CYTOREDUCTIVE

SURGERY AND HIPEC

DR AMIT DANGI

DEPARTMENT OF SURGICAL GASTROENTEROLOGY

KGMU

OUTLINE

• PERITONEUM AS ORGAN

• CYTOREDUCTIVE SURGERY

• HIPEC AND ITS TECHNIQUES

• CRS + HIPEC IN CRC, MALIGNANT MESOTHELIOMA, APPENDICIAL TUMORS, PSEUDOMYXOMA, GASTRIC CANCER, OVARIAN MALIGNANCY

• RESULTS/SURVIVAL

• INDIAN EXPERIENCE

EVOLUTION OF CRS AND HIPEC

WHY CRS AND HIPEC

WHY CRS AND HIPEC ???

• Dismal prognosis• Median survival about 9 months.• Now, long-term survival is possible in 25%–85% of patients

Canadian HIPEC Group. Curr Oncol, Vol. 22, Chu DZ et al 1989

Sadeghi B et al 2000 (EVOCAPE 1 multicentre prospective study.)Jayne DG et al; 2002.

Elias et alFranko et al

• Natural history studies

• Large proportion of patients develop isolated peritoneal recurrence, and become cause of death.

• These patients are appropriate for treatment by CRS and HIPEC.

Segelman et al 2012

Yan D et al 2006

Dawson et al 1983

• Two essential components.

CYTOREDUCTIVE SURGERY (CRS). – Removal of visible disease with peritonectomy

PERIOPERATICE CHEMOTHERAPY(HIPEC/EPIC)

– Effective Concentation With Low Systemic Side Effects.

PATIENT SELECTION

• Rule out the presence of distant extra abdominal metastases.

• USG/ CT/ MRI/ FDG PET all useful,• Standard is CT abdomen.

– sensitivity to detect Peritoneal cancer index (PCI), is 88% and

– accuracy 12% – low sensitivity in assessing small-bowel lesions (8%–

17%), which further drop down in less than 5mm lesion.

A. CYTO REDUCTIVE

SURGERY

Contra indications

• Extra abdominal metastasis

• Mesenteric Root Infiltration

• Massive Involvement Of Retroperitoneum

• Massively Infiltrated Pancreatic Capsule

• Expected Small Bowel Resection For More Than One-third Of The Whole Length And

• Unresectable Liver Metastases Are Widely Accepted Absolute Exclusion Criteria For Radical CRS.

Absolute contraindications

• BIOPSY PROVEN EXTRA-ABDOMINAL DISEASE LIKE LUNG METS, SCLN.

• EXTRAPERITONEAL DISEASE, SUCH AS

MORE THAN 3 LIVER METASTASES AND

N3 LYMPH NODES

UNKNOWN PRIMARY TUMOUR.

CANADIAN HIPEC GROUP GUIDELINES. Curr Oncol, Vol. 22 , 2015

ABSOLUTE AND RELATIVE CRITERIA FOR PATIENT SELECTION

CANADIAN HIPEC GROUP GUIDELINES. Curr Oncol, Vol. 22 , 2015

RELATIVE CONTRAINDICATIONS :

• Bowel Obstruction at time of HIPEC• Non responders to NACT (If Used To Downstage The Disease), • Grade 3 Adeno- Carcinoma (Including Signet-ring Cells And Pmca) • Frozen pelvis secondary to rectal cancer recurrence

SHORT INTERVAL B/W PRIMARY ADENOCARCINOMA & PC (SYNCHRONOUS OR <6 MONTHS)

• Careful selection of patients

• NACT Is Strongly Recommended Before Crs Plus HIPEC

• Patients with up to 3 liver metastases responding to NACT could be eligible if all other patient and disease criteria are favourable.

