Optimal Management of Peritoneal Carcinomatosis

(Complete cytoreductive surgery plus HIPEC)

Dominique Elias,

Institut Gustave Roussy, Villejuif, France

A New Therapeutic Concept...

To treat MACROscopic disease with complete surgical resection.

To treat remaining MICROscopic disease with intraperitoneal chemotherapy, which is specific by Its timing: immediate Its concentration (20 to 400 times higher than

I.V. route)

(Sugarbaker PH et al. Seminars Oncol 1989; 16: 83-97)

Importance of a complete macroscopical resection as a first step

Drug Reference Model Depth penetration

CisplatinBrincker (93) Mesothelioma 1-2 mmMc Vie (85) Ovarian 1-3 mm

Doxorub. Ozol (82) Ovarian 4-6 layers of cells

Methotr.West (80) Sarcoma 3-7 layers of cells5-FU Nederman (81) Glioma 0.2 mmMitoxant. Los (90) Sarcoma 5-6 layers of

cells

506 patients with colorectal PC28 teams, between May 1987 and December 2002

With numerous different techniques (with and without hyperther.) Médian follow-up: 53 months Mortality: 4% , morbidity: 23%

Residual Residual tumor < 2.5 mm tumor > 2.5 mm

Median Survival 32.4 8.4 (months)

p < 0.001

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

Copyright © American Society of Clinical Oncology

Glehen, O. et al. J Clin Oncol; 22:3284-3292 2004

Actuarial survival of 506 patients who had cytoreductive surgery combined with perioperative intraperitoneal chemotherapy, according to the completeness of

cytoreduction

Survival according to the Completness of the CRS (100 cases, colorectum)

Sugarbaker P. Cancer Chemother Pharmacol 1999; 43 (suppl) S15-25)

Verwaal 2005: 117 patients avec CP d’origine Colorectale

To cure the millimetric and microscopic residual tumor disease:

The « Chemical shock »

Hyperthermia potentiates the efficacy of Chemotherapy

- At a Tissular level:- Decreases dramatically the intertitial pressure in

tumors (from 13 to 0 mm Hg)- At a cellular level:

- Increases the penetration of the drugs (+ 78% for mito)- Increases their effect (30 to 50% for mito).

More high is the temperature, more efficient is the IPCH.

The aim: to be as close as possible to possible 43°C (+++)

Relation between the levelof Hyperthermia and dura-tion on tumor death.

Meta-analysis of studies < 1940Johnson HJ Amer J Cancer 1940; 38: 533-46

Straight line concerns in vivo results

42°C 20 hours

40°C 50 hours

44°C 8 hours

46°C 1 hour

O rg a n ig ra m tite l

21co m ple ted

38s ta rte d th .

51co n tro ls

19co m ple ted

33a d juva n t th .

49H IP E C

54e xp irim e n ta l

1 0 5 p a tie n ts

- Mitomycine

- 40-41°C

- 90 min

- Coliseum

Verwaal et al. Amsterdam

J Clin Oncol 2003; 21: 3737

Cytoreduction

Number

no macroscopic tumour ( R1 ) 18 (38%)

macroscopic tumour < 2.5 mm (R2a) 21 (43%)

macroscopic tumour > 2.5 mm (R2b) 9 (19%)

Survival

0 6 12 18 24 30 36

months from randomisation

0.0

0.2

0.4

0.6

0.8

1.0

prob

abil

ity

50 39 18 8 5 1 control

53 37 26 20 11 7 4 HIPEC

control

HIPEC

Log Rank p = 0.0013

At 3 years: 36% vs 10% (p< 0.01)

Différence entre les moyennes de survie restreinte

CHIP

Chimio

Retrospective comparative studyIn the control group: 3.4 lines of chemoMedian survivals: 25 months vs 60 months

(Elias et al. J Clin Oncol 2009; 27:681-5)

Trial «Chip 2-2» Survival rates of 30 colorectal patients

Overall Disease free

2 years 73% (59-88) 48% (32-66)

3 years 53% (39-72) 41.5% (27-59)

5 years 48.5% (31-66) 34% (19-52)(Elias et al. Gastroenterol Clin Biol 2006; 30: 1200-4)

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0 6 12 18 24 30 36 42 48 54 60Months

Overall survival

Disease free survival

Median follow-up : 55.03 months [30.33 , 84. ]

At risk

Survival rates of 30 colorectal patientsMedian follow-up: 55 months (31-84)

Survival according to the Completness of the CRS (100 cases, colorectum)

Sugarbaker P. Cancer Chemother Pharmacol 1999; 43 (suppl) S15-25)

Verwaal 2005: 117 patients avec CP d’origine Colorectale

At last……

After a complete cytoreductivesurgery followed with HIPEC, overall survival rate (40-50%) is thesame than those obtained after

partialhepatectomy for liver

metastases.

