Management of Colorectal Cancer Peritoneal Carcinomatosis – Current Standard of Care

Maheswari Senthil MD Assistant Professor

Division of Surgical Oncology Loma Linda University School of

Medicine

Peritoneal Carcinomatosis (PC)

•  Peritoneal surface –common site of metastases in colorectal cancer

•  Incidence of PC at the time of initial surgery for colon cancer is 10 to 15%

•  CRC recurrences - PC is reported in 20 to 45% of patients

•  10%-35% - recurrences confined to peritoneal surface •  Associated with poor survival

Dawson LE et al. J Surg Oncol 1983; 22: 95-99 Chu DZ et al. Cancer 1989;63: 364-367l Tong D et al. Am J Surg 1983; 145:382-386

Treatment Options

•  Supportive care •  Systemic chemotherapy •  Cytoreductive surgery (CRS) and Hyperthermic

intraperitoneal chemotherapy (HIPEC)

Supportive Care

•  EVOCAPE 1 •  Multi-Centre prospective French study •  CRC n=118 patients •  Resection of primary tumor – 75 patients •  Intestinal bypass – 26 patients •  5-FU chemotherapy – 46 patients •  Median Survival – 5.2 months •  Higher stage of PC - poor survival

Sadeghi B et al. Cancer 2000;88:358-363

Supportive Care

•  Singapore study - 3019 patients with CRC •  Retrospective study from 1989-1999 •  PC-349 patients

–  214 synchronous metastases –  135 metachronous metastases –  Median survival for Synchronous metastases – 7

months

Jayne DG et al. Br J Surg 2002; 89:1545-1550

Systemic Chemotherapy – 5 FU

Study   N   Chemotherapy   Median  Survival    In  months  

Chu  1989   45   5-­‐  FU   6    

Sadeghi  2000   118   5-­‐  FU   5.2  

Jayne  2002   392   5-­‐  FU   7  

Veerwal  2003   51   5-­‐  FU   12.6  

Treatment of Colorectal Peritoneal Carcinomatosis WithSystemic Chemotherapy: A Pooled Analysis of NorthCentral Cancer Treatment Group Phase III Trials N9741and N9841Jan Franko, Qian Shi, Charles D. Goldman, Barbara A. Pockaj, Garth D. Nelson, Richard M. Goldberg,Henry C. Pitot, Axel Grothey, Steven R. Alberts, and Daniel J. Sargent

See accompanying editorial on page 226

Jan Franko and Charles D. Goldman,Mercy Medical Center, Des Moines, IA;Qian Shi, Garth D. Nelson, Henry C.Pitot, Axel Grothey, Steven R. Alberts,and Daniel J. Sargent, Mayo Clinic,Rochester, MN; Barbara A. Pockaj,Mayo Clinic, Scottsdale, AZ; and Rich-ard M. Goldberg, University of NorthCarolina, Chapel Hill, NC.

Submitted June 14, 2011; acceptedAugust 10, 2011; published onlineahead of print at www.jco.org onDecember 12, 2011.

Supported by National Institutes ofHealth Grants No. CA25224 (NorthCentral Cancer Treatment Group);CA32102 (Southwest Oncology Group);CA21115 (Eastern Cooperative Oncol-ogy Group); and CA38926 (Cancer andLeukemia Group B).

Presented in part at the 47th AnnualMeeting of the American College ofClinical Oncology, June 3-7, 2011,Chicago, IL.

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Clinical Trials repository link available onJCO.org.

Corresponding author: Jan Franko, MD,PhD, 411 Laurel St, Ste 2100, Des Moines,IA 50314; e-mail: jan.franko@gmail.com.

© 2011 by American Society of ClinicalOncology

0732-183X/12/3003-263/$20.00

DOI: 10.1200/JCO.2011.37.1039

A B S T R A C T

PurposeSymptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is apaucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC).We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials ofchemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC).

MethodsA total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overallsurvival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used toassess the adjusted associations.

ResultsThe characteristics of the pcCRC group (n ! 364) were similar to those of the non-pcCRCpatients in median age (63 v 61 years, P ! .23), sex (57% males v 61%, P ! .23), andperformance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v96%, P ! .06), but differed in frequency of liver (63% v 82%, P " .001) and lung metastases(27% v 34%, P ! .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] ! 1.3; 95% CI, 1.2to 1.5; P " .001) and PFS (5.8 v 7.2 months, HR ! 1.2; 95% CI, 1.1 to 1.3; P ! .001) wereshorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained afteradjusting for age, PS, liver metastases, and other factors (OS: HR ! 1.3, P " .001; PFS: HR ! 1.1,P ! .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, andfluorouracil as a first-line treatment among pcCRC (HR for OS ! 0.62, P ! .005) and non-pcCRCpatients (HR ! 0.66, P " .001).

ConclusionpcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations ofmCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.

J Clin Oncol 30:263-267. © 2011 by American Society of Clinical Oncology

INTRODUCTION

Symptoms and complications associated with met-astatic colorectal cancer (mCRC) differ by meta-static sites. In clinical practice, the differences amongseveral distinct types of mCRC have been apparentfor decades. Best survival is achieved among thosefor whom a combination of contemporary systemicchemotherapy1-3 and a surgical resection is possible.Respective 5-year survival rates for selected popula-tions are nearly 60%, 40%, and 20% to 51% amongthose with resectable hepatic,4-6 pulmonary,7,8 andperitoneal metastases.9-11

Peritoneal carcinomatosis from CRC (pc-CRC) has been historically associated with avery poor prognosis. Studies including systemicchemotherapy and symptom-directed surgerywithout cytoreduction demonstrated a mediansurvival ranging from 5.2 to 7 months in the eraof fluorouracil (FU) -only treatment.12-15 Asubset of patients presenting with bowel ob-struction owing to peritoneal carcinomatosishave an even worse prognosis, with a medianoverall survival (OS) for those actively treatedof approximately 3 to 4 months and a 17%1-year survival rate.16,17

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© 2011 by American Society of Clinical Oncology 263

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  Two randomized controlled chemotherapy trials for metastatic CRC

  FOLFOX, Irinotecan and combination  Compared the outcomes of patients with pcCRC

with other CRC metastases  Study population n=2095   pcCRC n=364

Overall Survival by Peritoneal Carcinomatosis

Status

Franko J et al. JCO 2012;30:263-267

12.7 vs.17.6 months

Chemotherapy with Targeted Therapy

•  Two RCT - CAIRO and CAIRO 2 study for mCRC •  CAIRO 2- chemotherapy and targeted therapy •  Median OS was decreased in pc CRC •  CAIRO2 ( chemo+ targeted therapy) - 15.2 vs. 20.7

months

Klaver et al. Eur J Surg Oncol 2012;38: 617-23

What Next?

Cytoreductive Surgery (CRS)

•  Sugarbaker popularized cytoreductive surgery and HIPEC in the early 1990’s

•  Two major components –  Removal of all visible tumor –  Treatment of peritoneal surface with chemotherapy

•  Hyperthermic intraperitoneal chemotherapy (HIPEC)

•  Early postoperative intraperitoneal chemotherapy (EPIC)

Sugarbaker PH. Peritonectomy Procedures. Ann Surg 1995; 221:29-42

Rationale for Intraperitoneal Chemotherapy

•  Dose-intensive therapy •  Higher tissue

concentration •  Decreased systemic

toxicity

in the subperitoneal space of the cancer chemotherapy solution. Low systemic concentrations and reduced systemic toxicity are maintained by rapid metabolism and excretion of drug within the body compartment.

The marked increase in exposure of peritoneal sur-faces to chemotherapy solution, as compared to plasma, is illustrated in Figure 1. The chemotherapy agent, pacli-taxel, has a high molecular weight (853.9 Daltons) and is slow to cross the peritoneal cavity to plasma barrier. The naked molecule of paclitaxel is highly lipophilic. It is unique in cancer chemotherapy in that the intravascular or intraperitoneal administration of the drug requires it to be suspended in a detergent that maintains the drug in solution. The detergent molecules surround the paclitaxel molecule giving it additional size and a hydrophilic character. This large molecular size and hydrophilic behavior of the complex molecule result in slow passage across the peritoneal to plasma barrier. The AUC ratio for paclitaxel is approximately 1000 (Table 1).