CANADIAN HIPEC GROUP GUIDELINES. Curr Oncol, Vol. 22 , 2015

DISEASE WORK UP

• AN APPROPRIATE HISTORY AND PHYSICAL EXAMINATION; • APPROPRIATE BLOOD TESTS (CEA IN NON MUCINOUS DISEASE)• TOTAL COLONOSCOPY • CT IMAGING OF CHEST, ABDOMEN, AND PELVIS• PET-CT : (IF AVAILABLE IN CASES OF NON- MUCINOUS DISEASE) • CONFIRMATION OF DISEASE (THAT IS, PATHOLOGY REVIEW,

TISSUE BIOPSY, OR PROGRESSION ON IMAGING); AND • OTHER APPROPRIATE EXAMINATIONS, INCLUDING LAPAROSCOPY.

Dromain C, et al. J Comput Assist Tomogr 2003;27:327–32. Dromain C, et al. Staging of peritoneal carcinomatosis: enhanced ct vs. pet/ct. Abdom

Imaging 2008;33:87–93.

• 18F-FDGPET/CT and MRI No adv• 18F-FDG PET/CT between true relapses and

fibrotic scars caused by treatments is often difficult.

• Not all histological types show good glucose uptake at 18F-FDG PET/CT

• showed that both CT and 18F-FDG PET/CT were unable to give a correct staging of carcinomatosis.

• No noninvasive procedure can correctly evaluate PCI and expected cytoreduction index after treatment, especially if the lesions are small.

Pfannemberg et al 2009 . Passot G et al 2010

• Diagnostic imaging (CT and CT/PET) : First and mandatory diagnostic test for peritoneal carcinomatosis.

• When imaging-based PCI is in favor of enrolling the patient for treatment, VLS staging allows assessment of the true PCI, granting a correct selection of patients.

• 104/351 (29%) patients were excluded from surgical exploration because of massive infiltration of the small bowel or its mesentery basis detected by VLS.

• In a recent evaluation by Pasqual et al. preoperative CT and FDG- PET/CT failed to detect PC in 9% and 17% of cases

Valle et al

ROLE OF STAGING LAPAROSCOPY

LOCOREGIONAL STAGING

• A. JAPANESE CLASSIFICATION 1990

• A staging format for carcinomatosis from gastric cancer was proposed:

» P1 (FEW NODULES ABOVE THE

MESOCOLON) 21% 2 YR OS

» P2 (MODERATE AMOUNT OF NODULES

EVEN BELOW TRANSVERSE

MESOCOLON)

» P3 (MANY SPREAD NODULES) 4% 2

YR OS

B. PRIOR SURGICAL SCORE

• PSS uses abdominopelvic regions 0-8 to create an important quantitative prognostic indicator.

• No prior abdominopelvic surgery or biopsy : PSS of 0 • Up to 1 abdominopelvic region dissected : PSS of 1, • 2 – 5 abdominopelvic regions : PSS of 2 • 6 or more regions dissected : PSS of 3.

• PSS of 3 or higher had a significantly reduced survival than those patients with a PSS of 0, 1 or 2.

Look, M., Chang, D., Sugarbaker, P.H. 2003, Int. J. Gynecol. Cancer

C. GILLY’S CLASSIFICATION

Stage 0: no macroscopic signs of

disease

Stage I: nodules smaller than 5 mm,

confined to one abdominal region

Stage II: nodules smaller than 5 mm,

disseminated through the abdomen

Stage III: size of nodules between 5

mm and 2 cm

Stage IV: lesions larger than 2 cm

D. Dutch Simplified Peritoneal

Cancer Index (SPCI)• Tumor is recorded as

Large >5cmModerate 1–5cmSmall <1cmNone

• Seven abdominal regionsI PelvisII Right lower abdomenIII Greater omentum, transverse colon and spleenIV Right subdiaphragmaticareaV Left subdiaphragmatic areaVI Subhepatic and lesser omental areaVII Small bowel and small bowel mesentery

Disadvantage: Epigastric region not designated

ASCO Prog Proc 2002

E. Sugarbaker’s classification

-- PCI

In contrast to the PSS, the small bowel is assessed as an additional 4 abdominopelvic regions, designated AR-9 to AR-12 and includes the upper jejunum, lower jejunum,

upper ileum and lower ileum respectively. The summation of the lesion size score in each of the 13 abdominopelvic regions is the peritoneal cancer index

(PCI), ranging from 0 to 39

A high score would suggest a minimal palliative intervention.

