"Rational Versus Radical Therapy For Mesothelioma: A New Approach"

Dr. Robert Cameron, The David Geffen School of Medicine at UCLA, presented at MARF Symposium in Las Vegas, October 16, 2004.

Copyright of Dr. Robert Cameron.

Do not copy without permission

Mesothelioma: Lecture Outline

Pleurectomy/Decortication
– Rationale
– Therapy/disease models Preclinical data: IL-4 immunotoxin Clinical data: Interferon alpha The future

Mesothelioma: Histology

Epithelioid	Biphasic
Sarcomatoid	Undifferentiated

Mesothelioma: Treatment

Surgery
– Radical extrapleural pneumonectomy
– Radical pleurectomy and decortication

Radiation
– Intraoperative
– Postoperative

Chemotherapy

Biologic Therapy

Mesothelioma: Surgical Options

Radical extrapleural pneumonectomy

Radical pleurectomy/decortication

Pleurodesis

History of Radical Surgery

“Radical” Surgery No Better
Radical Mastectomy*

Segmental Mastectomy

“No Touch” Colectomy

Standard Colectomy

Pneumonectomy

Lobectomy/Segmentectomy

EPP

Pleurectomy/Decortication

Tutle, TM JACS. 2004 Oct;199(4):636-643

Mesothelioma: The Problem

Mesothelioma: Surgical Resections

Resection Classifications

Radical resection (amputation, muscle groups, etc.)

Wide local resection (2-3 cm margins)

Marginal resection (within tumor “capsule”)

Mesothelioma: The Problem

Mesothelioma: Chest Structures

Right Chest	Left Chest

Mesothelioma: “Radical” Surgery

Structures Requiring Removal

* Lung
* Pericardium
* Diaphragm
* 12 ribs
* 12 intercostal muscles
* Subclavian vessels
* Vertebral bodies (12)
* Sternum (partial)
* Superior vena cava (right side)
* Aorta (left side)
* Esophagus +/-
* Thymus (ipsilateral) +/-
* Trachea +/- (right side)

Mesothelioma: Margins

“You are only as good
as your CLOSEST surgical margin

Mesothelioma: Surgery

EPP versus P/D

Fracture parietal pleura/tumor off chest wall

Remove pleura/tumor off mediastinum

Remove pericardium (optional)

Remove diaphragm (partial or complete)

Remove mediastinal lymph nodes

Remove lung

Remove visceral pleura from lung (often not done completely)

Mesothelioma: EPP versus P/D

	EPP	P/D
Age	Younger	Almost any
Lung Status	Good PFT's	Almost any
?PFT's	??	+/-,?
Operative Time	Intermediate	Longer
Surgeon's Fee	$1,348.46-$2676.83	$1,249.68-$2,444.26
Margins	Minimal	Minimal
Mortality	3-6%	<1%
Radiation	Easier	Harder
Local recurrence	Harder to detect	Easier to detect

Mesothelioma: Pleurectomy

Myths

Cannot completely decorticate the lung

Cannot do surgery following talc pleurodesis

Cannot clear the fissure(s)!!!

Cannot preserve the diaphragm (partially)

Cannot preserve pericardium

Mesothelioma: EPP vs P/D

No Difference in Survival!

TABLE 4. Results for Extrapleural Pneumonectomy

Year	First Author	N	Median Survival (mo)	2-Year Survival(%)
2001	Rusch 166 *	61	17
2001	Schouwink 197  **	28	10
2000	Takagi	116		29.7
1999	Sugarbaker 146 **	183	19	38
1997	Pass 144	39	9.4
1996	Rusch 143	50	9.9
1994	Allen 255	40	13.3	22.5
1990	Geroulenos	18	20
1990	Harvey 256	7	5.4	28.5
1989	Ruffie 160	23	9.3	17
1988	Faber 257	33	13.5	24
1986	DaValle 258		17.8	24
1982	Chahinian 215	6	18	33
1978	Delaria 259	11	18
1976	Butchart 162	29	4.5	10.3

Modified from Singhal and Kaiser 260
* Postoperative hemithorax radiation therapy; all patients; stages I/II, 33,8; stages III/IV, 10.
** Intraopertive photodynamic therapy
+ Postopertive multimodal therapy
~ Phase I trials of photodynamic therapy or immunochemotherapy

