Columbia University

Mesothelioma Center www.mesocenter.org

Robert N. Taub MD PhD, director

Clinical Trials, Treatment, QOL

(surgery, intracavitary/systemic/targeted therapies)

Preclinical/Laboratory studies

molecular biology, drug discovery,

pharmacokinetics, intracellular platinum

distribution, experimental peritoneography

Peritoneal mesothelioma program

Mesothelioma Defined

--A primary malignant tumor arising in the lining membrane of the lung (pleura), heart (pericardium), intestines (peritoneum), or testis (tunica vaginalis).

Pleural mesothelioma = ~ 3,100 cases/yr

Peritoneal (Abdominal ) Mesothelioma

= ~ 450 cases/yr

Others (pericardial, testicular = <100 cases/yr

Normal Mesothelioma

Peritoneal Mesothelioma

Ascites

•Mesothelioma and Asbestos

Asbestos spinning,

1934, NJ

Chrysotile Insulation

Johns Mannville, NJ

Asbestos spinning,

2011,Yuyao, China

Dr. G. Zhibin, taken Nov 2011/ IMIG 2012

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Other causes:

-Zeolites – asbestos-like mineral (found in US Southwest, Turkey)

-Therapeutic radiation for Cancer- (Breast, Prostate, Uterus, Hodgkins)

-SV40 viral infection may be cofactor.

-Familial, genetic: (BAP1 mutation) may be cofactor.

HYPOTHESES:

None of these fully explain how mesothelioma develops.

1. Asbestos chemically

induces Receptor

Phosphorylation

and/or DNA Oxidation ?

2. Asbestos physically

“Harpoons” Macrophages

and/or their chromosomes?

4. Mutated BAP-1 epigenetic

effects on histones, genes?

3. NF2 (Merlin) Hippo/

LATS/ YAP Cascade?

Progression/Growth Pathways Initiation/Growth Pathways

Diagnosis of Mesotheliomas A tissue biopsy, read by a pathologist, is always needed.

Biphasic Epithelial/Sarcomatous

Epithelial

Sarcomatous

Malignant Mesotheliomas may be: epithelial /tubulopapillary (80%, not good); biphasic

epithelial/ sarcomatoid, (15%, bad); or pure sarcomatoid ( 5-10%, worst).

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Some “mesotheliomas” which present with abdominal distention

may be benign, seldom require surgery or chemotherapy. To be certain,

second pathology opinions and/ or special tests may be needed

Benign cystic

“mesothelioma”

Well-differentiated papillary

“mesothelioma”

Median Survival, Tubulopapillary vs. Non Tubulopapillary

(160 patients operated on at CPMC)

1. Peritoneal Mesothelioma: two (or three) different diseases?

Sarcomatous/Biphasic

Tubulopapillary--

Epithelial

No pain,

0-2+ ascites

Superficial

No pain,

1-4 + ascites

Intermediate

Much pain,

No ascites

Invasive

Epithelial v biphasic

gene microarrays,

Unsupervised

clustering, 15 patients

Different Genes:

The Challenge of Genome Instability:

Different mesothelioma cells may each

show different, very abnormal chromosomes

• Normal karyotype • Mesothelioma karyotype

Loss in Chromosome 14q

Frequency of chromosome loss and gain comparison between asbestos

induced cases (red, 10 pts ) and radiation induced cases (blue, 7 pts )

Original Copy Number

Analysis of Chromosome 14

including All Peritoneal

Mesothelioma Patients (n=31)

Chen et al, IMIG 2012

Treatment of Abdominal Mesothelioma

• CYTOREDUCTIVE SURGERY + LOCAL /

REGIONAL CHEMOTHERAPY

• SYSTEMIC CHEMOTHERAPY

----------------------------------------------------

• EXPERIMENTAL : Targeted Agents

• EXPERIMENTAL: Immunotherapies

• EXPERIMENTAL: Gene therapy

Combined Therapy of Peritoneal Mesothelioma

• SURGERY: Exploratory Laparotomy, Omentectomy, Cytoreduction, Implant Bilateral Subcutaneous Mediport i.p. Catheters, Heated CHEMOTHERAPY “Wash”

• Repeated (q 1-2wk)Intraperitoneal CHEMOTHERAPY with alternating Doxorubin with Cisplatin, 4 of each.

• SURGERY: 2nd-Look Laparotomy, Resection of remaining tumor, Removal of Mediports, Heated I.P. CHEMOTHERAPY

• Follow-up q 3mo X6, q 6mo X3, then yearly X3

Exploratory Laparotomy, Omentectomy, Cytoreduction, Implant Bilateral Subcutaneous Mediport i.p. Catheters

Bilateral Mediport- Attached

Intraperitoneal Catheters.

MEDIPORT

Closed System in OR: Roller Pump with

Constant Recirculation and Temperature:

Cisplatin 75- 100 mg/m2 +/- Mitomycin 10 mg/m2 + in 1-

2 liters N/S @ 41ºC for 90 min

Inter-Institutional Operative Variables

Columbia v Others

• Limited Exploration/Omentectomy; Second-

Look Surgery (two operations) v Radical

Pleurectomy/ Extirpative Surgery (one op.)

