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Originally published as JCO Early Release 10.1200/JCO.2008.19.4688 on December 1 2008 © 2009 American Society of Clinical Oncology.
In Reply
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
University of New Mexico, Albuquerque, NM
Dana-Farber Cancer Institute, Boston, MA
University of Pennsylvania, Philadelphia, PA
Case Western Reserve University, Cleveland, OH
Wayne State University, Detroit, MI
University of Kansas Cancer Center, Kansas City, KS
University of Michigan Health System, Ann Arbor, MI
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI
Eli Lilly and Company, Indianapolis, IN
University of Chicago, Chicago, IL Malignant peritoneal mesothlioma (MPeM) is a relatively rare disease even when compared to pleural mesothelioma. As noted in our article, it constitutes approximately 10% of all mesotheliomas.1 One can speculate as to why we had a median survival of 26.8 months versus the 5.6 months reported by Clements et al.2 In our study, patients with histologically confirmed MPeM not amenable to curative treatment with surgery and who had measurable disease were enrolled. In addition, patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 and adequate renal, hepatic, and bone marrow function. Median overall survival (OS) for all patients was 26.8 months (95% CI, 11.7 months to not reached; 50% censored). In the analyses by Clements et al the survival data were generated from a general database in which all patients with MPeM from New South Wales (NSW) were included. Therefore, patients did not necessarily need to meet the strict entry criteria outlined in our trial; it is conceivable that the majority of patients in NSW were not enrolled on clinical trials. Nevertheless, the CIs are wide and overlapping both in our study (95% CI, 11.7 months to not reached; 50% censored) and in the study by Clements et al (0 to 220 months). Our study also had a high censorship rate. Even better survival results have been reported in patients where surgical debulking was possible and who were treated with combined resection, intraperitoneal chemotherapy, and whole abdominal radiation therapy. Hesdorffer et al reported a median overall survival of 70 months with a 3-year survival of 67% (95% CI, 46% to 81%).3 Baratti et al reported their experience with patients with multicystic and well-differentiated papillary peritoneal mesothelioma treated by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HI-PEC), which yielded a 5-year survival rate of 90% with 79.7% of patients remaining progression free at 5-years.4 Admittedly these reports include highly selected patients with good prognosis to begin with. In another report by Elias et al, in a cohort of patients treated with surgical debulking and HI-PEC, median survival was not reached, but was expected to exceed 100 months.5 In unresectable patients with MPeM treated with systemic chemotherapy alone, survival was inferior, generally ranging between 12 and 14 months5-7; compared with this, our results are relatively promising. However, as pointed out in our article, our results have to be analyzed in the context of the relatively small sample size giving rise to the observed wide CIs. Our trial was designed to include all mesotheliomas. The pleural mesothelioma component of the trial has been reported by Janne et al.8 This report details our experience with patients with MPeM who were enrolled in this study. The statistical design of the trial that estimated the required sample size was based on the response rate in the whole patient population (pleural and peritoneal). This report on MPeM was intended to be a report of our observations based on a small number of patients and not intended to be an adequately powered study to show a treatment effect. The rarity of the disease precludes such adequately powered studies, though such studies are highly desirable. We therefore agree with the comments made by Park et al that large randomized trials or even straight phase II studies with significant numbers of patients are difficult to conduct. In addition, we also concur that international collaboration leading to intercontinental multicentric studies would be essential to accomplish randomized trials in this disease that will answer critical questions. Even then, it would be extraordinarily difficult to complete such efforts. It took 10 centers approximately 18 months to accrue the 20 patients enrolled