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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
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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).
-----------------------------------------------------------------------------------
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