PHARMACOKINETIC RATIONALE OF PERIOPERATIVE INTRAVENOUS COLORECTAL CANCER CHEMOTHERAPYNew pharmacological data suggests altered phar-macodynamics of intravenously administered cancer chemotherapy drugs when used intraoperatively during a HIPEC procedure. Figure 2 shows 5-fluorouracil concentrations in the plasma, peritoneal fluid, and tumor nodules after intravenous administration at the beginning of the HIPEC procedure. Almost immediately after intravenous administration, the 5-fluorouracil is transported from the plasma compartment to the expanded peritoneal cavity. There it is retained in the artificial ascites created by the HIPEC for a substantial amount of time, before reabsorption into the systemic compartment occurs. The metabolism of 5-fluorouracil

in the ascites fluid is greatly reduced as compared to metabolism in the plasma. Our data suggests that the artificial ascites created by the HIPEC provides a reservoir for the intravenously administered drug. The intraoperative administration of intravenous cancer chemotherapy might offer a pharmacologic advantage in killing residual tumor cells after cytoreduction. Timing of intravenous cancer chemotherapy (intraoperative vs pre- or postoperative) emerges as a new variable, which could ������� ���������� � ������� ��������� �������� �� ��������patients with a peritoneal surface malignancy.

Tissue distribution and penetration depthThe simplified two-compartment model described by Dedrick and colleagues might not provide an adequate theoretical model for penetration of the intraoperatively administered (either intravenous or intraperitoneal) chemo-therapy into the preperitoneal tissues and into the tumor nodules. Dedrick et al[36,37] proposed a mathematical model (Figure 3) addressing the tissue penetration of low-molecu-lar weight molecules. The drug diffuses from its peritoneal

22 January 15, 2010|Volume 2|Issue 1|WJGO|www.wjgnet.com

0 2 4 6 8 10 12 14 16 18 20 22 24t /h

100

10

1

0.1

0.01

0.001

Paclit

axel

( �g/m

L)

��� �������Plasma

Figure 1 Pharmacokinetic study of concentration vs time for intra-peritoneal paclitaxel. The chemotherapy agent at 30 mg/m2 was instilled directly into the peritoneal cavity as rapidly as possible in a 1.5% dextrose peritoneal dialysis solution. The concentration of paclitaxel was determined in �������� ��"���� �������� �� ����������

100

10

1

0.1

0.01

���� � ��������g

/mL)

0 15 30 45 60 90t /min

��� �������PlasmaTumor nodules (�g/gm)

Figure 2 Pharmacodynamics during HIPEC after intravenous administration of 400 mg/m2 of 5-fluorouracil given simultaneously with intraperitoneal chemotherapy in 3 L of chemotherapy solution. (Van der Speeten K, Stuart ������ �� ��������� �� �����!������������ �� ����"������ �������������������publication).

Sugarbaker PH et al . Pharmacology of carcinomatosis

Table 1 Molecular weight and area under the curve ratios of intraperitoneal exposure to systemic exposure of chemo-therapeutic agents used to treat peritoneal carcinomatosis

Drug Molecular weight (Daltons)

Area under the curve ratio

��������� 130.08 250Carboplatin 371.25 10Cisplatin 300.1 7.8Docetaxel 861.9 552Doxorubicin 579.99 230Etoposide 588.58 65Floxuridine 246.2 75Gemcitabine 299.5 500Irinotecan 677.19 N/AMelphalan 305.2 93Mitomycin C 334.3 23.5Mitoxantrone 517.41 115-255Oxaliplatin 397.3 16Paclitaxel 853.9 1000Pemetrexed 597.49 40.8

N/A: Not available.

Sugarbaker PH et al. World J Gastrointest Oncol 2010; 2:19-30

Advantages of Hyperthermia

•  Increases drug penetration into tissue •  Augments the cytotoxicity of selected

chemotherapy agents •  Heat has anti-tumor effects by itself

- Hyperthermia above 41°C induces selective cytotoxicity of malignant cells

Teicher BA et al. Cancer Res 1981;41:1096-9 El-Kareh AW et a;. Neoplasia 2004;6:117-27

Open and Closed HIPEC Techniques

Peritoneal Carcinomatosis – Patient

Selection

•  ECOG performance status ≤ 2 •  No evidence of extra abdominal disease •  No evidence of biliary or ureteral obstruction •  No evidence of intestinal obstruction at more than one

site •  Small volume disease in the gastrohepatic ligament

Verwaal et al. J clin Oncol 2003;21:3737-3743

Overall Survival

Median Survival Standard - 12.6 months CRS and HIPEC – 22.4 months

Verwaal et al. Ann Surg Oncol 2008;15:2426-2432

Survival

Verwaal et al. Ann Surg Oncol 2008;15:2426-2432

Cytoreduction Extent of Involvement

test was used to determine whether there was a significantrelationship between age and group (control vs cytoreduc-tive surgery combined with hyperthermic intraperitonealchemoperfusion). Chi-square tests were used to determinewhether there were any significant relationships betweengroup and the following categorical variables: sex, tumorgrade (grade I/II vs grade III), site of origin (colon vs rec-tum), liver lesion (absent vs present), and prior treatmentwith oxaliplatin, irinotecan, and biological agents.

