Peritoneal carcinomatosis

Matti Aapro MD

Genolier, Switzerland

Member ESMO Supportive Care Faculty

Past-President of MASCC( Multinational Association for Supportive Care in Cancer )

Honorary President of AFSOS (French-speaking Association for Supportive Care)

Advisor to JASCC ( Japanese Association for Supportive Care in Cancer)

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COI

Dr Aapro is/was a consultant for • Amgen, BMS, Celgene, Clinigen, Eisai, Genomic Health, GSK, Helsinn, Hospira,

JnJ, Novartis, Merck, Merck Serono, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro,Teva, Vifor

and has received honoraria for lectures at symposia of • Amgen, Bayer Schering, Biocon, Cephalon, Chugai, DRL, Eisai, Genomic Health,

GSK, Helsinn, Hospira, Ipsen, JnJ OrthoBiotech, Kyowa Hakko Kirin, Merck, Merck Serono, Mundipharma, Novartis, Ono Pharmaceuticals, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Tesaro, Taiho, Teva, Vifor

No responsibility accepted for involuntary errors or omissions. The list may be incomplete, and does not reflect consultancy for NGOs, Universities, Governmental agencies, and others

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Background information from a medical oncologist perspective

A GYN ONC COMMENT

AND WHEN IT COMES TO PALLIATION

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Special thanks to

• Dr Dharma Poonia

• Rajiv Gandhi Cancer Institute,

• NEW DELHI.

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Some background

Peritoneal carcinomatosis (GI and ovarian), mesothelioma, and sarcomatosis are included in the group of diseases collectively referred to, as peritoneal metastases.

Dismal prognosis of patients with PC with BSC/CT.• Chu DZ et al 1989• Sadeghi B et al 2000 (EVOCAPE 1 multicentre prospective study.)• Jayne DG et al; 2002.• Elias et al• Franko et al

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Background

Natural history studies à

Large proportion of patients develop isolated peritoneal recurrence, which is then the 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

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The pioneering effort • Sugarbaker 1989

Concept og loco regional disease but not a true metastatic process, thus amenable to curative loco-regional treatment.

Two essential components. • Cytoreductive surgery (CRS).

-Removal of visible disease with peritonectomy• Periop chemotherapy(HIPEC/EPIC)

- effective concerntation with low systemic side effects.

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Patient selection

• Rule out the presence of distant metastases in extra abdominal areas, which is an absolute criterion of exclusion.

• US/ 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.

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No “noninvasive” procedure

that 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

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Role of staging laparoscopy

Diagnostic imaging (CT and CT/PET) is still considered the 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.-Valle et al

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Sugarbaker’s classification - PCI

Location Lesion size

• The abdomen is divided into 9 sectors and small bowel into into 4 more parts.

• for each sector a score is assigned (Lesion Size score [LS]) related to the actual disease:

- LS 0: no macroscopic evidence

- LS 1: maximum diameter of the lesions up to 0.5 cm

- LS 2: maximum diameter up to 5 cm

- LS 3: maximum diameter larger than 5 cm or confluent nodules

• The total of the scores for all sectors gives the PCI.

Stage P1 to P2 of the Japanese classification

Gilly’s Stage I to II and to

Sugarbaker’s PCI of less than 13.

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Prognostic factors

• Histopathology

• The peritoneal cancer index (PCI),

• The completeness of cytoreduction score (CC),

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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 CRSà CC-0 and CC-1

Harmon RLSugarbaker PH

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Completeness of cytoreduction (CC) score

• If one has to consider Peritonectomy with HIPEC as a curative treatment of peritoneal carcinomatosis, 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 quality of life; it can therefore be considered as advanced palliative surgery.

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And comments based on Ovarian Cancer

• Jan B. Vermorken, MD, PhD• Department of Medical Oncology• Antwerp University Hospital• Edegem, Belgium

3rd ESO-ESMO Latin American Masterclass in Clinical Oncology, San Jose, Costa Rica, April 26-30, 2017

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Prognostic Factors in Advanced-Stage Ovarian CancerStages IIb-IV

Postsurgery During RelapsePre-chemotherapy Chemo

Residual disease Type of chemo Time since last CT

Performance status CA 125 fall Disease bulk

Stage Interval debulking Histology

Grade No. disease sites

Age Perf. Status

Ascites Time since DX

HistologyProliferation markers

Quantitative pathol. features

Ploidy

Molecular markers Eisenhauer et al, 1999 (modified)

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Epithelial Ovarian Cancer: Subtypes

HGSC CCC EC MC LGSC

Percentages:FIGO I-IIFIGO III-IV

39%86%

33%2%

22%7%

5%2%

1%3%

Genetic Risk BRCA1/2 HNPCC HNPCC None known None known

Other Risk Factors

  Risk with OC, pregnancy

None known  Risk with OC, � Risk with HRT

None known None known

Precursors STIC Endometriosis Endometriosis Unknown SBT

Presentation Ascites, GI sxs Adnexal mass Adnexal mass Adnexal mass GI sxs

Pattern of Spread

Peritoneal, nodal

Peritoneal, nodal, distal

Peritoneal, nodal, distal

Peritoneal +/-Pseudomyxoma

Peritoneal, nodal

Chemotherapy Response

Sensitive, then resistant

Resistant Sensitive Resistant Resistant

Molecular Genetics

p53, BRCA1/2, PI3K, HRD

PI3K, ARID1A, MSI

PTEN, bcatenin,

ARID1A, MSIKRAS, HER2

BRAF, KRAS, NRAS

Targets PARP, Angiogenesis

Angiogenesis ER, PR, mTOR HER2/neuBRAF,

MEK/ERK

Valencia Meeting 2015 (Bookman) 4th May, 2017 20

Advanced Ovarian Cancer1998-2017 Treatment

Paclitaxel + Carboplatin (TC)• Generally agreed standard• “Control Arm” of most recent randomized trials• No other regimen shown to outperform it