TABLE 3. Results for pleurectomy

Year	First Author	N	Median Survival (mo)	2-Year Survival(%)
2003	Sugarbaker  202 *	44	10-20
2002	Aziz 261	47	14
2002	Lee 177	26	18.1
2001	Martin-Ucar  262	51	7.2
2001	Takagi	73		26.1
1997	Pass  144	39	14.5
1996	Rusch 143	51	18.3	40
1994	Allen 255	56	9	8.9
1991	Brancatisano 161	45	16	21
1990	Harvey 256	9	11.9
1989	Ruffie 160	63	9.8
1988	Faber 257	33	10	12
1986	DaValle 258	23	11.2
1984	Law 151	28	20	32
1982	Brenner 181	69	15
1982	Rabinowitz 263	30	13	27
1976	Wanebo 264	33	16.1

Modified from Singhal and Kaiser.260
* All patients received intrapleural hyperthermic chemotherapy

Mesothelioma: Supportive Data

What data exists to support “debulking” surgery and adjuvant therapy?

Mesothelioma: Cytoreduction

Mesothelioma: Radiotherapy

Wound seeding:
- 21 Gy in 3 fractions
- Decreased wound nodules from 17/33 (51.5%) to 0/24 patients (0%)
- Once wound nodules are detected few respond to radiation

Boutin C Presse Med 1983 12:1823

Mesothelioma: “Rational” Therapy

Surgery may provide benefit from “debulking” tumor mass (ovarian cancer as prototype)

Radical procedures do not provide safer “margin” than more conservative procedures

Radiation may provide benefit with microscopic disease

Chemotherapy provides minimal benefit (exception: pemetrexed and cisplatin)

Mesothelioma: UCLA Approach

Radical parietal pleurectomy

Complete pulmonary decortication (radical visceral pleurectomy)

Removal of all pleural tumor off diaphragm, pericardium, mediastinum, and hilum

Lymph node dissection

Preservation of all tissue planes possible

Postoperative radiation therapy

Novel biologic therapies when available

Mesothelioma: UCLA Surgical Goals

Remove/destroy all tumor (gross)

Preserve tissue boundaries

Preserve vital organ function

Use effective adjuvant therapies

Use maintenance therapies

Develop screening/detection tests

Develop prevention stratagies

Mesothelioma: The UCLA P/D

Radiotherapy Fields for Mesothelioma

Mesothelioma: IMRT

Mesothelioma: Follow-up

CT scan: 30 months

Mesothelioma: Adjuvant Therapy

Chemotherapy

Immunotherapy

Photodynamic therapy

Hyperthermia

Anti-angiogenic therapy

Other targeted therapies

Mesothelioma: Other Models?

Lung Cancer		NO!
Abdominal Carcinomatosis		NO!
Ovarian Cancer		NO!
Other Disease Models		?
High blood Pressure      Diabetes      Acute presentations Chronic illness "Field"-like effects		YES!
Tuberculosis		?

Mesothelioma: Adjuvant Therapy

The IL-4 Story

Mesothelioma: IL-4 Actions

Mesothelioma: IL-4 Receptors

Identified on breast cancer, lung cancer, colon cancer, melanoma, ovarian carcinoma, renal cell carcinoma, and neurofibrosarcoma

High density (271-3831 sites/cell but >10,000 sites/cell in mesothelioma), high affinity IL-4 receptors

Present on some epithelial cells and resting T- and B- lymphocytes (<300 sites/cell)

Kd 100-600 pM

Competitive Binding

Mesothelioma: IL-4 Toxin

Pseudomonas Immunotoxin

Chimeric protein created by fusing a circularly permuted IL-4 mutant gene to a truncated Pseudomonas exotoxin gene

In vitro studies with RCC demonstrate an IC50 of 700pM and a Kd of 800pM

In vitro, IL-4 toxin demonstrates minimal toxicity for B cells, T cells, and promonocytic cells

In Vitro Cytotoxicity

Beseth B, et al Ann Thor Surg 78:436, 200

Immunohistochemistry

Beseth B, et al Ann Thor Surg 78:436, 2004

Tumor Growth

Survival

Beseth B, et al Ann Thor Surg 78:436, 2004

Mesothelioma

Inhibition of Angiogenesis

Mesothelioma: VEGF & bFGF

Characterization of expression of:
– Vascular Endothelial Growth Factor (VEGF) 4 isoforms of VEGF: VEGF121,
VEGF165, VEGF189, VEGF206
– Basic Fibroblast Growth Factor (b-FGF)

