Trial Information

"Phase II Study: Palliative Treatment With Liposomal Doxorubicin Plus Cisplatin for Patients With Malignant Pleural Mesothelioma "

Background:

Malignant pleural mesothelioma (MPM) is an invasive primary neoplasm associated with a rapid
progression. It is usually diagnosed in the fifth to seventh decades of life, with a strong
male predominance. 80% of the patients with MPM have a history of asbestos exposure. MPM
develops only in 10% of the people with asbestos exposure, suggesting that other factors may
be important in the development of this malignancy. MPM is classified into three
pathological types: epithelial, sarcomatoid, and mixed. The epithelial type represents 50%
of all the cases whether the sarcomatoid type the15%. Clinically the sarcomatoid type is
related to a poorer prognosis compared with epithelial or mixed types MPM presents unique
challenges with regard to diagnosis, staging, and treatment. Survival rates are
approximately 6 months in patients without surgical treatment. 90% of the patients with MPM
are not candidates for a surgical treatment because they arrived at advanced stages or with
a poor lung function. In addition, surgery as a single modality has failed to improve
survival, and several researches have explored the use of combined modality therapy
incorporating radiation and chemotherapy. Given that the prognosis for patients with
advanced MPM is poor regardless of the type of anticancer treatment, palliation of symptoms
has been the primary goal. Chemotherapy remains the main palliative therapeutic modality,
although either surgical intervention or local radiation therapy may be useful for the local
control of pain or symptoms often associated with pleural fluid accumulation.

Most single chemotherapeutic agents have been tested in MPM obtaining response rates of <
20%. The impact of chemotherapy on the survival of patients with MPM remains uncertain.
Platinum analogues have been extensively studied in MPM both single and combined regimens.
There have been studies of patients with MPM treated with cisplatin 60 mg/m2 and doxorubicin
60 mg/m2 on day 1 with a 3 or 4 week interval demonstrating response rates of 20 to 25%
with and overall survival of 10 months.

Liposomal doxorubicin (LD) consists on doxorubicin encapsulated in liposomes that are
composed of phosphatidylcholine and cholesterol. LD can extravasate into tumors with
abnormal vascular endothelium but may not penetrate normal tissues lowering its toxicity and
increasing its efficiency. Combining LD with cisplatin could be an effective new
chemotherapy treatment for MPM.

Objective:

Increase chemotherapy response rates, progression free survival and overall survival in
patients with MPM treated with LD plus cisplatin as a palliative treatment for MPM.

Methods:

We conducted a prospective analytical study between September 2006 and April 2009. Thirty
patients with epithelial, sarcomatoid or biphasic histological confirmed diagnosis of MPM
from the Instituto Nacional de Cancerología and the Instituto Nacional de Enfermedades
Respiratorias were included to receive LD 60mg/m2 plus cisplatin 80 mg/m2 every 4 weeks for
6 cycles. During the first cycle of chemotherapy, a scintigraphic image study was done with
LD labeled with Tc-99m (LD-Tc-99m). The imaging study (SPECT/CT) was done 1h after
administration to evaluate biodistribution and accumulation of LD-Tc-99m in tumoral tissue.
Patients were evaluated by a surgeon after 2 cycles of chemotherapy, if surgery was not
possible, chemotherapy continued until tumor progression. Clinical and biochemical
evaluations were obtained before chemotherapy administration. An axial computed tomography
was requested before chemotherapy and every 2 months in the first 6 months and every 4
months during following 2 years. Treatment response was according to RECIST criteria and
toxicity was evaluated with National Cancer Institute Common Toxicity Criteria version 3.0.
The statistical analysis was made using SPSS v.10 software. For descriptive purposes,
continuous variables were summarized as arithmetic means, medians, and standard deviations;
and categorical variables with 95% confidence intervals. Disease-free progression and
over-all survival were evaluated by Kapplan-Meier.