RESULTS
A total of 53 patients were included in the study. Median age was 58 years (range: 33?79 years). Mean duration of follow-up was 14 months (range: 4?82 months). Disease-free status and overall survival were 11 months (range: 3?50 months) and 14 months (range: 4?82 months), respectively. Factors that individually predicted better prognosis were younger age (<50 years), having undergone surgery, having received radiotherapy, and having undergone multimodality treatment.
CONCLUSION
Further comprehensive and randomized studies are required to better understand biological behavior of MPM in order to obtain more successful results in the management of the disease.
Keywords: Chemotherapy; malignant pleural mesothelioma; multimodality treatment; radiotherapy; survival
In this retrospective study, we reported the single institutional 7 years experience of the clinicopathologic and therapeutic characteristics and the factors affecting survival and the factors that individually predicted better prognosis in patients with MPM.
Clinical records of our Radiation Oncology Clinic registry were analyzed for sex, age, exposure to asbestos, Eastern Cooperative Oncology Group (ECOG) performance status, tumor cell type, lymph node involvement, stage of the disease, treatment modalities, chemo-and radiotherapy-related adverse events, follow- up period, response to treatment, site of metastasis and data on survival.
The patients were staged based on the pathologic
and clinical findings, including imaging studies, according
to TNM staging system proposed by the International
Mesothelioma Interest Group (IMIG) Staging.
[
Multimodality management
The choice of chemotherapy agent, dose, and
schedule were at the discretion of the treating medical
oncologist. Before chemotherapy administration, following
criteria were established; adequate bone marrow
function as indicated by: platelets ≥100 000/mm3
and hemoglobin 10 g/dL and neutrophils >1.5x103/
mm3; adequate renal function as indicated by serum
creatinine: <1.5 x the upper limit of normal; adequate
liver function as indicated by serum bilirubin level <1.5
x the upper limit of normal and AST or ALT less than
two times the upper limit of normal.
First and second line regimens were used in chemotherapy
for 46 patients. We used gemcyitabine and cisplatin for 13 of them, pemetrexat and cisplatin for 30
of them, 2 of them had adrioblastyn and one of them
had etoposyd.
Gemcitabine was administered 1200 mg/m2 on the
1st and 8th day, cisplatin 75 mg/m2 on the 1st day once in
every 21 days, pemetrexed 500 mg/m2 on the 1st day and
cisplatin 75 mg/m2 on the first day once in every 21 days.
After chemotherapy, radiotherapy was performed
in a group of patients for adjuvant or palliative purposes
for 26 patient. So that we didn"t have Conformal RT
or IMRT devices at the time of the study, we used Conventional
RT. Two different doses were applied; 55 Gy
were applied for 9 patients and 46 Gy were applied for
22 patients. The combination of photon and electron
was used as a radiotherapy technique. Patients who underwent
EPP were given 46 Gy beam in 23 fractions
covering whole hemithorax, mediastinum, surgical
and drainage scars and subsequently, higher doses were
administered, by protecting medulla spinalis and heart.
For cases who underwent partial pleurectomy or
who couldn"t be operated, a photon- electron combination
was preferred. The area of lung was determined in
conventional simulator and an appropriate block was
poured. 6-15 MV photon beam was given to peripheral
areas using linear accelerator (GE Saturn 41) by
providing lung protection and subsequently electron
energy of 9-12 meV was applied to the covered lung
volume from both front and back side.
Response to treatment and survival
Statistical methods
Several factors, including; age, gender, epithelial histology,
stage, type of treatment modality, type of surgical
intervention, chemotherapy regimen, the dosage of
radiotherapy were analyzed to whether they have any
influence on survival or not.
Data were entered in data base and statistical tests
were performed using SPSS 13. Kaplan-Meier method
was used in analysis of survival. P value was taken as
significant if found to be less than 0.05.
A group of patients were referred to our clinic after
surgery. Depending on whether the treatment goals
were palliative or curative, 4 surgical options were performed
for these patients. 11 patients had gone EPP, 6
patients had decortication, pleurodesis was established
for 5 of them, and two of them had radical pleuroctomy.
Extrapleural pneumonectomy (EPP) was defined
as an en bloc resection of the pleura, lung, ipsilateral
diaphragm, and pericardium. Radical pleurectomy/
decortication, which removed all gross tumor without
removing underlying lung, was performed in patients
who had minimal visceral pleural tumor or poor pulmonary
function.
Responses (complete response, partial response, stationary
disease and progressive disease) to treatment
were defined in accordance with the criteria by World
Health Organization (WHO handbook for reporting
of cancer treatment. Geneva) and post-treatment response
was assessed via thoracic CT or MRI. Time to
progression was defined as the time from diagnosis to
relapse, metastases or death due to other reasons before
development of relapse, whereas overall survival
was defined as the time from diagnosis to death.
In terms of histological subtypes, 35 patients (66%) were epithelial, three (5.7%) were sarcomatous, seven (13.2%) were mixed type and eight (15.1%) had undefined pathology.
In terms of stages, 17 patients (32.1%) were stage 1, 18 (34%) were stage 2, 7 (13.2%) were stage 3 and 11 (20.8%) were stage 4.
A total of 19 patients were referred to our clinic after surgery. Twenty- six patients combined treatment with radiotherapy plus chemotherapy and trimodality were performed in 12 patients, respectively. The treatments were in general well tolerated, but the serious adverse events were observed, including grade III-IV myelosuppression [Grading of hematologic toxicity was based on the NCI Common Terminology Criteria for Adverse Events version 3.0. Grade 3 (severe) and grade 4 (life-threatening) hematologic toxicities were noted as follows: hemoglobin (grade 3, <8 g/dl-6.5 g/ dl; and grade 4, <6.5 g/dl); neutrophils (grade 3, <1000/ mm3 -500/mm3 and grade 4, <500/mm3); and platelets (grade 3, <50,000/mm3 -25,000/mm3; and grade 4, <25,000/mm3)] and radiation pneumonia determined by physical examination and confirmed radiologically in 4 and 6 patients, respectively.
