The article by Drs. Mineo and Ambrogi provides a comprehensive overview of clinical, genetic, and molecular prognostic markers in malignant pleural mesothelioma. In addition, the authors discuss the current staging of mesothelioma as well as the proposed new International Association for the Study of Lung Cancer (IASLC) staging system designed to help clinicians better stratify patients. The role of various molecular pathways that influence the progression of mesothelioma is also very well laid out.
Although there has been an unprecedented increase in our knowledge of mesothelioma biology in the past decade, insufficient evidence exists to support the use of any of the new molecular markers to guide treatment decisions in routine clinical practice. The main determinants of prognosis for mesothelioma patients continue to be clinical factors and basic pathological studies. Tumor histology is arguably the single most important factor that influences patient survival, with the nonepithelioid histologic subtype being a negative prognostic indicator. Patients with sarcomatoid histology have the worst prognosis, and current therapies, such as surgery or chemotherapy, offer little benefit.[1] However, the clinical course of patients with biphasic histology is more complicated. This may be due in part to subtype misclassification resulting from sampling error, which may complicate up to 20% of cases (and up to 50% of biphasic cases) diagnosed by pleural biopsies.[2-4] Ongoing efforts to characterize tumor histology by differences in gene expression may in the future allow for more accurate stratification of patients.[5,6]
Tumor stage is another important determinant of prognosis in patients with pleural mesothelioma. As has been nicely summarized by Drs. Mineo and Ambrogi, tumor staging in mesothelioma is rather complex. The most widely used staging system is the TNM staging developed by the International Mesothelioma Interest Group (IMIG) in 1995.[7] However, because this is a surgical staging system, its use in a nonsurgical setting has limitations, and this has provided the impetus to develop a staging system capable not only of better identifying which patients should undergo surgery, but also of providing prognostic information. Both IASLC and IMIG are currently undertaking this work and have already established a large data set of surgically treated patients. The two organizations are now prospectively collecting data on patients who are not managed surgically.[8]
In addition to the factors mentioned above, a number of clinical parameters have been associated with worse prognosis; these include male gender and poor functional status.[9-12] Pain and dyspnea also have prognostic value.[13] Several prognostic scoring systems that incorporate various clinical and laboratory features are commonly used to stratify patients. The two widely used systems include the Cancer and Leukemia Group B (CALGB) scoring system,[11] which consists of patients’ performance status, age, platelet count, chest pain, and lactate dehydrogenase level; and the European Organisation for the Research and Treatment of Cancer (EORTC) scoring system,[14] which includes performance status, histological subtype, sex, certainty of diagnosis, and white blood cell count.
The prognostic value of genetic and molecular markers is less clear. Much of this information derives from small studies, and although promising, insufficient evidence precludes its routine clinical use. However, some of these markers show potential value and could be used routinely if validated either individually in multicenter studies or as secondary endpoints in large surgical series or clinical trials. In addition to prognostic markers, the identification of markers that can be used to predict therapeutic response is equally important. The best-studied predictive markers in mesothelioma include the thymidylate synthase (TS) and excision repair cross-complementation group 1 (ERCC1) proteins, since these influence response to pemetrexed(Drug information on pemetrexed) (Alimta) and cisplatin(Drug information on cisplatin), the current frontline therapy for mesothelioma.[15,16]
In conclusion, significant advances have been made in our understanding of the factors affecting the prognosis of malignant mesothelioma, and a number of biomarkers appear promising. However, at present it may be more fruitful to better define and characterize clinical factors that are well recognized as significantly impacting patient survival. Although tumor histology is the single most important predictor of survival, there is a need for pathologists, surgeons, and oncologists to better characterize patients with biphasic tumors. The significant diagnostic discordance reported between pleural biopsies and specimens obtained from surgical resections in biphasic tumors—and the resultant histologic subtype misclassification—has a direct impact not only on patient management but also on prognostication efforts. The second area that needs refinement is surgical staging; fortunately, this work is currently ongoing. Both the CALGB and EORTC prognostic criteria are simple and useful tools for elucidating patient prognosis, and they can be reliably used in routine clinical practice. Hopefully, validation of several promising genetic and molecular markers as described in the review by Dr. Mineo and Dr. Ambrogi will allow physicians to better stratify patients into different prognostic groups that will guide treatment decisions.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