French on-going trial « Prodige 7 »

Complete resection of PC

Randomization

HIPEC No HIPEC

Any types of systemic chemotherapy are autorized…

The French Multicentric DatabaseOfficial report of the 2008 AFC’s congress

Each year, the French Association of Surgery (AFC) selects one subject as main topic for its congress.

This topic is selected 3 years before the congress and comitted to 2-3 experts who are in charge to organize a national retrospective data base.

After analysis, the results of this multicentric data base are presented during the first general session of the congress, and published in a specific book (AFC ‘s monography).

Colon-Rectum

523 patients treated in 23 centres (1990-2007)

Mean age: 53 ± 12 years 7% came from rectum

Complete cytoreductive surgery (CC0) in 85% of the cases

With HIPEC: 86%, with EPIC: 14%

Morbi-mortality

Postoperative deaths: 3% Morbidity (grade 3-4): 30% Mean hospital staying: 22,5 days

Multivariate study:1. The extent of the PC (Sugarbaker’index)(p< 0.0001)2. The centre (p< 0.0001)3. With a lower impact:

- EPIC (more morbid than HIPEC) (p=0.03)

Overall Survival of the 523 patients

Median survival: 30 months 5-years survival: 27%

Survival according to the Radicality of the Surgery (p< 0.0001)

Survival according to the Extent of the Péritoneal Carcinomatosis (p< 0.0001)

Survival according to the Lymph Node Involvement (n= 125) (p= 0.02)

Survival according to the presence of associated Liver Metastases (n= 65) (p= NS)

Survival according to the Grading (p=0.09)

Multivariate study

Variable p Relative risk

P. Index <0.0001 1.052Each increasing of one point increases the risk of death of the rapport of risk, i.e. of 5.2%.

CC-Status 0.05 1.398In three classes: CCR-0, CCR-1, and CCR-2. To pass from one class to another increases of 39.% the risk of death.

Lymph node 0.02 1.534

Adjuv. Chemo 0.002 0.578

Survival of the 416 patients of the CC0-Group

Median survival: 33 months

5-years survival: 30%

Survival according to the Extent of the Peritoneal Carcinomatosis (p< 0.0001)

Survival according to the Centre (p= 0.003)

Survival according to the Type of I.P.Open / Close / EPIC (=NS)

HIPEC: for which patients ?

1) Physiologic aging 65 years.2) No extraperitoneal localization (except 1-3

LM).3) Moderate extent of the PC (operative report

+++, rectal exam., CT-scan). 4) No occlusion in more than 1 site5) No ascitis growing under chemo. 6) Chemosensitive patient (?).

Results of a Systematic Second-Look Surgery in Pts at High risk

of developing Colorectal Peritoneal Carcinomatosis

(Elias et al. Ann Surg 2008; 247: 445-450)

Rationnal

HIPEC is all the more « light » and all the more efficient that the PC is minimal. But to detect early minimal PC is possible neither with clinic neither with imaging.

It is the reason why it is logical to propose a systematic second-look to asymptomatic patients presenting high risks to develop a PC, with the aim to treat PC at an early stage.

We chose the delay of 1 year…

Patients et Methods From 1999 to 2006, 29 patients with a high risk to develop a PC

(without clinical, radiologic or biologic symptoms), underwent a second look, 12 months after their first surgery.

Selected: 3 groups of patients: 16 who presented a minimal macroscopic PC synchronous to the

primary (and which was completely resected during the same session) 4 who presented synchronous ovarian metastases, 9 who presented a perforation of their primary tumour.