The mean duration of follow-up was 14 months (4- 82). The number of patients who responded to treatment was 29 (54.7%). Post-treatment response was assessed via thoracic CT or thoracic MR and complete response was achieved in two patients (3.8%) and partial response in 12 patients (22.6%). 34 patients (64.2%) had stable disease. Post-treatment progression was detected in 5 patients as locoregional relapse (9.4%). No abdominal relapse was observed. 17 of patients (32.1%) are still alive. Disease-free survival is 11 months (3-50) and overall survival is 14 (4-82) months. Although, survival according to gender was not detected to be significantly different (p=0.079), overall survival was established to be longer in women.
Overall survival and disease-free survival according to age were found to be higher in patients aged under 50 (p=0.04 for overall survival, p=0.033 for disease-free survival). Although epithelial histology was superior numerically to histological type in terms of overall survival and disease-free survival in the study, it did not reach statistical significance (p=0.682 for overall survival, p=0.617 for disease-free survival).
Overall survival was found to be statistically significantly higher in the group with surgery when compared to the group without surgery (p=0.007), while overall survival according to types of surgery was not statistically significantly different (p=0.909).
Overall survival was found to be statistically significantly longer in patients who received radiotherapy (p=0.001). Survival was observed statistically significantly higher in the group with both chemotherapy and radiotherapy (p=0.001).
Most importantly overall survival was found to be statistically higher in the trimodality group (p=0.01). Six (66.7%) of nine patients who were given radiotherapy over 50 Gy are still alive and 18 (81.8%) of 22 patients with lower than 50 Gy are alive. The effect of radiotheraphy dose on overall survival was not statistically significant (p=0.677).
The remaining parameters failed to be significantly associated with survival in the univariate analysis.
Since respiratory exposure to asbestos which plays
a pivotal role in the etiology pleura is the most commonly
(90%) encountered location.[
In a number of series published, exposure to asbestos
has been reported in 50-80% of cases with malignant
pleural mesothelioma. In our study, six (11.3%)
patients declared exposure to asbestos by anamnesis.
Mesothelioma is a well-known complication of
therapeutic radiation for lymphoma, breast cancer,
lung cancer, and other malignancies. Patients with
Hodgkin lymphoma, for example, experience a 20-fold
increased risk of mesothelioma after radiotherapy.[9]
As a matter of fact, we identified the asbestos exposure
just in 6 (11.3%) patients.
The mean age of presentation in malignant pleural
mesothelioma is 60 years.[
Several factors affecting prognosis in malignant
pleural mesothelioma include age, gender, serum LDH
level, thrombocyte count and performance status.
However, a number of studies published have reported
that early stage (Stage-I and II), epithelial type, N0 disease
and complete resection enhance survival.[
A study of 183 patients by Sugarbaker et al. concluded
that patients with epithelial histology had a superiority
over other histological types in terms of overall
survival (the mean overall survival is 26 months for
epithelial type (p=0.001).[
In a number of studies, mean survival has been
reported to be 4-12 months in patients with nonepithelial
histology.[
Our patient"s main clinicopathologic characteristics
is similar to the other main clinicopathologic characteristics
of MPM patients. Epithelial type was the most
common tumor histologic type. However, only a small
number of patients were given multimodality therapy.
By analyzing all, the prognosis of our series was dismal:
overall survival is 14 (4-82) months.
Our data reveal the individual effect on survival of
the following patient-related survival factors: younger
age (<50 years), having undergone surgery, having received
radiotherapy, having undergone combined chemotherapy
and radiotherapy and finally having undergone
trimodality treatment.
Recent studies have focused on the identification
and evaluation of potential prognostic factors for survival
in MPM patients. According to Borasio et al.
significant predictors of survival include performance
status, platelet count, histology and degree of involvement
of pleural cavity.[
Treasure T. et al. aimed to assess the clinical outcomes of patients who were randomly assigned to EPP
or no EPP in the context of trimodal therapy in the
Mesothelioma and Radical Surgery (MARS) feasibility
study. 23 patients in the EPP group and 26 in the no
EPP group consented to quality-of-life assessment and
12 and 19 patients completed the quality-of-life questionnaires,
respectively. Median quality- of-life scores
seemed to be lower for the EPP group than the no EPP
group, with the lowest median score shortly after surgery;
however, there were no statistically significant
differences between treatment groups.[
A few of the major limitations of our series are the
retrospective nature of the study, limited number of patients,
particularly in subgroups analysis, and lack of
control group; however, we tried to compare our data
with available data in the literature.
In conclusion, this retrospective study reflects the
single institutional 7 years experience on consecutive
cohort of pathologically confirmed MPM patients who
referred to our radiation oncology clinic and treated
with combined or multimodality treatment strategy
including surgery, chemotherapy and radiotherapy.
Disease-free survival is 11 months (3-50) and overall
survival is 14 (4-82) months in our series. Factors that
individually predicted better prognosis were younger
age (<50 years), having undergone surgery, having
received radiotherapy, having undergone combined
chemotherapy and radiotherapy and finally having undergone
trimodality treatment. Further comprehensive
and randomized studies are required to understand
better biological behaviour of MPM and to obtain
more successful results in the management. Hence,
currently the most appropriate approach should be a
modality treatment in accordance with characteristics
of the patient.
Disclosure Statement
The authors declare no conflicts of interest.