Stage P1 to P2 of the Japanese classification

Gilly’s Stage I to II and to

Sugarbaker’s PCI of less than 13 (>20 is relative C/I).

SURVIVAL

PROGNOSTIC FACTORS

Completeness of cytoreduction

(CC) score

• Major prognostic factor for survival in PC patients.

• Absolute R0 resection is not necessary.• According to this residual tumor classification,

– CC-0 no visible peritoneal seeding after CRS. – CC-1 Persisting nodules less than 0.25 cm after CRS

indicates, – CC-2 nodules between 0.25 and 2.5 cm indicates and – CC-3 nodules greater than 2.5 cm indicates.

• The aim of CRS CC-0 and CC-1Harmon RLSugarbaker PH

• If one has to consider CRS with HIPEC as a curative treatment of PC, patients who cannot be classified as expected CC0 should be excluded from the procedure.

• CC1 cases (residual lesions between 0.25 and 2.5 mm) in HIPEC-responder patients can also be considered CC0 after cytoreduction.

• In CC1 HIPEC nonresponders, CC2, and CC3, the integrated treatment offers limited increase in OS but a marked improvement in QOL; it can therefore be considered as advanced palliative surgery.

Completeness of cytoreduction (CC) score

Verwal Prognostic Score

• Prognostic score : 0.592C + 0.448D + 0.487H + 0.343 Re

C: 1 if CRC, 0 if not

R: 1 if CRC, 0 if not

D: 1 well/moderately well differentiated, 2 poor

H: 1 if no signet ring, 2 if there is signet ring

Re: Number of affected regions (1-7)

SURGICAL

CONSIDERATIONS

ASSESSMENT PHASE

CYTOREDUCTIVE PHASE

HIPEC PHASE

Cytoreductive surgery is divided

into 3 phases:

• ASSESSMENT PHASE: Rule out extraperitoneal disease (>3 liver mets or N3 LN)To evaluate if a resection is feasible. Measurement of PCI. The decision to proceed—or not—is then made.

• CYTOREDUCTION PHASE: Resection of all macroscopic disease Evaluation of completeness of cytoreduction (cc)

• HIPEC Phase: Delivery of HIPEC is performed, followed by creation of diverting stomas (if required). The abdomen is then closed.. Reconstructions are performed either before or after HIPEC.

ASSESSMENT PHASE

• In the case of a high PCI discovered at laparotomy, or when a CC 0 resection is not achievable, three subsequent strategies are possible:

SITUATION 1

• Close the abdomen and consider NACT until the best tumour response has been achieved

and then try again

• Encouraged in the case of grade 1 or 2 classical adenocarcinoma, when a CC-0 resection

seems hard to achieve as demonstrated by the assessment or when a very-high- risk resection

seems the only way to achieve CC-0.

SITUATION 2

• Proceed to a double cytoreduction with or without systemic chemotherapy between the procedures. This approach is used mainly in the case of DPMA or PMCA-i with a PCI Score exceeding 20.

• The goal of the first procedure is to remove all tumour from the upper or the lower abdomen; during the second procedure, the goal is to remove all remaining tumour and to proceed to the hipec phase.

SITUATION 3

• • Close the abdomen and consider best supportive care if neoadjuvant systemic chemotherapy is not an option.

• A decision to go ahead with the procedure should be reserved for very motivated and highly selected patients. The relevant situations are

• DEFINITIVE END STOMA WITH CONCOMITANT

ILEAL BLADDER (PELVIC EXENTERATION),

• WHIPPLE PROCEDURE,• SHORT-BOWEL SYNDROME, OR

• MAJOR HEPATECTOMY.