Survival was measured from the date of diagnosis ofperitoneal disease to the date of last follow-up or deathand was estimated using the Kaplan-Meier method. Log-rank tests were performed to examine the univariate asso-ciations between survival and clinical variables. Cox pro-portional hazard models were built using all variables withP <.2 in univariate testing. Other variables that were feltto be important10,18 predictors of survival were also inves-tigated, such as chemotherapy agents, tumor grade, andmetastatic versus nonmetastatic status at presentation.Because tumor grade violated the proportional hazardassumption, both grade-stratified and unstratified modelswithout tumor grade were created. Statistical significancewas assumed at .05.

RESULTSThere was no statistical difference between the groups indistribution of sex, tumor grade, site of origin (colon vsrectum), and T and N classification of the original tumor.However, the control group was older (mean 59 years inthe control group vs mean 51 years in the hyperthermicintraperitoneal chemoperfusion group; P<.001), had ahigher proportion of patients who were diagnosed withcarcinomatosis at their initial presentation (76% vs 42%;P<.001), and had a higher proportion of patients withliver lesion (35% vs 15%; P! .014).

All patients received systemic chemotherapy. Therewere no differences between the 2 groups in administra-tion of 5-fluorouracil and irinotecan, but the controlgroup was less likely to receive oxaliplatin (47% vs 78%;P! .001) and biological agents (bevacizumab and/orcetuximab, 18% vs 59%; P<.0001). Six patients in thecytoreductive surgery combined with hyperthermic intra-peritoneal chemoperfusion group received a suboptimaldebulking (R2), but remained included in the study.

Median survival measured from the diagnosis ofperitoneal disease was longer with cytoreductive surgerycombined with hyperthermic intraperitoneal chemoper-fusion (34.7 months vs 16.8 months; P<.001; Fig. 1).

Besides cytoreductive surgery combined with hyperther-mic intraperitoneal chemoperfusion, only chemotherapywith biological agents and absence of liver metastasis wereassociated with survival advantage in the univariate testing(Table 1). Sex, tumor grade, site of primary tumor origin(colonic vs rectal), and presence of carcinomatosis at ini-tial cancer diagnosis (stage I-III vs stage IV/carcinomato-sis) were not associated with survival.

Multivariate Cox proportional hazards modelingwas performed on all patients with available data. Tumorgrade was the only variable that violated the proportionalhazard assumption. On detailed analysis, there is someevidence that tumor grade affects survival, particularly atearly times. Conversely, tumor grade is not a confounder,because it is not associated with cytoreductive surgerycombined with hyperthermic intraperitoneal chemoper-fusion treatment.

Therefore, 3 Cox proportional hazard regressionmodels were developed, where the latter 2 represent sensi-tivity analysis and point to the robustness of the results.There were 91 cases available for the first model, whichincluded significant predictor variables from univariatetesting (Table 2). Tumor grade lacked the predefinedentry P value and consequently was not included in thismodel. Delivery of cytoreductive surgery combined withhyperthermic intraperitoneal chemoperfusion was asignificant predictor of survival after adjusting for all othervariables. Presence of liver metastasis was a negativesignificant predictor of survival, and its effect size wascomparable to that of cytoreductive surgery combinedwith hyperthermic intraperitoneal chemoperfusion.

Figure 1. Kaplan-Meier estimator curves comparing the grouptreated with cytoreductive surgery combined with hyperther-mic intraperitoneal chemoperfusion (CS-HIPEC) versus thecontrol group are shown. Chemo indicates chemotherapy.

