2005 ASCO Mesothelioma Abstracts
The following abstracts on continuing mesothelioma research were presented at the 2005 American Society of Clinical Oncology meeting held in Orlando, FL
Combined Resection, Intraperitoneal Chemotherapy, and Whole Abdominal Radiation for Malignant Peritoneal Mesothelioma (MPM)
Abstract No: 7175
Author(s): R. N. Taub, M. E. Hesdorffer, M. L. Keohan, J. A. Chabot, K. S. Fountain, S. Talbot, M. Gabay, S. Lee
Background: We have carried out a prospective single-institution Phase I-II trial of surgical debulking, intraperitoneal chemotherapy and immunotherapy followed by whole abdominal radiotherapy in patients with malignant peritoneal mesothelioma (MPM).
Methods: Between 1997 and 2000 27 patients with malignant peritoneal mesothelioma were enrolled, 23 with the epithelial subtype, and 4 with a sarcomatoid or mixed subtype. The treatment regimen consisted of: initial exploratory laparotomy with surgical debulking and placement of indwelling intraperitoneal (ip) catheters; four ip courses of doxorubicin alternating with four ip courses of cisplatin; 4 ip doses of gamma interferon; a second laparotomy with biopsy verification of complete response or attempted resection of residual disease; intraoperative hyperthermic (41 degrees centigrade) ip perfusion with mitomycin plus cisplatin; and finally whole abdominal radiotherapy.
Results: The median overall survival was 68 months with a 3 year survival of 67% (95% CI: 46-81%). Thirteen patients died from their disease at a mean of 37.2 (range 8-68) months after initiation of treatment. Ten patients are alive with a laparotomy-verified complete pathologic response and without further evidence of disease at a mean of 58.5 (range 39-78) months. Four patients are alive with disease at a mean of 62 (range 54-81) months. The entire regimen was well tolerated; there were no patients with Grade III or IV hematological toxicities, 2 patients with Grade III ototoxicity, and 3 patients with Grade III gastrointestinal toxicity.
Conclusions: Based on the results of this study intensive multimodality therapy appears feasible and effective in this group of MPM patients.
A phase 2 clinical trial of pemetrexed (P) plus gemcitabine (G) as front-line
chemotherapy for patients with peritoneal mesothelioma (PM).
Abstract No: 7235
Author(s): G. R. Simon, P. A. Janne, C. J. Langer, C. F. Verschraegen,
A. Dowlati, S. M. Gadgeel, K. Kelly, L. Taylor, C. K. Obasaju, H. L. Kindler
Background: P in combination with cisplatin is approved for the treatment of malignant pleural mesothelioma. In an Expanded Access Program, P ± cisplatin was shown to have activity in peritoneal mesothelioma. P plus G are synergistic in preclinical models, but the activity of this combination in peritoneal mesothelioma is unknown. The median overall survival for all peritoneal mesotheliomas is below one year. This study was conducted to determine overall survival of pts with PM.
Methods: Nineteen pts were accrued with malignant peritoneal mesothelioma. Treatment consisted of G 1250 mg/m2 given over 30 minutes on D 1 and 8, with P 500mg/m2 given over 10 minutes on D 8, immediately before G. Treatment was repeated every 21 days for a total of 6 cycles or until progressive disease. All pts received folic acid, vitamin B12 and steroid prophylaxis. There is no staging system for PM to quantify anatomic response. Patients were followed for survival only.
Results: Data are available on fifteen pts. Median age was 68 years (range: 46 - 79). Pathologic diagnosis epithelial:other = 10:5, M:F = 11:4, and ECOG PS 0:1:2 = 7:4:3. Grade 3/4 events included neutropenia (46.7%), febrile neutropenia (13.3%) (including one toxic death), fatigue (13.3%), abdominal pain (6.7%), and dyspnea (6.7%). A total of 67 cycles within the first 6 cycles of treatment were administered. For P plus G, median number of doses was 5 and 11 and median dose intensity was 96.1% and 86.2%, respectively. Median TTP was 10.4 months (95% CI = 4.4, --), and at 12 months, 63% of patients had disease progression.
Conclusions: Though these data are preliminary and reflect a small sample size, P plus G was well tolerated and median TTP was promising in peritoneal mesothelioma.