Peritonectomy procedures

The initially described six peritonectomy procedures have recently been modified. SUGARBAKER 1995,1999, 2013

• Peritonectomy procedures should address only macroscopic disease.

• Normal appearing peritoneal surfaces are not stripped.

• Only structures or organs coated by disease are resected.

Sugarbaker 2013

• Isolated tumor nodules are removed using electro-evaporation using ball tip cautery (viable tumor cells at margin)

• Electroevaporation/ electrosurgery

– Less blood loss,

– less dissemination

of tumor cells.

– High energy likely to

kill tumor cells at

resection margin

CYTO-REDUCTION IN 2

STEPS• In selected cases of a high PCI score and DPAM OR PMCA-I,

performing the cytoreduction as two separate procedures is an option if

• Complete Cytoreduction Is Expected To Last More Than 10–15 Hours,

• If Blood Loss Is Too High, Or • If Surgical Complications Make Proceeding With HIPEC a

Contraindication.

• In such a situation, First Surgery : Infra-mesocolic area is addressedSecond surgery : Supra- mesocolic + HIPEC

CRS WITHOUT PERI-OPERATIVE

IPC

SURGICAL TECHNIQUES

• Vertical median xipho- pubic incision is performed.

• The incision should always include the umbilicus since, in cases of peritoneal carcinomatosis, this anatomic site is at a very high risk of cancer involvement.

• SELECTIVE AND RADICAL PERITONECTOMY

Locations of peritoneal surface

malignancy

• 3 IMPORTANT anatomic sites . 1. THE RECTOSIGMOID COLON : non-mobile, dependent

site and frequently layered by peritoneal metastases. 2. THE ILEOCECAL VALVE 3. ANTRUM OF THE STOMACH which is fixed to the

retroperitoneum at the pylorus. • Tumor coming into the foramen of Winslow accumulates in

the subpyloric space and may cause GOO.• Large volumes of tumor in the lesser omentum combined

with disease in the subpyloric space may require total gastrectomy for complete cytoreduction

Carmignani CP, Sugarbaker TA, ET AL Cancer Metastasis Rev 2003;22:465-72.

Sugarbaker PH. Eur J Surg Oncol 2002;28:443-6.

ABDOMINAL EXPOSURE

Elevation of the edges of the abdominal incision. Skin traction on

a self-retaining retractor facilitates dissection of abdominal wall

structures and minimizes the likelihood of damage to bowel loops

adherent to the abdominal wall.

Xiphoidectomy

Xiphoidectomy is used to gain maximal exposure

beneath the right and left hemidiaphragms

Total anterior parietal peritonectomy

Peritoneal window is necessary to assess the need for total anterior parietal peritonectomy

Lateral dissection of the parietal peritoneum away

from the posterior rectus sheath and the

abdominal wall musculature completes the

anterior parietal peritonectomy.

Lysis of adhesions

• “Tumor cell entrapment hypothesis”

• All adhesions are separated, resected and submitted as a pathological specimen.

• Cancer cells trapped within the scar tissue : may not be eradicated by the perioperative chemotherapy.

Self-retaining retractor provides

continuous exposure of all

quadrants of the abdomen

including the pelvis.

Left subphrenic peritonectomy

LEFT SUBPHRENIC

PERITONECTOMY COMPLETED

Greater omentectomy and

possible splenectomy

• To free the mid-abdomen of a large volume of tumor, the greater omentectomy-splenectomy is performed.

• Great care is taken not to traumatize the body or tail of the pancreas

Right subphrenic peritonectomy

• Peritoneum is stripped from beneath the right posterior rectus sheath to begin the peritonectomy in the right upper quadrant of the abdomen.

• Strong traction on the specimen • Again, ball-tipped electrosurgery on pure cut is

used to dissect at the interface of tumor and normal tissue.

• Coagulation current is used to divide the blood vessels between diaphragm and peritoneum as they are encountered and before they bleed.