All these patients received the adjuvant standard treatment after the first surgery: 6 months of systemic chemotherapy (Folfox or Folfiri)

Patients et Methods (2) Careful exploration of the whole abdominal cavity Mean duration of surgery: 6 hours

29 patients

16 with PC 13 without PC

16 Cytoreduc Surg + HIPEC

Nb of positive areas: 5.6 gp + initial PC: 6 HIPEC

Mean peritoneal index: 10 (2-24)

7 others: No HIPEC

C C R S + H IP E C1 6 pa tie n ts

P re sen ce o f P C 1 6 p a tie n ts : 5 5%

p ro p h yla ctic H IP E C6 pa tien ts

E xp lo ra to ry la p a ro to m y7 pa tien ts

A b sen ce o f P C1 3 pa tie n ts

S e con d -lo o k ( 2 9 p a tien ts)

Results A macroscopic PC was found and treated in 16/29 (55%) patients,

Respectively: In gp with a PC at the first look: 10 of 16 patients had PC (63%) In gp with ovarian metastasis: 3 of 4 had PC (75%) In gp with perforarion of the I, 3 of the 9 patients had PC (33%)

No mortality (0%) Morbidity (grade III/IV) was 14%. Mean duration of hospital stay was 16 days

(Elias D et al. Ann Surg 2008; 247: 445-450)

Survival (early results) After a mean follow-up of 27 months (6-96):

For the 16 patients who underwent a resection of PC + HIPEC: - 8 (50%) are free of disease, - 4 (25%) recurred on peritoneum, - 4 (25%) recurred outside the peritoneum.

For the 6 patients who underwent HIPEC, without detectable PC (prophylactic):

- No recurrence (+++)

For the 7 patients who did not undergo HIPEC: - 3 developped a PC (+++)

Future French randomized multicentric trial

High-risk group after first surgery(information, signed consent, registration)

6 months of IV Folfox(then complete work-up: if no detectable recurrence:)

Randomization [8th month]

Nothing Surgery, with HIPEC « de principe »

Conclusion / Colon-rectum

1. Cytoreductive surgery + HIPEC has become the new therapeutical standard (when feasible) Dramatic impact of the completness of the cytoreductive

surgery Less clear prognostic impact of HIPEC

Low impact of associated liver metastases Two other important prognostic factors:

- The extent of the PC (= confirmation)- The adjuvant systemic chemo (= new)

2. Possibly, in high-risk patients, prophylactic surgery + HIPEC could be benefit

Peritoneal Pseudomyxomas

Pseudomyxomas Origin: appendix, (> 90%)

From benign to malign forms (Ronnett): Low grade=Diffuse peritoneal adenomucinosis Intremediate grade High grade =Mucinous peritoneal carcinomatosis

But a benign disease is able to kill…..

Tumor nodule on stomach

Grade 0 ???

Grade 1: Bordure Unicellulaire

Grade 1: bordure unicellulaire, sans atypie

Grade 3: + présence de blocs tumoraux

Classical treatment: Iterative « optimal » cytoreductive surgery

1. Gough et Coll. 1995 (Mayo Cinic): 56 patients (1957-83)

- 33% with complete surgery

- 5-year survival: 53%, 10-year survival: 31%- 97% with recurrence

2. Miner et Coll. 2005 (Memorial SK): 97 patients

- 53% with complete surgery

- 31% received IP chemo- Mean of 2.2 laparotomy per patient- 10-year survival: 21%- 88% with recurrence at 5 years

(Ann Surg 1994; 219: 112-9) (Ann Surg 2005; 241: 300-8)

Pseudomyxome: nettoyage du pédicule hépatique

Pseudomyxomas: Results of Incomplete Cytoreduction in 174 patients

(Glehen, Sugarbaker Ann Surg 2004; 240: 278-85)____________________________________________________

= 27% of the 645 operated patients 76 received EPIC, and 61 received IPCH Mortality: 0%, mortality 33%

Survival rates: 3-y = 34%, 5-y = 15%

Assesment by tumor histology (5-y survival rates): Grade 1 and grade 2: 20% Grade 3: 10% p=0.01

Conclusion: incomplete cytoreduction results in poor long-term survival.

Results / SurvivalSeries Nb de Pts 5-y Survival

Sugarbaker 2004 501 72%

Zoetmulder 2006 103 60%*

Loggie 2006 110 50%*

IGR 2007 105 80%

AFC 2008 301 75%

* Some incomplete surgery

AFC’s Report 2008:301 patients

18 centres

between mars 1993 and October 2007

Origin: appendix in 91% of the cases

Treatement

Complete resection in only 73%

I.P chemotherapy:- HIPEC in 90% with:

* 80% with Coliseum technique* 62% with oxaliplatine

- EPIC in 10% of pts

Morbi-Mortality Mortality: 4.4%

Morbidity (grades 3-4): 41%with 18% of re-surgery.