Original Article

3758 Cancer August 15, 2010

Cytoreductive Surgery and HyperthermicIntraperitoneal Chemoperfusion VersusSystemic Chemotherapy Alone for ColorectalPeritoneal CarcinomatosisJan Franko, MD, PhD; Zuhaib Ibrahim, MD; Niraj J. Gusani, MD; Matthew P. Holtzman, MD; David L. Bartlett, MD;

and Herbert J. Zeh, III, MD

BACKGROUND: Survival benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfu-

sion was demonstrated by a prospective randomized trial for colorectal peritoneal carcinomatosis. Because of a

recent substantial improvement in chemotherapy, the authors analyzed treatment options of colorectal carcinomato-

sis in the current era. METHODS: Consecutive patients with colorectal carcinomatosis treated by cytoreductive sur-

gery combined with hyperthermic intraperitoneal chemoperfusion from 2001 to 2007 were included. The control

group patients with carcinomatosis received contemporary chemotherapy alone. Overall survival was the primary

endpoint. RESULTS: All patients underwent systemic chemotherapy. The cytoreductive surgery combined with hyper-

thermic intraperitoneal chemoperfusion group (n!67) was similar to the control group (n!38) in sex, tumor grade,

site of tumor origin, T status, and N status. The control group was, however, older (59 vs 51 years; P<.001). Median

survival measured from the diagnosis of peritoneal disease was longer with cytoreductive surgery combined with

hyperthermic intraperitoneal chemoperfusion (34.7 months vs 16.8 months; P<.001). Presence of liver metastasis was

a significant negative predictor of survival (hazard ratio, 2.13). CONCLUSIONS: The authors concluded that 1) contem-

porary chemotherapy is associated with prolonged survival among patients with carcinomatosis as compared with

historical controls, and 2) addition of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfu-

sion to modern chemotherapy regimens may significantly prolong survival. Cytoreductive surgery combined with

hyperthermic intraperitoneal chemoperfusion and systemic chemotherapy are not competitive therapies, and they

both have a role in a multidisciplinary approach to patients with carcinomatosis. Cancer 2010;116:3756–62. VC 2010

American Cancer Society.

KEYWORDS: colon, rectal, cancer, peritoneal, mitomycin.

Peritoneal carcinomatosis from colorectal cancer has been historically associated with poor survival ranging from 5to 7 months, and few therapeutic or palliative options.1-4 These patients more than many other cancer patients suffer fromsignificant and disabling symptoms as a direct result of local tumor progression. As a result, development in this field haslargely focused on innovative surgical approaches in an attempt to control or palliate the locoregional progression in theabsence of systemic extraperitoneal disease. Multiple institutional5-9 and multi-institutional series10,11 have suggestedimproved survival with cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion. Nevertheless, these werecohort studies with no internal controls; comparison was made to historical controls.

To our knowledge, there are only 2 published studies on cytoreductive surgery combined with hyperthermic intra-peritoneal chemoperfusion for colorectal carcinomatosis with internal controls: a Dutch prospective randomized trial12

and a French case-control retrospective study.13 In the former, significantly prolonged median survival was observed inthe group receiving cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion and systemicchemotherapy (12.6 vs 22.3 months; P! .032), as compared with the best systemic chemotherapy alone.12,14 Given the

DOI: 10.1002/cncr.25116, Received: September 2, 2009; Revised: October 11, 2009; Accepted: October 21, 2009, Published online May 13, 2010 in Wiley Inter-Science (www.interscience.wiley.com)

Corresponding author: David L. Bartlett, MD, Division of Surgical Oncology, University of Pittsburgh Medical Center, 5150 Centre Avenue, Room 415, Pittsburgh,PA 15232; Fax: (412) 692-2520; bartlettdl@upmc.edu

Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

We thank A. Schneider and S. Winters for their assistance with cancer registry data.

3756 Cancer August 15, 2010

Original Article

34.7 vs. 16.8 months

Survival Comparison with Colorectal Liver

Metastases

Sugarbaker P H JCO 2003;21:762-764 ©2003 by American Society of Clinical Oncology

Author/year  

n   Morbidity(%)   Mortality  (%)   Median  survival  (  months)  

Overall  Survival  (months)  

Survival  CC  -­‐0/1    

Veerwaal/2003  

105   35   8   22   28  (3-­‐y)   45  (5-­‐y)  

Glehen/2004  

506   23   4   19   39(3-­‐y)   47(3-­‐y)  

Shen/2004   77   30   12   16   25(3-­‐y)   49(3-­‐y)  

Morbidity and Mortality

Conclusions

•  Cytoreductive surgery and HIPEC should be considered for all patients with CRC peritoneal carcinomatosis

•  Patient selection is critically important •  Complete cytoreduction is essential to achieve survival

benefit