Despite New Therapies, Malignant Pleural Mesothelioma Outcomes Are Not Improved

BUFFALO, NY-While a combination of pleurectomy and intracavitaryphotodynamic therapy marginally improves survival rates for somepatients with malignant pleural mesothelioma, "there existsno compelling evidence that treatment of any kind is superiorto no treatment," reported Hiroshi Takita, MD, DSc, chiefof the Department of Thoracic Surgery, Roswell Park Cancer Institute.

Dr. Takita presented his findings at the Multidisciplinary CancerCare in the 21st Century conference, hosted by Roswell Park CancerInstitute and made possible through an educational grant fromBristol-Myers Squibb Oncology.

Approximately 3,500 Americans are diagnosed annually with malignantpleural mesothelioma-an uncommon, generally fatal thoracic cancerassociated with asbestos exposure. Twenty years to 40 years afterexposure, 5% to 7% of asbestos workers will die of this disease.

Although a simple chest x-ray will accurately diagnose malignantpleural mesothelioma, early symptoms-localized chest pain, cough,weight loss, fever-are vague and often ignored by the patientuntil the disease becomes life-threatening. No curative or standardtherapy currently exists for this disease, and even with treatment,death usually results within 1 year of diagnosis.

A Surgical Disease

Up to two thirds of patients with mesothelioma die of locallyadvanced disease without distant metastases. "This tellsus that mesothelioma is a surgical disease," Dr. Takita said.But while surgery alone may produce median survival rates of upto 18 months, it still leaves much to be desired, particularlyradical pleuropneumonectomy with its high surgical mortality andpoor postoperative survival.

"The survival benefit of surgery alone is no different thanthat found in patients who have nonsurgical or no treatment,"Dr. Takita said. "Clearly, we need to ask ourselves: Whattherapy should we be combining with surgery to both justify treatmentand improve long-term survival?"

Dr. Takita discussed the results of several studies that havecombined surgery, chemotherapy, and/or radiation therapy for theaggressive treatment of the disease. "Again, we are seeingslight improvements in median survivals, some as long as 23 months,"he said, "but these increases are negligible and underscorethe reality that significantly enhanced survival remains elusive."

He also mentioned that the effectiveness of these combined therapieshas been difficult to assess because the extent of disease ofeach treated patient is not well described.

Over the past decade, Dr. Takita and his Roswell Park colleagueshave used photodynamic therapy (PDT) alone or in combination withsurgery to diagnose, treat, or palliate various thoracic cancers.Dr. Takita described one Roswell Park phase II study in which30 mesothelioma patients with stage I through IV disease weretreated with surgery and intracavi-tary PDT.

In this study, PDT was administered as an adjunct therapy to preventlocal tumor recurrence in the chest cavity and at the site ofsurgical incision. Photodynamic therapy combines tissue-penetratingred laser light and a nontoxic, light-sensitive chemical that,when injected into the body, remains in tumor tissue. Red lightdelivered through fiberoptics strikes the chemically sensitizedcancer cells, releasing tumor-destructive oxygen.

Two days preoperatively, patients received an intravenous injectionof the photosensitizer Photofrin (dihematopor-phyrin ethers).To remove gross evidence of tumor, pleuropneumonectomy or pleurectomywas performed, after which intracavitary PDT was administered.

Postoperative survival was analyzed according to intraoperativestaging proposed by the American Joint Committee for Cancer Staging.Overall estimated median survival was 12 months and for stageIII and IV patients, 7 months. "By this staging system, thereappeared to be a good correlation between the outcome and stageof the disease of our patients," Dr. Takita noted.

Patients with stages III and IV disease had high postoperativemorbidities and a short median survival. Nine patients with stagesI and II disease, all of whom had grossly complete resection bypleur-ectomy, experienced a median survival of 21 months.

"From these results, we conclude that pleurectomy and intracavitaryPDT appear to enhance local control in early-stage disease,"Dr. Takita said. While this combined therapy offers some patientsan alternative, it joins the rank and file of current malignantpleural mesothelioma treatments that "unfortunately neithercure nor significantly improve patient quality of life."

Biologic Therapies

Dr. Takita also reviewed several studies that have tried biologictherapies-intrapleural RNA, interleukin-2, gamma interferon.Results of these earlier studies were encouraging, he noted, butthere has been a subsequent dearth of follow-up studies. "Weare eagerly awaiting the results of the Philadelphia phase I genetherapy trial, which is using adenovirus as a vector," hesaid.

Dr. Takita believes that the most dramatic improvements in therapyleading to enhanced survival benefit will come from a greaterunderstanding of the pathogenesis of the disease. Until then,interventions should target early detection and avoidance of causativeagents, he said.