapy

Hyperthermic Intraperitoneal Chemotherapy

With excision of macroscopic tumor, microscopic remnants can be treated

Up to 20 times the bioavailability of systemic chemotherapy

Hyperthermia Cytotoxic Increases tissue penetration of chemotherapy Synergistic effect on cytotoxicity of

chemotherapy

Sugarbaker Technique

Pearlman Technique

Pearlman Technique

The EvidenceThe Evidence

Verwaal, et. al. J Clinical Onc. 2003 Phase III RCT of 109 patients HIPEC vs standard chemo for carcinomatosis

secondary to colorectal cancer

HIPEC using Sugarbaker technique and mitomycin C Began standard chemotherapy at 6-12 weeks post-

op

Standard therapy was Fluorouracil and leucovorin

Cytoreduction and HIPEC versus standard chemotherapy:

Survival

Cytoreduction and HIPEC versus standard chemotherapy:

Survival

Verwaal et. al, 2003

Adequacy of Cytoreduction

Adequacy of Cytoreduction

Verwaal et. al, 2003

Degree of CarcinomatosisDegree of Carcinomatosis

Verwaal et. al, 2003

MorbidityMorbidity

Stephens et. al, 1999

Morbidity n %

Peripancreatitis 12 6.0Fistula 9 4.5Postoperative bleeding 9 4.5Hematological toxicity 8 4.0Anastomotic leak 6 3.0Pulmonary complication 6 3.0Gastrointestinal toxicity 6 3.0Pleural effusion tapped 6 3.0Sterile collection tapped 5 2.5Pneumothorax 5 2.5Cardiovascular toxicity 5 2.5Wound sepsis 5 2.5Line sepsis 4 2.0Bile leak 4 2.0Systemic sepsis 4 2.0Deep vein thrombosis 2 1.0Neurological complication 1 0.5Pulmonary embolism 1 0.5Severe pain 0 0.0Combined grade III/IV morbidity 54 27.0Treatment-related mortality 3 1.5

MorbidityMorbidity

Statistically significant variables affecting morbidity

0.066Dose of Mitomycin

0.0083Intraoperative Blood Loss

0.0078Number of Suture lines

>0.0001# of peritonectomy procedures and resections

>0.0001Duration of Operation

P

Stephens et. al, 1999

ConclusionsConclusions

Definite survival benefit Median survival

22.4 months with HIPEC 12.6 months with standard chemo

Degree of carcinomatosis predicts survival

Historical median survival with systemic FU and leucovorin Median survival ~ 5 months

Follow UpFollow Up

Verwaal, et. al. Ann Surg Onc. 2005. Included previous study participants

plus additional participants If complete macroscopic

cytoreduction successfulMedian Survival- 42.9 months 5-year survival rate- 43%

Quality of Life at > 3 Years

Quality of Life at > 3 Years

89.486.8

92.6

77.1

94.990.2

87.8

68.2

76.273.7

67.5

60.4

81.4 80.3

75

64.6

0

10

20

30

40

50

60

70

80

90

100

PhysicalFunction

RolePhysical

Bodily Pain Vitality SocialFunction

RoleEmotional

MentalHealth

GeneralHealth

Surv

ey S

core

HIPEC Age Matched National Average

McQuellon et. al, 2003

Application to Other Cancers

Application to Other Cancers

Diffuse Malignant Peritoneal Mesothelioma Yan, et. al, 2006 Median Survival 59 months, 5-year survival

49% Appendiceal Mucinous Tumors Yan, et. al, 2007

Repeated cytoreductions with HIPEC improve survival

5- and 10- year disease free survival, 70% and 67%

Gastric Cancer, Pseudomyxoma Peritonei, Ovarian Cancer, etc.

Shortcomings…Shortcomings…

Limited data No standard procedure No standard chemotherapy Morbidity Selection of patients Severe carcinomatosis may make

complete cytoreduction impossible

Standardized TherapyStandardized Therapy

Esquivel, et. al. Annals Surg Onc. 2007 Consensus Statement

Pearlman (Closed) or Sugarbaker (Open) technique -> Surgeon’s choice

5 days of immediate post op intraperitoneal chemotherapy with 5-FU -> Surgeon’s choice

HIPEC only for patients in which complete cytoreduction is deemed possible Can perform palliative HIPEC if malignant ascites

Perform HIPEC with mitomycin C, oxaliplatin promising

Selection CriteriaSelection Criteria

FutureFuture

Proven benefit in colorectal carcinomatosis

Need Phase III studies to extend to other cancers

Bottom LineBottom Line

Cytoreduction with HIPEC improves survival

Therapy associated deaths do not exceed deaths of those receiving standard chemo

QOL not diminished by therapy

Cytoreductive Surgery with HIPEC Works

ReferencesReferences Cameron, JL. Current Surgical Therapy. 9th ed. 2008. Verwaal, VJ, et. al, Randomized Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy

versus Systemic Chemotherapy and Palliative Surgery in Patients with Peritoneal Carcinomatosis ofColorectal Cancer. J Clinical Onc. 2003; 21(20): 3737-3743.

Yan, TD, et. al, A Systemic Review and Meta-analysis of the Randomized Controlled Trials on Adjuvant Intra-peritoneal Chemotherapy for Resectable Gastric Cancer. Annals Surg Onc. 2007; 14(10): 2703-2713.

Smeenk, RM, et. al, Survival Analysis of Pseudomyxoma Perotinei Patients Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. Annals Surg. 2007; 245(1): 104-109.

Yan, TD, et. al, Critical Analysis of Treatment Failure After Complete Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Peritoneal Dissemination from Appendiceal Mucinous Neoplasms. Annals Surg Onc. 2007; 14(8): 2289-2299.

Yan, TD, et. al, Morbidity and Mortality Assessment of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Diffuse Malignant Peritoneal Mesothelioma. Annals Surg Onc. 2007; 14(2): 515-525.

Esquivel, J, et. al. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Peritoneal Surface Malignancies of Colonic Origin. Annals Surg Onc. 2007; 14(1): 138-133.

Verwaal, VJ, et. al. Long-Term Survival of Peritoneal Carcinomatosis of Colorectal Origin. Annals Surg Onc. 2005; 12(1): 65-71.

Al-Shammaa, HAH, et. al. Current status and future strategies of cytoreductive surgery plus interperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. World J Gastroenterol. 2008; 14(8): 1159-1166.

Stephens, AD, et. al. Morbidity and Mortality Analysis of 200 Treatments with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy using the Coliseum Technique. Annals Surg Onc. 1999; 6(8): 790-796.

Sugarbaker, P. www.surgicaloncology.com