Rational Versus Radical Therapy For Mesothelioma: A New Approach

Resection Classifications

• Radical resection (amputation, muscle groups, etc.)

• Wide local resection (2-3 cm margins)

• Marginal resection (within tumor "capsule")

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)

"You are only as good
as your CLOSEST surgical margin

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)

EPP

P/D

Age

Younger

Almost any

Lung Status

Good PFT's

Almost any

ΔPFT'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

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

No Difference in Survival! TABLE 4. Results for Extrapleural Pneumonectomy

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

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

What data exists to support
"debulking" surgery and adjuvant therapy?

Pass HI, et. al. Curr Probl Cancer. 2004 28:93-174

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

• 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)

• 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

• 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

Radiotherapy Fields for Mesothelioma

CT scan: 30 months

• Chemotherapy

• Immunotherapy

• Photodynamic therapy

• Hyperthermia

• Anti-angiogenic therapy

• Other targeted therapies

The IL-4 Story

* produced by activated T helper cells (TH2), mast cells and basophils

• 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

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, 2004

Immunohistochemistry

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

Tumor Growth

Survival

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

Inhibition of Angiogenesis

• 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

Western Blots

VEGF

FGF

Control 110 140 370 625 755 785

Control 110 140 370 625 755 785

• 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

• 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

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

August 1994

↓ Surgery

IFN
→

→

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

• 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%)

• 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

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 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)

• 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

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
My Patients!!!!