Stripping of tumor from glisson’s

capsule

Electroevaporation of tumor from the liver surface with

resection of Glisson’s capsule

Completed right subphrenic

peritonectomy

Lesser omentectomy and

cholecystectomy with stripping

of the hepatoduodenal ligament

Circumferential resection of the

hepatogastric ligament and

lesser omental fat by digital

dissection

Stripping of the omental bursa

after dividing the peritoneal

reflection between left caudate

lobe and superior vena cava

Stripping of peritoneum from the

floor of the omental bursa and

body of the pancreas has been

completed.

A. Division of the pont hepatique (hepatic bridge) for

cytoreduction along the umbilical ligament AND

B. Pont hepatique (hepatic bridge) divided showing

tumor nodules on the umbilical ligament beneath the

divided liver parenchyma. The umbilical ligament will be resected at its entrance into the liver parenchyma.

The complete pelvic

peritonectomy includes uterus

and ovaries, rectosigmoid colon

and pelvic peritoneum.

Resection of rectosigmoid colon and

cul-de-sac of Douglas.

Vaginal closure and low

colorectal anastomosis

Left colon mobilization for a

tension-free low colorectal

anastomosis

Optimization of cytoreduction of

small bowel and its mesentery

ELECTROSURGICAL DESTRUCTION

(ELECTROEVAPORATION) OF TUMOR

NODULES ON SMALL BOWEL

MESENTERY DURING HYPERTHERMIC

INTRAPERITONEAL CHEMOTHERAPY

USING THE OPEN TECHNIQUE.

CYTOREDUCTION OF SMALL

BOWEL AND ITS MESENTERY

Type 1 - non-invasive tumor nodules are usually

resectable using a curved Mayo scissor.

Techniques & procedure

Radicality of the Peritonectomy Procedure

• Depends upon histology of primary tumor & pattern of spread in peritoneal cavity

• Aggressive complete peritonectomy reserved for – Generalized peritoneal carcinomatosis

– Pseudomyxoma peritonei

– Appendix cancer ( Cystoadenocarcinoma G1, G2, G30

– Colorectal cancer ( Mucinous G1, G2, G3)

– Diffuse malignant mesothelioma

– Ovarian cancer (Mucinous)

Techniques & procedureOstomy ?

• 13 studies mentioned about stoma

• In most studies bowel complications same in spite of stoma

• If rectum excised– Perform diversion

• If rectum spared– Can avoid stoma

J Surg Oncol 2004

Eur J Surg Oncol 2006

Surg Oncol Clin N Am 2003

Timing of Bowel Anastomoses

• Before HIPEC

Advantages

1. Reduce costs and

operation time

Disadvantages

1. Mechanical traction during perfusion can impair integrity of anastomoses

• After HIPECAdvantages

1. Effect of heat & chemotherapy on suture healing

2. Possibility to treat bowel margins against eventual implantation of tumor cells

Disadvantages 1. Bowel edema so Technically more difficult.

HIPEC

THE FIRST HIPEC

B. Peri operative intra peritoneal Chemotherpy

NIPS

HIPEC

EPIC : First 4 or 5 days after surgery in normothermic conditions (EPIC)

Or Combination of both or all.

• Term HIPEC coined by the group from the Netherlands Cancer Institute.

Gonza´lez-Moreno S. Peritoneal surface oncology: 2006

Why HEAT ????

• Hyperthermia.• Exhibits a selective cell-killing effect to malignant cells

• potentiates the cytotoxic effect of chemotherapy agents,

• Enhances the tissue penetration of the administered drug.

Sticca RP, Dach BW. Rationale for hyperthermia with intraoperative intraperitoneal chemotherapy agents.

Surg Oncol Clin N Am 2003;12:689–701.

VARIABLES

• Chemotherapy agents

• Duration of HIPEC

• Level of heat for hyperthermia

• Different techniques for abdominal irrigation

• Laparoscopic HIPEC in selected patients.