in our trial. We also agree with Park et al that significant improvements in currently available technologies for early detection of both pleural and peritoneal mesothelioma are needed. Surveillance for progression of MPeM is particularly difficult. Computed tomography (CT) scans of the abdomen and fluorescent deoxy-glucose positron emission tomography scans (FDG-PET) are designed to image and detect masses rather than the sheet-like or the multitude of sesame seed–like growths that can speckle the lining of the peritoneum. At one of our centers (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL), we have performed repeated exploratory laparotomies, the frequency of which is determined by clinical signs and symptoms of tumor recurrence. We have often found tumors in the abdomen when the CT scans of the abdomen and FDG-PET scans were reportedly negative. By doing repeated laparotomies and debulking procedures, usually operating before the patient proved inoperable, we have been able to keep patients alive, ambulatory, and functional. Indeed, in a study by Feldman et al, favorable outcome was associated with younger age, patients with a history of previous debulking, lack of invasive tumor growth, and minimal residual disease after tumor resection.9 In conclusion, the optimal treatment strategy for MPeM remains to be elucidated. However, prolonged survival is possible, especially in patients in whom surgical debulking is feasible. Currently available imaging techniques are inadequate, necessitating repeated exploratory laparotomies. Developing a serum marker with high sensitivity and specificity to both detect recurrence and facilitate early diagnosis is a matter of high priority. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Guangbin Peng, Eli Lilly & Co (C); John Gill, Eli Lilly & Co (C); Coleman K. Obasaju, Eli Lilly & Co (C) Consultant or Advisory Role: George R. Simon, Eli Lilly & Co (C); Pasi A. Janne, Eli Lilly & Co (C); Corey J. Langer, Eli Lilly & Co (C); Karen Kelly, Eli Lilly & Co (C); Gregory P. Kalemkerian, ImClone (C), Merck (C) Stock Ownership: John Gill, Eli Lilly & Co; Coleman K. Obasaju, Eli Lilly & Co Honoraria: George R. Simon, Eli Lilly & Co; Afsin Dowlati, Eli Lilly & Co, Genentech; Shirish M. Gadgeel, Eli Lilly & Co; Karen Kelly, Eli Lilly & Co; Gregory P. Kalemkerian, Eli Lilly & Co, Genentech Research Funding: George R. Simon, Eli Lilly & Co; Pasi A. Janne, Eli Lilly & Co; Corey J. Langer, Eli Lilly & Co; Afsin Dowlati, Eli Lilly & Co, Celgene, GlaxoSmithKline; Shirish M. Gadgeel, Eli Lilly & Co; Gregory P. Kalemkerian, Eli Lilly & Co, Abbot Pharmaceuticals, Millennium; Anne M. Traynor, Eli Lilly & Co, Pfizer, Novartis; Hedy L. Kindler, Eli Lilly & Co Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on December 1, 2008 REFERENCES
1. Simon GR, Verschraegen CF, Janne PA, et al: Pemetrexed plus gemcitabine as first-line chemotherapy for patients with peritoneal mesothelioma: Final report of a phase II trial. J Clin Oncol 26:3567-3572, 2008 2. Clements M, Berry G, Shi J, et al: Projected mesothelioma incidence in men in New South Wales. Occup Environ Med 64:747-752, 2007 3. Hesdorffer ME, Chabot JA, Keohan ML, et al: Combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for the treatment of malignant peritoneal mesothelioma. Am J Clin Oncol 31:49-54, 2008[Medline] 4. Baratti D, Kusamura S, Sironi A, et al: Multicystic peritoneal mesothelioma treated by surgical cytoreduction and hyperthermic intra-peritoneal chemotherapy (HIPEC). In Vivo 22:153-157, 2008 5. Elias D, Bedard V, Bouzid T, et al: Malignant peritoneal mesothelioma: Treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy. Gastroenterol Clin Biol 31:784-788, 2007[Medline] 6. Janne PA, Wozniak AJ, Belani CP, et al: Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: Outcomes of an expanded access program. Clin Lung Cancer 7:40-46, 2005[Medline] 7. Garcia-Carbonero R, Paz-Ares L: Systemic chemotherapy in the management of malignant peritoneal mesothelioma. Eur J Surg Oncol 32:676-681, 2006[CrossRef][Medline] 8. Janne PA, Simon GR, Langer CJ, et al: Phase II trial of pemetrexed and gemcitabine in chemotherapy-naive malignant pleural mesothelioma. J Clin Oncol 26:1465-1471, 2008 9. Feldman AL, Libutti SK, Pingpank JF, et al: Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol 21:4560-4567, 2003
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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