Treatment of Malignant Pleural Mesothelioma

Treatment of Malignant Pleural Mesothelioma. Malignant Pleural Mesothelioma is an asbestos -related disease along with rising incidence. Diagnosis is regularly late in the path of the disease due to its insidious onset. Treatment is difficult due to the natural resistance of this tumor-entity. The diagnostic work-up as well as therapeutic choices are outlined in this review article.

I. Introduction Malignant Pleural Mesothelioma

Before 1950, Malignant Pleural Mesothelioma (MPM) was a pretty rare condition. along with the rising use of asbestos after Globe War II it became much more frequent. In the early nineteen-sixties the link between asbestosexposure and MPM was initial recognized (Wagner and Sleggs, 1960; Thomson 1963). Asbestos exposure is either occupational or environmental. The latter can easily be as a result of air pollution by asbestos-processing facilities or “natural” exposure in the soil (Constantoupolos et al, 1985).
Although the use of asbestos was widely abandoned because 1980 in the western countries, the incidence of MPM will certainly go on to rise until approximately 2020 (Peto et al, 1999). This is as a result of the long latency between asbestos exposure and development of MPM (up to 58 years) (Kroidl et al, 2000).
Other risk factors for the development of MPM are the simian-virus 40 (SV-40) and ionizing radiation. SV-40 DNA can easily be found in approximately 60% of MPM however likewise in ependymomas, brain and bone tumours (Rizzo et al, 1998). The virus is a potent inhibitor of tumoursuppressor genes and is considered a co-factor in carcinogenesis. Simian virus 40 was a contaminant in polio vaccines administered to 10-30 million people in the United States, mostly children, between 1955 and 1963 (Stratton et al, 2002). However, the role of the virus in the pathogenesis of MPM is yet unproven (MacLachlan 2002; Rate and Ware 2004).
The use of the radioactive, alpha-emitting contrast medium 232ThO2 (Thorotrast®) is yet another risk factor. Up Thorotrast produced MPM (Andersson et al, 1995). There is likewise a greater incidence of MPM in survivors of the Hiroshima and Nagasaki nuclear attacks (White and Abratt 2005).
In summary, the crucial risk factor for MPM is undoubtedly asbestos which is responsible for approximately 70-90% of cases (Yates et al, 1997). MPM is a devastating disease along with a grim prognosis. Median survival ranges from approximately 4 to 18 months depending on the histological subtype (sarcomatous has actually a worse prognosis compared to epithelial subtype), tumour stage and some patient derived factors (general condition, age, weight loss, pain, platelets, asbestos exposure) (Manegold et al, 2006). In a collection of 49 consecutive patients at our institution median progression free survival was 8 months (Figure 1).

II. Diagnosis of MPM

A. Signs and Symptoms

The onset of symptoms in MPM is subtle and nonspecific, so diagnosis is regularly late in the path of disease. The majority of patients present along with dyspnea and/ or chest pain (Lee et al. 2000). Fatigue, fever and night sweats are likewise common.

B. Imaging techniques

The initial diagnostic step after clinical examination is a chest X-ray. The most frequent finding here is a pleural effusion (Lee et al, 2000).

Heigener et al: Treatment of malignant pleural mesothelioma

In one collection the majority of MPM is located on the right side, in 5 percent of cases there is a bilateral involvement (Antman 1981). But in our patients there were no bilateral manifestations and 65% right-sided locations in a collection of 49 consecutive patients (unpublished data).
The next diagnostic step once MPM is suspected need to be a computed tomography or a nuclear magnetic resonance imaging (NMR) of the chest. The former is much more available compared to the latter and of nearly similar accuracy. NMR provides little much more short article concerning chest wall and diaphragm invasion (Heelan et al, 1999). The addition of positron-emitting tomography (PET) can easily recommendations distinguish between benign pleural thickening and foci of malignancy and makes mediastinal lymph-node staging much more accurate (Wang et al, 2004).
However this way is not readily available in lots of institutions. MPM is characterized by local spread involving the mediastinal lymph nodes. There are lots of case reports regarding distant metastases in MPM, But in general they seldom occur. Therefore we do not perform any sort of timetable imaging technique (i.e. bone-scintigraphy or NMR of the brain) beyond thoracical imaging.
Staging need to be done based on the TNM staging system by the Worldwide mesothelioma interest group (IMIG): the T-descriptors are designated as T1 to T4 describing the local extend of the tumour. T1 is localized disease on the pleura (T1a: parietal pleura only; T1b: involvement of visceral pleura), T2 describes diaphragmal or direct lung involvement, T3 describes involvement of the endothoracic fascia or mediastinal fat (locally advanced however technically resectable) and T4 the diffuse invasion of the chest wall, peritoneum, spine, peri- or myocard as well as the contralateral pleura (locally advanced, unresectable). The N-descriptors N1 to N3 are identical as the ones used in the staging of lung cancer: N1 describes ipsilateral pulmonary or hilar nodes, N2 ipsilateral or subcarinal mediastinal nodes and N3 contralateral mediastinal or supraclavicular nodes. M0 denotes the absence and M1 the presence of distant metastases. The corresponding stages are shown in Table 1 (Rusch 1995).