Impacting factors: (multivariate study):- Extent of the PC Sugarbaker’s index) (p= 0.002)

- Histological grade 3 (p= 0.03)

Overall Survival

- 75% at 5 years- 55% at 10 years

After a CC0 surgery:- 84% at 5 years- 61% at 10 years

Survival according the completness of surgery(p < 0.0001)

Survival according to Sex (p= 0.02)

Survival according to the extent of the PC (p< 0.0001)

Survival according to the Grading (Ronnett) (p =0.03)

Survival according to the technique of I.P. Chemo. (p= 0.001)

Multivariate study of pronostic factors

1. The extent of the PC (p= 0.002), strongly correlated with incomplete resection rate.

2. Histological grading and presence of invaded lymph nodes (p=0.02)

3. The technique of IP chemotherapy (p= 0.005)

Analysis of the 220 CC0-patients

The Extent of the PC (p=0.004)

Experience of the centre (P < 0.01)

But the grading losts its impact (+++)

Conclusion

PMP are rare but deadly.

There is different forms of PMP, but prognosis is almost similar if the resection is complete.

The gold standard treatment is complete cytoreductive surgery plus HIPEC, when feasible.

Peritoneal Mesotheliomas

Mesotheliomas

Abdominal pain Increasing of the abdominal volume Alteration of the general status Ascitis

Coelioscopy: biopsy and meticulous description of all the lesions (+++)

A rare pathology

200 cases /year in France

Numerous differential diagnosis

Diagnosis possible only histology: It must be a constant thought….

Histo. Diagnosis is difficult: Immunohistochimy (+++)

MPM AdénoKEpiderm

Calrétinine + 90% 10%WT1 + (T. Wilms) 70% 0% 0%

Ber-Ep4 - 85% ovary:0%B72-3 - 90% 20%ACE - 90% 10%

Numerous histological types

High grades: Sarcomatoid Biphasique Many epithelioid (the more frequent)

Low grades: Papillairy forms of epithelioid Multikystiques

Typical MPM

Papillary Mesothelioma

Epithelioid Mesothelioma

MPM (girl of 14 years)

Kystique Mesothelioma (1)

Kystique Mesothelioma (1)

Kystique Mesothelioma (2)

Classical treatment

Systemic chemo : Alimta* (premetexed) + Platine Gem-ox Tom-ox Navelbine + Platine

Median survival : 12-15 months (5-years survival : 15-25%)

Survival with classical treatement

Authors Year Nb Pts Median /months

Markman 1992 19 9Neumann1999 74 12Eltabbali 1999 15 12.5

IGR : Pts treated with CCRS + HIPEC (1996-2004; mean follow-up: 55 months)

26 patients 1 postop. Death (4%) Morbidity: 54%

Median de survival > 100 months Overall 5-year syrvival: 63%

Low grades >> High grades

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D ise ase -fre e surv iv al

Mean floow-up: 53.75 months [6.39 , 131.64 ]

At risk

Per itoneal M esotheliomas: S urvival Rates

Results of HIPEC for MPM

Author Year No Pts Médiane Survie 5 ans  Sugarbaker8 2006 100 52 46%Alexander92003 49 92 59%Deraco10 2006 49 NA 57%Glehen11 2003 15 36 29%Loggie12 2001 12 34 33%IGR 2006 26 100 63%AFC 2008 83 45 44%7 gps (Yan) 2009 405 53 47%

Conclusion / Mesotheliomas

Different pathological types with different prognosis.

When feasible the gold-standard treatment is the complete cytoreductive surgery plus HIPEC.

Other results and indications of Complete cytoreductive surgery plus HIPEC

AFC’s Report 2008

Origin Nb Pts Survival rate

Stomach 159 3-y: 12%K. Appendix 49 5-y: 56%Small Bowel 45 5-y: 33%Serous primitive 33 5-y: 58%Sarcomatosis 28 3-y: 27%

What about Ovarian cancer ?Gynecologists are late…….

Results are very poor as « salvage » treatment.

High probability of efficacy if early proposed (even at the first-look, even at the « intervalle surgery », possibly at a second-look).

Modality of HIPEC must be defined…

Conclusion: only in prospective trials.

Thank-you !

Multivariate Study for the CC0 Group

Variable p Relative risk

Perit. Index <0.0001 1.054

Adjuv. Chemo 0.03 0.719

Experience <6y 0.01 1.841

Synchr. LM 0.01 1.623

Criteria of Exclusion Major criterias:

Age > 70 years, OMS status 2, Extra-abdominal localizations LM (except if 3 and peripheric) Progression under chemo

Minor criterias: Extended PC on clinic or CT-scan Occlusion Other intra-abdominal metastase (except liver

or ovary)