Proper selection of chemotherapy agents for HIPEC

THE HEAT-AUGMENTED DRUGS WITH THE MOSTFAVORABLE AUC RATIOS AREMITOMYCIN CDOXORUBICIN,GEMCITABINE, ANDPEGYLATED-LIPOSOMAL DOXORUBICIN.

HEAT-AUGMENTED DRUGS WHICH HAVE APROLONGED RETENTION AREGEMCITABINE ANDPEGYLATED- LIPOSOMAL DOXORUBICIN.

• Acute phase drugs• Heat augmented (MITOMYCIN C, DOXORUBICIN, GEMCITABINE,

AND PEGYLATED-LIPOSOMAL DOXORUBICIN).

• High AUC• Prolonged retention and slow clearance (GEMCITABINE

AND PEGYLATED- LIPOSOMAL DOXORUBICIN)

• Continous infusion of drug (ifosfamide)• Repeated dosing of the chemotherapy agents.

Sugarbaker. J Gastrointest Oncol 2016;7(1):29-4

PRODIGE 7 : FRENCH TRIAL

Between HIPEC/EPIC

• NO Randomized controlled studies.

• HIPEC alone VS HIPEC followed by EPIC or EPIC alone,

↓ LESS MORBIDITY IN HIPEC (FISTULA FORMATION)

EQUAL SURVIVAL. Elias D et al 2007

• Survival advantage of HIPEC over EPIC Glehen et al 2003

Rationale of HIPEC

• The intraperitoneal route, when properly used, will

– allow uniform distribution by surgeon/ positional changes

– high concentration of anticancer therapy at the site of the malignancy, when disease load is minimal

– Prevent TUMOR CELL ENTRAPMENT

• Currently, protocols exist attempting to use HIPEC to reduce or eradicate local- regional failures in those patients who are at risk for subsequent local failure and/or peritoneal metastases.

• The COLOPEC trial is currently active in the Netherlands and

• the PROMENADE protocol is in the process of being activated from Rome, Italy.

Adjuvant HIPEC in High Risk Colon Cancer (COLOPEC). Available online: https://clinicaltrials.gov/ ct2/show/NCT02231086 Sammartino P, Societa Italiana di Chirurgia Oncologica (SICO).

PROMENADE Trial (PROactive Management of ENdoperitoneal spreAD in colonic cancer).2015.

Complications

• Over all complication rates : 30-45%

• Chemotherapy toxicity to kidneys, bone marrow, liver, lungs- 2-5%

• Organ damage secondary to hyperthermia

(Careful intra-operative monitoring avoids them)

• Surgical complications – 25-30%

– MC small bowel fistula

• Mortaility during procedure- 0-5%EJSO 2008

TWO MAIN METHODS

1. OPEN ABDOMEN TECHNIQUE

2. CLOSED ABDOMEN TECHNIQUE.

3. MIXED METHODS (SEMIOPEN OR SEMICLOSED) HAVE BEEN REPORTED.

OPEN METHOD OF

HIPEC

CLOSED METHOD OF HIPEC

CREDITS AND DEBITS OF TWO DIFFERENT TECHNOLOGIES FOR HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY

“PERITONEAL CAVITY EXPANDER” (PCE)

• Variation of the open technique

• Acrylic cylinder containing inflow

& outflow lines, secured over

laparotomy wound

• Rarely been used outside Japan.

Fujimura and colleagues and Yonemura and colleagues

PERITONEAL CARCINOMATOSIS FROM COLORECTAL ORIGIN

PROGNOSTIC FACTORS

• 47 studies including 4 comparative studies and 43 observational studies of CRS with PIC

• Significant survival advantage with HIPEC (P < 0.0001).

• No advantage of EPIC only.

• Combined liver and PC should not be excluded from resection if feasible

Two main approaches to HIPEC in colorectal PC

1. THE USE OF MITOMYCIN C FOR 60-90 MIN AT 41 ℃

2. OXALIPLATIN FOR 30 MIN AT 43 ℃.

PREVENTIVE ROLE OF CRS

HIPEC

Sugarbaker PH. Second-look surgery for colorectal cancer: revised selection factors and new treatment options for greater success. Int J Surg Oncol 2011;2011:915078.

