Systemic Treatment of Malignant Pleural Mesothelioma

Future Perspective

Only modest improvements in the systemic treatment of MPM patients have been made in the last decade, after the presentation of the results of the EMPHACIS Phase III study, which led to the registration of pemetrexed and cisplatin in this disease. With the continued worldwide increase in MPM, there is an urgent need for more effective treatment.

Recent research has pointed out that individuals carrying a mutation in the BAP1 gene are at greater risk of developing mesothelioma and uveal melanoma. Unfortunately, this finding has so far had no impact on the treatment of this tumor, since no curative intervention is available; however, it represents a crucial advance in understanding the biology of mesotheliomas and emphasizes the importance of a detailed genetic analysis of human tumors.^[99]

A potential strategy to improve the efficacy of chemotherapy is represented by customization of treatments through the identification of predictive markers of chemotherapy sensitivity. Ongoing trials are investigating TS and ERCC1 as possible markers for pemetrexed and cisplatin, respectively.

Many novel agents have been recently explored, often with only tenuous rationale for testing, sometimes based only on mechanisms that were successfully exploited in other cancers. Targeted therapies invariably resulted in a very limited RR with an overall discouraging median PFS and OS. Here, one of the major unsolved questions is whether objective response should still be considered an appropriate end point for therapeutic efficacy for targeted therapies, especially in a disease with a peculiar growing pattern that is different from other diseases, such as lung cancer, and where Response Evaluation Criteria In Solid Tumors (RECIST) apply poorly. PFS should be the preferred primary end point of future studies exploring the activity of targeted agents in this disease.

Although rare, the detection of some objective responses and the prolonged disease control seen in a few MPM patients treated with targeted therapies might indicate that a subset of patients could definitely benefit from these treatments. The molecular biological research should focus on specific pathways and biomarkers to define these sensitive patients in order to maximize the efficacy of targeted agents. Translational studies aimed at improving the knowledge of tumor biology and, therefore, at identifying druggable targets and biomarkers are the priority for future studies. A novel and interesting field of research concerns miRNAs; post-transcriptional regulators of the expression of target genes that may behave as oncogenes or tumor suppressors. Specific miRNAs are dysregulated in mesothelioma and some of these miRNAs may represent potential targets for new therapeutic approaches.^[100] Advances in mesothelioma therapy can indeed solely derive from well-designed clinical studies addressing the role of treatments as directed by the molecular profiling of the individual patients tumor. The key point to allow these and future studies is the availability of an adequate amount of tumor tissue from biopsies. Also, for these reasons, patients' referral to centers with dedicated multidisciplinary teams is strongly recommended.

Acknowledgments
No writing assistance was utilized in the production of this manuscript.

Table 1. Selected Phase II and III studies of combination and single-agent chemotherapy trials as first-line therapies.
Chemotherapy	Phase	Patients (n)	RR (%)	Median PFS (months)	Median OS (months)	Ref.
Chemotherapy vs ASC alone	III	409	12.0	5.6 vs 5.1	8.5 vs 7.6	[17]
Cisplatin + pemetrexed vs cisplatin	III	456	41.3 vs 16.7	5.7 vs 3.9	12.1 vs 9.3	[20]
Cisplatin + pemetrexed vs Carboplatin + pemetrexed	EAP EAP	843 861	26.3 21.7	7.0 6.9	63% (1 year) 64% (1 year)	[26]
Cisplatin + raltitrexed vs cisplatin	III	250	23.6 vs 13.6	5.3 vs 4.0	11.4 vs 8.8	[27]
Pemetrexed	II	64	14.1	4.7	10.7	[36]
Vinorelbine	II	29	24.0	Not available	10.6	[37]

ASC: Active symptoms control; EAP: Expanded access program; OS: Overall survival; PFS: Progression-free survival; RR: Response rate.

Table 2. Selected studies of second-line chemotherapy.
Regimen	Phase	Patients (n)	RR (%)	PFS (months)	Median OS (months)	Ref.
Pemetrexed vs BSC	III	243	DC 59.0 vs 19.0	3.6 vs 1.5	8.4	[40]
Vinorelbine	II	63	16.0	Not available	9.6	[43]
Vinorelbine + gemcitabine	II	30	10.0	2.8	10.9	[44]
Gemcitabine + epirubicin	II	23	13.0	6.3	9.3	[45]
Cisplatin + pemetrexed Pemetrexed	EAP	96 91	32.0 5.0	Not available	7.6 4.1	[41]
Pemetrexed	EAP (pretreated)	396	12.1	6.0	Not available	[42]

BSC: Best supportive care; DC: Disease control; EAP: Expanded-access program; OS: Overall survival; PFS: Progression-free survival; RR: Response rate.

Table 3. Selected studies on target agents in mesothelioma.
Novel agent	Phase	Patients (n)	Median PFS (months)	Median OS (months)	Ref.
Gefitinib	II	43	2.6	6.8	[58]
Erlotinib	II	63	2.0	10.0	[59]
Bevacizumab + CG vs CG	II	115	6.9 vs 6.0	15.6 vs 14.7	[66]
Vatalanib	II	47	4.1	10.0	[67]
Sorafenib	II	51	3.7	10.7	[72]
Sunitinib	II	23	3.5	5.9	[74]
Valproic acid + doxorubicin	II	45	2.5	6.7	[89]
NGR–hTNF	II	57	2.8	12.1	[90]

CG: Cisplatin + gemcitabine; hTNF: Human TNF-α; OS: Overall survival; PFS: Progression free-survival.

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

My Alerts