A multicenter, double-blind, placebo-controlled randomized phase II trial
of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo in patients
(pts) with malignant mesothelioma (MM)
Abstract No: 7019
Author(s): H. L. Kindler, T. Karrison, C. Lu, D. R. Gandara, J. Stevenson, L. Krug, P. Janne, T. L. Guterz, W. M. Stadler, E. E. Vokes
Background: MM pts have the highest VEGF levels of any solid tumor, and high VEGF is a poor prognostic factor. Anti-VEGF antibodies decrease MM growth in pre-clinical models. Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to VEGF. GC is an active regimen in MM.
Methods: We are conducting a multi-center, double-blind, placebo-controlled randomized phase II trial of GCB vs. GCP in MM pts. Primary endpoint: time to progression. Eligible pts have unresectable, histologically confirmed MM; no prior chemotherapy; PS 0-1; measurable disease; no tumor involvement of major vessels; no bleeding or thrombosis. Pts are stratified by PS (0/1) and histology (epithelial/other). Pts receive G 1250 mg/m2 days (D) 1, 8, Q 21D, C 75 mg/m2 D1 Q 21D, and B or P 15 mg/kg D1 Q 21D, for 6 cycles, then single-agent B or P Q21D. CT scans are obtained Q2 cycles. Plasma VEGF levels are obtained pretreatment. 102 pts enrolled 12/01-11/04 at 10 centers, 95 (47 GCB, 48 GCP) are evaluable. Pt characteristics (GCB/GCP): male 74%/83%; median age 62/63.5 (range 20-83); PS: 0 32%/29%, 1 68%/71%; epithelial 74%/77% sarcomatoid/biphasic 26%/23%; site of origin: pleura 91%/90%, peritoneum 9%/8%, tunica vaginalis 0%/2%; thrombocytosis 36%/40%.
Results: Cycles administered: 588 (range 1-39, median 5). Grade ¾ hematologic toxicity (%pts, GCB/GCP): neutropenia 23%/21%; anemia 0%/6%; thrombocytopenia 15%/15%; other toxicity (all grades, grade ¾): epistaxis 34%/6%, 4%/0%; proteinuria 36%/23%, 2%/0%; hypertension 28%/6%, 11%/2%; thrombosis 7%/6%, 7%/6%; visceral perforation 0%/0%. Median baseline plasma VEGF 114.5/179 pg/ml.
Conclusion: The study arms are well-balanced. Grade ¾ toxicities were not statistically greater for GCB except for hypertension (all grades p=0.006) and epistaxis (all grades p=0.001). Individualized treatment assignments and efficacy outcomes remain blinded until 106 evaluable pts enroll.
Decreased PET SUV after induction chemotherapy is associated with improved
survival in malignant pleural mesothelioma (MPM).
Abstract No: 7066
Author(s): R. M. Flores, T. Akhurst, L. Krug, M. Gonen, J. Dycoco, K. Rosenzweig, S. M. Larson, R. J. Downey, V. W. Rusch
Background: Our prior studies showed that PET detects metastatic disease not identified by CT and that PET SUV predicts survival. However, no study has yet shown whether change in SUV correlates with response to chemotherapy or survival. We prospectively evaluated PET before and after induction therapy in MPM patients subsequently undergoing surgery.
Methods: Patients with MPM who were enrolled in clinical trials of induction chemotherapy followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation and who had PET scans before and after chemotherapy. Patients fasted and received a minimum of 10 mCi of F18-flourodeoxyglucose. Whole-body emission studies were acquired, followed by whole-body transmission scans with iterative reconstruction. Survival was analyzed by Kaplan Meier.
Results: From 1999-2004, 24 consecutive patients (19 men and 5 women; median age 62 years) had PET scans before and after cisplatin-based induction chemotherapy. EPP was performed in 15, pleurectomy/decortication in 1, and biopsy only in 8. Histology was 17 epithelioid and 6 non-epithelioid. AJCC stage II was observed in 8 patients, stage III in 5, and stage IV in 11. The mean change in SUV from baseline was 0.125; maximum decrease was 9 and maximum increase was 19, with a median follow-up of 11 months. Patients with a decrease in SUV (n=16) after chemotherapy had a significantly better survival compared to patients with an increase in SUV (n=8). Median survival was 58.5 months versus 34.8 months, respectively (log rank p-value=0.03)
Conclusions: A decrease in PET SUV after induction chemotherapy is associated with a significant improvement in survival. These findings suggest that PET is useful in restaging patients after induction therapy and selecting them for surgery.
