Chemotherapy for Advanced Peritoneal Mesothelioma presented by Robert N. Taub, MD, PhD of Columbia University at the Mesothelioma Applied Research Foundation conference in New York, NY on September 28, 2012. www.curemeso.org

1. Columbia University
Mesothelioma Center
www.mesocenter.org
Robert N. Taub MD PhD, director
Peritoneal mesothelioma program
Clinical Trials, Treatment, QOL
(surgery, intracavitary/systemic/targeted therapies)
Preclinical/Laboratory studies
molecular biology, drug discovery,
pharmacokinetics, intracellular platinum
distribution, experimental peritoneography

2. 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

3. Peritoneal Mesothelioma
Normal
Mesothelioma Ascites

4. •Mesothelioma and Asbestos
Dr. G. Zhibin, taken Nov 2011/ IMIG 2012
Asbestos spinning, Chrysotile Insulation Asbestos spinning,
2011,Yuyao, China Johns Mannville, NJ 1934, NJ
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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.

5. HYPOTHESES:
Initiation/Growth Pathways Progression/Growth Pathways
1. Asbestos chemically
induces Receptor 3. NF2 (Merlin) Hippo/
Phosphorylation LATS/ YAP Cascade?
and/or DNA Oxidation ?
2. Asbestos physically 4. Mutated BAP-1 epigenetic
“Harpoons” Macrophages effects on histones, genes?
and/or their chromosomes?
None of these fully explain how mesothelioma develops.

6. Diagnosis of Mesotheliomas
A tissue biopsy, read by a pathologist, is always needed.
Epithelial Biphasic
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 Well-differentiated papillary
“mesothelioma” “mesothelioma”

7. 1. Peritoneal Mesothelioma: two (or three) different diseases?
Tubulopapillary- Sarcomatous/
Epithelial
- Biphasic
No pain, No pain, Much pain,
0-2+ ascites 1-4 + ascites No ascites
Superficial Intermediate Invasive
Median Survival, Tubulopapillary vs. Non Tubulopapillary
(160 patients operated on at CPMC)
Different Genes:
Epithelial v biphasic
gene microarrays,
Unsupervised
clustering, 15 patients

8. The Challenge of Genome Instability:
Different mesothelioma cells may each
show different, very abnormal chromosomes
• Normal karyotype • Mesothelioma karyotype

9. 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

10. Treatment of Abdominal Mesothelioma
• CYTOREDUCTIVE SURGERY + LOCAL /
REGIONAL CHEMOTHERAPY
• SYSTEMIC CHEMOTHERAPY
----------------------------------------------------
• EXPERIMENTAL : Targeted Agents
• EXPERIMENTAL: Immunotherapies
• EXPERIMENTAL: Gene therapy

11. 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

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

13. Bilateral Mediport- Attached
Intraperitoneal Catheters.
MEDIPORT

14. 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

15. 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.

16. 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%

17. Mesothelioma Experimental Targeted Treatment
(I am probably leaving out some treatments)
Preclinical
Clinical
Humanized NGR-TNF*
Anti-Mesothelin Ab
SSIP-dsFv-P38
EGFR Inhibitors VEGF Inhibitors HDAC Inhibitors Miscellaneous Morab009*
Gefinitib Bevacizumab Vorinostat Ranpirnase Not yet BAY 94-9343*
Erlotinib Vatalanib Panobinostat Interferon alpha
Tested, not Cediranib Valproic Acid Interferon gammaFully Vaccines-anti WT1
terribly PDGF Inhibitors Semaxanib Belinostat Rapamycin
Imatinib Sorafenib Bortezomib
tested, anti mesothelin
effective Dasatinib Dendritic Cell Vaccine
Sunitinib
Thalidomide
Cycle Inhibitors
CBP501
but
PARP Inhibitors Adenovirus -HSV-thymidine
Olaparib PI3 Inhibitors IMC A12 hopeful Kinase
Temsirolimus *Available at Columbia

18. 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.

19. 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.

20. 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.

21. 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.

25. Paradigm of tumor formation

26. The Challenge of Personalized
Treatment
Chromosome
? ?
? ?
Great Selection Great Selection of
Of targets? missiles?

29. 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.

30. 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)

31. Columbia Mesothelioma Center
Current Combined Treatment of
Peritoneal Mesothelioma
Normal Mesothelioma
– Debulking Surgery, I.P. Portacath
– I.P. Chemo (Dox, Cisplatin, IFN)
– 2nd Surgery, Hot Chemoperfusion

32. 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