Columbia University Mesothelioma Applied Research Foundation Mesothelioma Center

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1 Columbia University Mesothelioma Center Multimodal clinical trials, treatment (surgery, radiation, chemotherapy) Peritoneal mesothelioma program Immunotherapy translational, experimental Antigen discovery, immunization Preclinical studies Microarray analysis, drug discovery, mineral fiber studies, epidemiology, molecular biology

2 Multimodal Treatment of Peritoneal Mesothelioma Ex Officio- K Antman Medical Oncology -- R Taub, ML Keohan, M Hesdorffer, Elethea Hare Surgery J Chabot, Nicole Goetz, John Allendorf, Michael Kluger Radiation Oncology K Fountain Pulmonary Medicine C Powell Pathology A Borczuk 2

3 Multimodal Treatment of Peritoneal Mesothelioma Normal Mesothelioma 3

4 Phases of Peritoneal Program Earliest Clinical Trials of Trimodal Therapy Combine Several Trials to Gain Insights Talk About Complications Look at a Combined Series of All Patients Treated Including Those for Palliative Intent Observations and Current Approach 4

5 Abdominal Mesothelioma Statistics (SEER Database : 601 patients) US Incidence = 10 per million 24% abdominal in women 8% abdominal in men 5 Year Survival = 16% 22% for women 10% for men Median Survival 11 Months Treated Patients 8 Months Untreated patients 1 Year Survival 1970 s 47% 1980 s 49% 1990 s 44% Vershraegen, Key, Hassan. Clinical Presentation and Natural History of Mesothelioma: Abdominal. Malignant Mesothelioma. Eds. Pass, Vogelzang, Carbone. Las Vegas: Springer Science,

6 Abdominal Mesothelioma Statistics (SEER Database : 601 patients) 3 Treatment Options 18% surgery alone 27% chemotherapy ± hormone therapy 16% 2 or more treatment modalities Vershraegen, Key, Hassan. Clinical Presentation and Natural History of Mesothelioma: Abdominal. Malignant Mesothelioma. Eds. Pass, Vogelzang, Carbone. Las Vegas: Springer Science,

7 Multimodality Treatment Improves Survival CASE SERIES of Multimodalities for Abdominal Mesothelioma Series Author Year N Median Survival (mos) Sugarbaker Alexander Deraco > 60 Glehen Loggie REFERENCES Yan et al. Eur J Surg Oncol DOI: /j.ejso Feldman et al. J clin Oncol 2003; 21: Deraco et al. 7 Ann Surg Oncol 2006; 13: Glehen et al. J Clin Oncol 2003; 21: Loggie et al. Am Surg 2001; 67:

8 Phase I-II Multimodal Treatment of Peritoneal Mesothelioma ELIGIBILITY Histologic diagnosis of mesothelioma Negative chest radiography SWOG performance status 0-1 No prior RT 0-2 prior systemic chemotherapy regimens 0-1 prior intraperitoneal chemotherapy 8

9 Multimodal Treatment of Peritoneal Mesothelioma SURGERY (NeoNeoadjuvant) Midline vertical incision Omentectomy Debulking of all disease nodules > 0.5 cm Tissue sampling (path, RNA) Bilateral portacaths for i.p. chemotherapy 9

10 Patient E

11 Patient E

12 Patient E

13 Multimodal Treatment of Peritoneal Mesothelioma INTRAPERITONEAL THERAPY(Neoadjuvant?) Cisplatin 100mg/m2 weeks 1,3,5,7 alternating with Doxorubicin 25mg total dose weeks 2,4,6,8, then Gamma Interferon 9 million IU biw X2 doses, then 30 million units X 6 doses (weeks 9-12) 13

14 Multimodal Treatment of Peritoneal Mesothelioma SURGERY (Definitive Surgery plus I.P.H.P.) Midline vertical incision If minimal or no gross disease seen, then closed IntraPeritoneal Heated Perfusion at 41º C for 60 minutes with mitomycin 10 mg/m2 plus cisplatin 100mg/m2 Tissue sampling (path, RNA) Removal of bilateral portacaths 14

15 Patient B 15

16 Patient C 16

17 Patient A 17

18 Patient D 18

19 Multimodal Treatment of Peritoneal Mesothelioma WHOLE ABDOMINAL RADIATION cgy to abdomen and pelvis, with kidney blocks placed to anterior and posterior portals after cgy. 19

20 Multimodal Treatment of Peritoneal Mesothelioma Patient Characteristics: Number of patients = 27 (20 male, 7 female Age: mean years, range Histology: Epithelioid 22, Biphasic/Sarcomatoid 4, Unclassified 1. Hx Asbestos exposure: Male= 10/20, Female =0/7 Pleural Plaques: Male = 4/20, Female= 1/7 20

21 MEDIAN SURVIVAL, ALL PATIENTS Months Median Survival (Kaplan-Meier): 68 months 3-year survival: 67% (95% CI: 46 81%) 21 Probability of Survival

22 Multimodal Treatment of Peritoneal Mesothelioma RESULTS: Median overall survival 68 mos after start of Rx. 3 year survival 67% (95% C.I.) 10 pts alive, NED, at mean of 58.5 (39-78) mos. 4 pts alive with disease at mean of 62 (45-81) mos. 13 patients died at mean of 37.2 ( 8-68) mos. This includes all 4 pts with sarcomatoid disease who died at mean of 4 (1-11) mos. 22