Western Blot and RT-PCR

Mesothelioma: Angiogenesis

Western Blots

VEGF
Control 110, 140, 370, 625, 755, 785

FGF
Control 110, 140, 370, 625, 755, 785

Mesothelioma: Interferon Alpha

Wide variety of immune effects

Modest antiangiogenic effects

Direct anti-tumor effects

1980 Interferon alpha inhibits endothelial cell motility in vitro (Brouty-Boye, et al Science)

1987 Interferon alpha inhibits angiogenesis in mice (Sicky YA, et al Cancer Research)

1989 Interferon alpha inhibits angiogenesis in a patient (White CW, et al NEJM)

1992 20 cases of life-threatening hemangioma treated by inteferon alpha (Ezokowitz, RAB, et al NEJM)

1994 bFGF is overexpressed by growing hemangiomas (Takahashi K, et al J Clin Invest)

1995 Interferon alpha down regulates bFGF mRNA in human tumors (Singh RK, et al PNAS)

Inhibitor Mechanisms

Mesothelioma: Interferon Studies

J Clin Oncol 1996, 14, 878±885.
– Given with cisplatin
– Response rate = 40%

Proc Am Soc Clin Oncol 1996, 15, 390
– Given with cisplatin and mitomycin
– Response rate = 21%

Eur J Cancer 1997, 33,1900-1902
– Given with cisplatin
– Response rate = 27%
*

Bull Cancer 1998, 85, 495
– Given with cisplatin and interleukin-2
– Response rate = 15%

Br J Cancer. 1999 Aug;80(11):1781-5
– Given with cycles of Methotrexate
– Median survival = 17.0 months

Cancer. 2001 Aug 1;92(3):650-6
– Given with doxorubicin
– Median Survival = 9.3 months

Mesothelioma: Interferon Alpha

Giant Cell Tumor of Bone (Mandible)
Kaban, LB Pediatrics 103:1145, 1999

August 1994

Giant Cell Tumor of Bone (Mandible)
Kaban, LB Pediatrics 103:1145, 1999

Mesothelioma: Clinical Experience

139 Patients evaluated for mesothelioma

65 Patients underwent P/D
– 94% had “complete” gross resection
– 0% operative deaths (<30 days)

50 Received full dose (45 Gy) radiation
*

47 male (72%) and 18 female (28%)

Epithelioid in 39 (60%), biphasic in 22 (33.8%) and sarcomatoid in 4 (6.2%)

Right side in 40 (62%) and left in 25 (38%)

Stage I/II in 34 (52.3%) and III/IV in 31 (47.7%)

Mesothelioma: Interferon Patients

8 patients eligible for and elected to have adjuvant “maintenance” therapy

Interferon alpha 2b from 200,000 to 2 million units/m2 s.c. daily

Few side effects
– 3 patients had dose reductions 2o to ¯WBC
– Many “tired” (difficult to distinguish from post-surgical and radiation effects)

8 patients

37.5% male/62.5% female

Mean age: 57.5 years

Asbestos exposure history: 50%

Histology: 62.5% epithelioid/37.5% biphasic

75% right side/25% left side

Stage: 37.5% stage I/62.5% stage III
– 37.2% T2/62.5% T3
– 75% N0/25% N2

Compete resection: 100%; XRT: 100% *

Median follow-up: 26.7 months

Mesothelioma: Clinical Experience

Median survival for all patients (intent to treat) : 13.2 mos

Median survival for patient completing surgery and radiation: 17.7 months

Median survival for patients receiving interferon alpha: not reached (>> 26 months; p<0.001)

Mesothelioma: Conclusions*

Mesothelioma has no “best” therapy: “rational” therapy may be equivalent to or even better than “radical” therapy *

Organized trials are needed to define true therapeutic results

Novel treatments are needed (and may be soon available = IL-4 toxin/angiogenesis inhibition)

History of Radical Surgery

Radical Mastectomy*		Segmental Mastectomy
“No Touch” Colectomy		Standard Colectomy
Pneumonectomy		Lobectomy/segmentectomy
Amputation		Limb Salvage
EPP		Pleurectomy/Decortication

Mesothelioma: Future Directions

Explore the use of IL-4 toxin intraoperatively (possibly with hyperthermia)

Continue to investigate the use of interferon alpha and possible mechanisms of action (CXC chemokines + immunoangiostasis)

Consider other agents, ie., interleukin-2 priming

Mesothelioma: Collaborators

Robert B. Cameron M.D.
Shahriyour Andaz, M.D.
Bryce Beseth, M.D.
Raj Puri, Ph.D.
Michael Fishbein, M.D.
Michael Selch, M.D.
Jeff Gornbein, Ph.D.
Rusela Bedrejo, R.N.
Robert Strieter, M.D.
Marie Burdick
Thi Le

Mesothelioma: UCLA Approach

 

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