However, results far from perfect:• Median TTP: 12-18 mo• 5-Year OS: <35%

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How to Improve Outcome in Advanced OCBeyond PAC-CARBO

• Increase rate of optimal cytoreduction

- NACT followed by IDS of benefit for some patients

• Increase efficacy of cytotoxic chemotherapy

- adding a third cytotoxic drug → no OS benefit

- maintenance/consolidation with cytotoxics → no OS benefit

- Maintenance with targeted therapy??

- dose-dense therapy with taxanes improves PFS/OS

• Modulate resistance

- modulating agents no benefit in the clinic

- Intraperitoneal chemotherapy improves OS (12 mo in OD pts)

• The use of targeted therapies

- anti-angiogenic compounds and PARP inhibitors beneficial

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IP Chemotherapy in ADOVCA

“It requires expertise and should be standard of care for optimally resected EOC patients”

Vermorken JB. Ann Oncol 2006; 17 (suppl. 10): x241-x246Walker JL. Ann Oncol 2013; 24 (suppl. 10): x41-x45

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And when it comes to palliation

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MASCC/ESMO Antiemetic Guideline 2016Updated information

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Antiemetic Guideline 2016

These slides are provided to all by the Multinational Association of Supportive Carein Cancer and can be used freely, providedno changes are made and the MASCCand ESMO logos, as well as dateof the information are retained.

For questions please contact:Matti Aapro at maapro@genolier.netChair, MASCC Antiemetic Study Groupor Alex Molassiotis at alex.molasiotis@polyu.edu.hkPast Chair, MASCC Antiemetic Study Group

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Antiemetic Guideline 2016

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A Case Scenario

Mrs Sick Patient is 67 years old and admitted with M1 Cancer of unknown origin. She takes no medications. She has often nausea, eats poorly and vomitsoccasionally. Brain mets, metabolic issues, bowel obstruction, are ruled out.

What do you prescribe?

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COMMITTEE IX (1a/3): Advanced Cancer

Treatment of Nausea and Vomiting in Advanced Cancer:Drugs of Choice.

The antiemetic drug of choice in advanced cancer is metoclopramide (titrated to effect).

MASCC Level of Consensus: HighMASCC Level of Confidence: ModerateESMO Level of Evidence: IIIESMO Grade of Recommendation: C

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A Case Scenario

Mrs Sick Patient is 67 years old and admitted with M1 Cancer of unknown origin. She takes no medications. She has often nausea, eats poorly and vomitsccasionally. Brain mets, metabolic issues, are ruled out. She has diffuse peritonealcarcinomatosis. There is no specific occlusion.

What do you prescribe?

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Which alternatives to metoclopramide?

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Which alternatives to metoclopramide?

• Haloperidol

• Levomepromazine

• Olanzapine

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COMMITTEE IX (2a/3): Advanced Cancer

• Treatment of Nausea and Vomiting in Advanced Cancer:

Bowel Obstruction

• The drug recommended in bowel obstruction is octreotide, dosed around the clock, and given alongside a

conventional antiemetic (with the committee recommending haloperidol).

• MASCC Level of Consensus: High

• MASCC Level of Confidence: High

• ESMO Level of Evidence: II

• ESMO Grade of Recommendation: A

• If octreotide plus antiemetic is suboptimal, the use of anticholinergic anti-secretory agents (e.g. scopolamine

butylbromide, glycopyrronium bromide) and/or corticosteroids is recommended as either adjunct / alternative

interventions.

• MASCC Level of Consensus: High (Moderate for corticosteroids)

• MASCC Level of Confidence: Moderate (Low for corticosteroids)

• ESMO Level of Evidence: IV

• ESMO Grade of Recommendation: D

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A Case Scenario

Mrs Sick Patient is 67 years old and admitted with M1 Cancer of unknown origin. She has been prescribed opioids for her diffuse bone pain, along with laxatives. She has often nausea, eats poorly and vomits occasionally. Brain mets, metabolicissues, subocclusion are ruled out.

What do you prescribe?

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COMMITTEE IX (3/3): Advanced Cancer

Treatment of Nausea and Vomiting in Advanced Cancer:Opioid-induced Emesis

No recommendation can be made about specific antiemetics, although various antiemetics may help. Opioid rotation and route switching may be effective approaches. There is no data to support prophylactic antiemetics in this situation.

MASCC Level of Consensus: HighMASCC Level of Confidence: LowESMO Level of Evidence: VESMO Grade of Recommendation: D

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A Case Scenario

Mrs Sick Patient is 67 years old and admitted with M1 Cancer of unknown origin. She has been prescribed opioids for her diffuse bone pain, along with laxatives. She was on corticosteroids which were withdrawn a week earlier. She now has often nausea, eats poorly and vomits occasionally. Brain mets, and subocclusion are ruled out.

What do you prescribe?

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Thank you

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