Role of second look surgery

Future Trials

• Several randomized trials :

PROPHYLOCHIP

GASTRICHIP

PROMENADE

explore the strategy of surgery plus HIPEC in high risk patients

The median survival : 13 to 29 months, and 5-year survival rates ranged from 11% to 19%.

CC-0 : benefited most, with median survival varying from 28 to 60 months and

5-year survival ranging from 22% to 49%.

Diffuse malignant peritoneal mesothelioma (DMPM)

• Rare disease.

• Progressive peritoneal seeding

• Ascites, abdominal pain, and asthenia

• CT : Ascites, peritoneal thickening, abdominal mass, and mesenteric thickening.

• Median survival of about 1 year

• Cisplatin and pemetrexed.

• 2nd line vinorelbine and gemcitabine +/-platinum compounds.

• CRS and HIPEC Median survival grew from 12 months with a systemic chemotherapy treatment to 53 months with CRS with HIPEC, with 50% 5-year overall survival.

Deraco M, et al. J Surg Oncol 2008]

PERITONEAL CARCINOMATOSIS FROM APPENDICEAL/PMP ORIGIN

• Basingstoke group in 1987 first described CRS + IPCT in PC from appendicial origin.

• 3 types

DISSEMINATED PERITONEAL ADENOMUCINOSIS (DPAM)

PERITONEAL MUCINOUS CARCINOMATOSIS (PMCA)

PMCA WITH INTERMEDIATE OR DISCORDANT FEATURES(PMCA I/D).

Ronnett et al

WAKE FOREST CLASSIFICATION(NEW CLASSIFICATION OF PC)

• LOW-GRADE MUCINOUS CARCINOMA PERITONEI

• 62% 5 YR OS.• DPAM, 36 % 10 yr OS

• PMCA I/D. 28 % 10 yr OS

• well differentiated mucinous carcinomatosisand

• HIGH GRADE MUCINOUS CARCINOMA PERITONEI

• 37% 5 YR OS.• moderately or poorly

differentiated adenocarcinomas,

• cases with signet-ring cell component

• PMCA 3% 10 yr OS.

SELECTION CRITERIA BASED ON THE GRADE OF THE APPENDICEAL PRIMARY.

• LOW-GRADE APPENDICEAL CANCER

CRS attempted regardless of the volume of disease.

Patients with voluminous liquid ascites/ CC-0 CRS HIPEC.

In patients without symptomatic ascites but with excessive post-CRS residual disease the perfusion is aborted.

• HIGH-GRADE / NON-MUCINOUS APPENDICEAL

CA

• IF CC-0 not possible : Not taken for cytoreduction

• Systemic chemotherapy followed by restaging imaging to evaluate for resectability.

PROGNOSTIC FACTORS

1. HISTOPATHOLOGICAL TYPE2. COMPLETE CRS 3. TUMOR MARKERS

• Complete cytoreduction is the standard of care in PMP. • ? Role of HIPEC is under trial.

To date, there is no published prospective randomized trial comparing CRS with CRS/HIPEC (although several trials have been attempted).

• ? Extent of peritonectomyUnlike other gastrointestinal primaries of PC, resection of all peritoneal surfaces is highly recommended.

PERITONEAL CARCINOMATOSIS FROM GASTRIC ORIGIN

• Despite initial R0 resection, peritoneal metastasis develops in 60% of cases with T3 and T4 tumors.

• 10% to 20% of patients with gastric cancer have peritoneal deposits at presentation.

• OS 5-6 months with morbidity.

• Therefore, role of CRS HIPEC should be considered.

• Therapeutic

• Preventive

Treatment-related mortality was 3.9%,major complications occurred in 23.6%

The median survival rate was 15.8 months, with 1-, 2-, and 5-year survival rates of 66%, 32% and 10.7%,

respectively

PERITONEAL CARCINOMATOSIS FROM SMALL BOWEL ORIGIN

• Rare disease

• Grave prognosis (median OS 9 to 20 months)

• 25% of the patients have synchronous PC OS 3.1 mo with palliative tt.