Survival update of a subset of previously treated patients with malignant
pleural mesothelioma (MPM) in an expanded access program (eap) of pemetrexed
(P) alone or combined with cisplatin (cis).
Abstract No: 7173
Author(s): M. Orlando, T. F. Wozniak, P. A. Janne, C. P. Belani, M. L. Keohan, H. J. Ross, J. Polikoff, D. M. Mintzer, Z. Ye, C. K. Obasaju
Background: P plus cis demonstrated superiority versus cis alone for pts with malignant pleural mesothelioma. Prior to the approval of the regimen there was an increased demand for patient access to P. To gather additional efficacy and safety data, an Eli Lilly and Company EAP was opened to allow access to all eligible pts.
Methods: Pts were treated q 21 days with P 500mg/m2 alone or in combination with cis 75mg/m2 for a maximum of 6 cycles. Chemotherapy-naïve pts received the combination of P plus cis, while pre-treated pts received P alone. All pts received were supplemented with folic acid, vitamin B12, and received steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all pts enrolled in the EAP.
Results: There were 1056 pts MM that received at least one dose of study drug at 462 sites in the United States. Of these pts, 187 were previously treated pts with MPM. Median age of this subset analysis was 65.9 years (range: 27- 87). The most commonly reported SAEs in the overall EAP regardless of causality were: dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%).
Conclusions: The toxicity observed for all pts enrolled in the EAP group is acceptable. The respective disease control rates are provocative in this poor prognostic patient population.
No. of pts received study drug
|No. of pts evaluable for response||73||80|
|Median No. of Cycles for SD Pts||4.0||5.0|
|SD Pts receiving > 6 Cycles||11||13|
|Overall Response Rate (ORR) %, (95% CI)||5.5% (1.5%,13.4%)||32.5% (22.4%,43.9%)|
|Disease Control Rate (ORR + SD), (%)||46.6%||68.8%|
|Median survival, months (95% CI)||4.1 (3.2, --)||7.6 (6.5,11.0)|
Survival update on a subset of peritoneal mesothelioma (PM) patients in an expanded access program (EAP) of pemetrexed (P) alone or combined with cisplatin in the treatment of malignant mesothelioma (MM).
Abstract No: 7174
Author(s): J. Bloss, T. F. Wozniak, P. A. Janne, C. P. Belani, M. L. Keohan, H. J. Ross, J. Polikoff, D. M. Mintzer, L. Taylor, C. K. Obasaju
Background: A phase III trial of mesothelioma pts showed improved efficacy for P with cisplatin versus cisplatin alone, leading to a demand for patient access to P prior to regulatory approval. In order to gather additional efficacy and safety data, an Eli Lilly and Company EAP was opened to allow access to P for all eligible pts with MM.
Methods: Patients were treated once every 21 days with P 500mg/m2 alone or with cisplatin 75mg/m2, for a maximum of 6 cycles. Chemotherapy naïve pts received the combination of cisplatin plus P, while pre-treated pts received P alone. All pts were supplemented with folic acid, vitamin B12, and received steroid prophylaxis.
Results: There were 1056 pts with MM that received at least one dose of study drug at 462 sites in the United States. Of the 98 pts with PM there were 38 chemotherapy naïve pts (M 74%, F 26%; Median age: 65), 57 previously treated pts (M 56%, F 42%; Median age: 58), and 3 missing. The most commonly reported serious adverse events in the EAP regardless of causality were: dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). In seventy-three pts evaluated for response there were: 4 CRs (5.5%), 15 PRs (20.5%), 33 SDs (45.2%), and 21 PDs (28.8%) for an objective response rate of 26.0% (95% CI 16.5-37.6%). Median survival has not been reached for chemotherapy naïve pts (95% CI=7.6, --; 81.6% censorship) and median survival is 13.1 months for previously treated pts (95% CI=7.8, 13.1; 77.2% censorship).
Conclusions: The toxicity observed for all pts enrolled in the EAP group is acceptable. The disease control rate (CRs+PRs+SDs) of 71.2% in the subset of pts with peritoneal mesothelioma indicates activity in this patient population.