23 RESULTS: OVERALL SURVIVAL (Kaplan-Meier) Probability of Survival Months Epithelial Biphasic 23

24 OTHER OBSERVATIONS: 3 patients, all biphasic/sarcomatoid, were unresectable at first laparotomy. Bulky disease (nodules >1 cm) did not preclude long term (>60 mo) survival. Conversely, NED at 2 nd look did not preclude later relapse. There were no voluntary dropouts. 4 patients (epithelioid) did not complete chemotherapy. 4 did not complete radiotherapy. 24

25 TOXICITY OF TREATMENT PERIOPERATIVE TOXICITIES: Aspiration pneumonia, ( 1 pt) i.p. catheter sepsis. (1 pt) Multiple abdominal abcesses/fistulae (1 pt). CHEMOTHERAPY TOXICITIES (grade 3 or 4): Grade 3 ototoxicty ( 2 ps) Gastrointestinal (3 pts) Pain (reflex sympathetic dystrophy) (1 pt) 25

26 Early Experience Combined All Epitheliod Biphasic N Median Survival Early Mortality Early Morbidity 55 mo 70 mo 2.6 mo 2% 0 25% 36% 33% 75% 26

27 Methods 78 consecutive patients who underwent surgical debulking and repeated intraperitoneal chemotherapy for mesothelioma between 2/97 through 6/06 by a single surgeon (JC) were reviewed. 7 patients were excluded from this study: 4 who were still undergoing treatment, 1 who had pleural involvement, and 1 who was discovered to have nonmesothelial pathology. 27

28 Statistical Analysis Overall survival, from the date of operation to the date of death or the date of last follow-up, was calculated by the Kaplan-Meier method and differences in survival between the histologic groups (epitheliod/tubulopapillary versus sarcomatous/mixed/ biphasic) were tested with the log-rank test. Chi-square analysis and ANOVA were used to determine differences in patient age and gender, tumor resectability at initial surgery, outcomes, and major treatment complications between the groups. A p-value of <.05 was considered significant. 28

29 Minimal Selection 29

30 Patient Characteristics Epithelial Biphasic Overall (n=58) (n=12) (n=71) p-value Mean Age (yrs; range) (14-75) (35-74) (14-75) Gender (%F; n) 37.9 (22) 50.0 (6) 20.8 (29) NS Resectable at first operation (%;n) 79.3 (46) 16.7 (2) 67.6 (48) <

31 Outcomes Epithelial (n=58) Biphasic (n=12) Overall (n=71) p-value Median survival (months; 95% CI) 55.0 [24.2;*] 5.4 [2.6;13.7] 45.4 [13.7;70.3].0001 Status (%; n) NED AWD Expired Major complications (%; n) 34.5 (20) 15.5 (9) (2) (20) 15.5 (11) 50.0 (29) 83.3 (10) 56.3 (40) 29.3 (17) 66.7 (8) 35.2 (25) NS NS: not significant *upper limit not available because 50% censored 31

32 Survival: All Patients Survival Distribution Function n=71 Median: 45.4 months Legend: Product-Limit Estimate Curve Censored Observations Months Kaplan-Meier curve for the overall group (n=71). Note: overall group included one patient whose histopathology was unclassified. 32

33 Survival of Histopathologic Groups Survival Distribution Function Legend: Epithelial Biphasic Censored Epithelial Censored Biphasic Epithelial (n=58) Median: 55.0 months 0.00 Biphasic (n=12) Median: 5.4 months Months Kaplan-Meier curve for epithelial versus biphasic histopathologic groups. 33

34 Survival After Recurrence 1.00 Survival Distribution Function n=18 Median: 32.8 months Legend: Product-Limit Estimate Curve Censored Observations Months After Recurrence Kaplan-Meier curve showing days of survival for epithelial patients who showed evidence of recurrence (n=18). Months after recurrence was calculated as date of death or latest follow-up minus date of recurrence. 34

35 Observations We have documented by second-look laparotomy that intensive multimodal local treatment can be effectively applied in mesothelioma patients to mitigate or eradicate even widespread intraperitoneal tumor. This result is rarely achieved by either surgery or chemotherapy alone. This treatment is less effective in patients with biphasic/sarcomatoid mesothelioma. -more- 35

36 OTHER OBSERVATIONS: (II) In patients who recurred or who had persistent small amounts of disease, these often were found in areas less open to penetration by chemotherapy, such as the upper surface of the liver or between abutting loops of bowel. 6 month PET scan - liver 2 nd look surgery-positive 36

37 Observations III Reoperation for delayed localized recurrence has resulted in meaningful survival Surgery for late recurrence or bowel obstruction is not excessively risky Lack of disease at second laparotomy does not guarantee cure Presence of disease at second laparotomy does not preclude prolonged absence of demonstrable disease and symptoms 37

38 Current Program Delete Radiation Treat for Ascites Palliation Add HIPEC to First Operation Aggressively Pursue Limited Recurrences Apply These Concepts To Pleural and Multicavity Disease Biphasic/Sarcomatoid Disease 38

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