Sadeghi et al

• Chua et al (retrospective trial)reported median disease free and overall survival rates of 12 mo and 25 mo in 7 patients who underwent complete CRS and HIPEC or early postoperative intraperitoneal chemotherapy.

• In multivariate analysis, OS was influenced by CC SCORE

TYPE OF CHEMO PERFUSION DRUG

NODAL STATUS

TUMOR GRADE.

• In a Cox regression model, independent predictors of overall survivalCC SCORE

TUMOR GRADECeelen and coworkers

PREDICTOR OF OS

Divided treatment into time points:

FRONT-LINE,

FRONTLINE FAILURE (PERSISTENT DISEASE AT THE END OF FRONT-LINE TREATMENT),

CONSOLIDATION(MAINTENANCE TREATMENT)

RECURRENT DISEASE.

Frontline therpay

• Combination of CRS and chemotherapy. The median OS for patients:

– Combination IV/IP chemotherapy : 65.6 months

– CRS WITH IV CT ONLY: 49.7 months

Gynecologic Oncology Group (GOG) study 172/ 104/ 114

IP chemotherpy• A Cochrane Collaboration meta-analysis of all

randomized studies using IP therapy for EOC (Epithelial ovarian tumors) significant survival advantage for IP delivery.

– optimal regimen for IP chemotherapy ?

– adding HIPEC

FL Failure

• A study of CRS and HIPEC in this setting was instituted by surgeons at the Instituto Tumoriin Milano but closed early because of excessive morbidity and poor study accrual.

Consolidation

• Multiple trials of maintenance (consolidation) therapy, there is still no proven method.

» continuation of systemic chemotherapy beyond 6 cycles,

» use of intraperitoneal therapy, and

» experimental treatments including immunotherapy.

• No RCTs investigating HIPEC for consolidation, but those that have been performed suggest that HIPEC may have beneficial effects in this situation.

• Few retrospective studies

(Bae JH & Gori J)

RECURRENT

In the HYPERO report, despite 85% of the women treated for recurrence havingPC and 29% being platinum resistant, the median OS was 23.5 months

• Long term results of HYPERO (Helm et al ) awaited.• 3 large, ongoing, randomized studies investigating

HIPEC based in 3 different European countries.• Netherlands Cancer Center

– Role of HIPEC after NAC (at interval debulking).

• French CHIPOR study.– patients with platinum-sensitive recurrent disease

receive chemotherapy with carboplatin and liposomal doxorubicin or paclitaxel and then undergo CRS.

– CC-0/CC-1 : Randomized to HIPEC with cisplatin 75 mg/m2 versus no HIPEC

• Italian HORSE, – patients with platinum-sensitive recurrence will be

randomized to CRS with HIPEC with cisplatin 75 mg/m2 versus CRS alone.

Sarcomatosis

• High loco-regional recurrence/relapse

• Conventional therapy : 2 year survival in patients with local-regional disease progression or sarcomatosis.

• CRS + HIPEC 5-year OS >30%.

• Large benefits in pts with Uterine Sarcomatosis.

Laparoscopic HIPEC

• Four studies– Used in patients with malignant ascites in view of

palliation

Valle et al. in 52 patients with refractory malignant ascites observed one clinical recurrence of the ascites after laparoscopic HIPEC

Less invasive

Limited experience.

STUDIES ON COMBINED LAPAROSCOPIC

CYTOREDUCTIVE SURGERY AND HIPEC

Characteristics of patients undergoing CRS and HIPEC

Operative findings in 384 patients treated with CRS and HIPEC

Morbidity and Mortality in patients undergoing CRS and HIPEC

Sugarbaker 2015

Current indications for cytoreductive surgery and perioperative intraperitoneal chemotherapy

Sugarbaker 2015