• HIPEC: Cisplatin 50-75mg, 41.5o C, 90 min,

v Cisplatin 100-200mg +/- Mitomycin C,

42.5o C, 60-90 min.

• Outpatient i.p. chemo X8, Dox/Cisplatin v

no outpt i.p. chemo, v 5d i.p. chemo.

Chemotherapy for Mesothelioma, Response Rates

Pemetrexed + DDP 42% (corrected, 20.5%) in randomized Phase III. Median Survival 12.5 mo. FDA approved. –

Ralitrexed + DDP, (~20%RR) Randomized Phase III Median Survival 11.6 mo.

Gemcitabine + Cisplatin or Oxaliplatin ( 20-40% in Phase II)—not tested in Phase III.

Doxorubicin +Cisplatin (21-28% in Phase III, 1993)

Mitomycin + Cisplatin (21-28% in Phase III, 1993)

Single Agents: Navelbine, pemetrexed, Doxil, gemcitabine---less than 12%

Mesothelioma Experimental Targeted Treatment (I am probably leaving out some treatments)

Preclinical

Clinical

EGFR Inhibitors

Gefinitib

Erlotinib

VEGF Inhibitors

Bevacizumab

Vatalanib

Cediranib

Semaxanib

Sorafenib

Sunitinib

Thalidomide

PDGF Inhibitors

Imatinib

Dasatinib

HDAC Inhibitors

Vorinostat

Panobinostat

Valproic Acid

Belinostat

PARP Inhibitors

Olaparib

Cycle Inhibitors

CBP501

IMC A12

PI3 Inhibitors

Temsirolimus

Miscellaneous

Ranpirnase

Interferon alpha

Interferon gamma

Rapamycin

Bortezomib

Tested, not

terribly

effective

Humanized NGR-TNF*

Anti-Mesothelin Ab SSIP-dsFv-P38

Morab009*

BAY 94-9343*

Vaccines-anti WT1

anti mesothelin

Dendritic Cell Vaccine

Adenovirus -HSV-thymidine

Kinase

*Available at Columbia

Not yet

Fully

tested,

but

hopeful

How should patients choose treatment?

1. Conventional v. Experimental Treatment:

Previously untreated patients who are symptomatic

from advancing disease should first choose

conventional chemotherapy treatment with a

recognized record of objective responses and/or

tumor shrinkage.

Previously untreated asymptomatic patients might first

choose experimental treatment, to increase their

available options; they can get conventional treatment

at a later time.

Choosing Conventional Treatment?

Patients should ask their doctor to justify his choice of

treatment --- literature experience, personal experience of

expected benefits and possible risks, number of patients

personally treated, whether QOL is being measured.

A second medical opinion is always important, even if the

first opinion is obtained at a major academic Cancer Center.

Patients cared for by community oncologists should abide by

their opinions. If local oncologists are unfamiliar with the

treatment, patients should arrange periodic visits at a major

center to review the treatment being given.

Choosing Experimental Treatment?

1. More than 80% of experimentally tested Phase I and Phase II drugs are

deemed ineffective. Hesitate before enrolling. Do not pin your hopes on

any one drug, be prepared to try several therapies. Second opinions are

particularly important. MARF can provide you with a list.

2. Choose late-stage Phase III studies or investigator-initiated Phase II

studies with a clear rationale that you comprehend, where care will be

provided by the investigator both during and after the trial.

3. Ask whether the investigator will cover additional costs of care that

might be incurred if there are unexpected adverse events or side effects.

4. The investigator (not a surrogate) should personally spell out all the

risks and possible benefits of the study and answer all questions. There

should be many questions.

5. Ask to speak with other patients who have gone through the trial. The

trial should have a QOL component.

In 10 years…

• There will be fewer asbestos-related

peritoneal mesothelioma cases in the US,

more in China.

• Drug treatment will be determined by

genomics.

• Surgical and intraperitoneal treatment for

peritoneal mesothelioma will at least be

better standardized; at best, unnecessary.

Paradigm of tumor formation

The Challenge of Personalized

Treatment

Great Selection of missiles?

Great Selection Of targets?

Chromosome

? ?

? ?

Hypothesis

• 1. Peritoneal Mesothelioma comprises not one but several

diseases, which may differ in cell of origin, cellular appearance, and

mechanism of development: And recognizably, in clinical symptoms

and course.

Chemotherapy for Mesothelioma

Pemetrexed (MTA, Alimta®) + cisplatin (41% (20.5% on review) in randomized Phase III) v cisplatin alone

Gemcitabine + Cisplatin (12-44% in Phase II) Ralitrexed + Oxaliplatin (~40% Phase II) Gemcitabine + Oxaliplatin (~40% Phase II) Doxorubicin + Cisplatin (12-28% in Phase III) Mitomycin + Cisplatin (12-28%in phase III) Gemcitabine alone (7% in phase II)

Columbia Mesothelioma Center

Current Combined Treatment of

Peritoneal Mesothelioma

– Debulking Surgery, I.P. Portacath

– I.P. Chemo (Dox, Cisplatin, IFN)

– 2nd Surgery, Hot Chemoperfusion

Normal Mesothelioma

Conclusion: Optimism

• Advances in molecular biology and genetics

of mesothelioma.

• Improved, more selective surgical and

combined modality treatment

• Discovery of new drugs

• Environmental elimination of asbestos