B. Achievement of a tissue diagnosis

Evidence of MPM in pleural fluid is found in 33- 84% of cases (Whitaker 2000). Aspiration-cytology of pleural fluid (if present) is individual however lacks sensitivity. The latter can easily be improved along with the measurement of hyaluronic acid in the pleural fluid which is markedly elevated in MPM compared to Various other malignant effusions (Welker et al, 2007). Nevertheless, obtaining a histological specimen is regularly important for an exact diagnosis. Image guided, trans -thoracical core-biopsies lack direct visualisation of the tumor and therefore carry a greater risk of false-negative results compared to direct thoracoscopic forceps-biopsy either in local anaesthesia or video-assisted under general anaesthesia (VATS). Immunhistochemistry need to be performed for an exact diagnosis. Typical positive markers are calretinin (epithelial subtype), MNF 11six and AE1/ AE3 cytokeratins, vimentin and lots of much more (Mueller 2005).

C. Serum markers

Two markers deserve special consideration: Serum mesothelin-related protein (SMRP) and serum
osteopontin. SMRP has actually a sensitivity of 83% and a specifity of 95% in detecting MPM in one study. There are likewise level-modifications parallel to the tumour size, suggesting that it may be a good diagnostic tool for monitoring (Robinson, 2005). The addition of the tumour-marker CA125 did not improve sensitivity (Creaney et al, 2007).
Serum osteopontin is significantly elevated in patients along with asbestos exposure and MPM compared to patients along with asbestos exposure alone (Pass, 2005). It appears to have actually a lower diagnostic accuracy compared to SMRP as a result of its
Table 1. Stages of MPM (Rusch, 1995)
Stage                       TNM
Ia                             T1aN0M0
Ib                             T1bN0M0
II                             T2N0M0
III                           any sort of T3M0; any sort of N1M0; any sort of N2M0
IV                           any sort of T4, any sort of N3; any sort of M1
low specifity (Grigoriu, 2007). However, by now -lacking large validation series- both markers are not routinely used in our clinical practise.

III. Therapy of MPM

A. Role of radiation therapy

External beam radiation of the hemithorax as a single treatment of MPM has actually no effect on survival (Baldini 2004). But some collection suggest that it may have actually its place in a multimodality approach to improve local control, especially once using modern techniques (see below) (Rice et al, 2007; Lee et al, 2002; Rusch et al, 2001). yet another questionable indication for radiotherapy in MPM is the irradiation of surgical wounds and drainagesites, fearing that otherwise the tumour will certainly spread to the subcutaneous layer along the surgical tract.
There are three small randomized controlled trials and some case series. One of the controlled trials showed a small benefit on local regulate (Boutin et al,1995) and the Various other two showed no benefit at all (Bydder et al, 2004; O´Rourke et al, 2007). In one case collection of 85 consecutive patients treated along with different chemotherapy regimens devoid of radiation none produced surgical tract metastasis (Pinto et al, 1995). As a result, the practise is discussed along with considerably controversy and we do not recommend this procedure routinely Even though it is implemented in the guidelines of the British Thoracic Society (British
Thoracic Society Standards of Care Committee, 2007). External beam radiation is moderately effective in the reduction of pain as a result of MPM. In one case collection of 189 patients 50% had a benefit in terms of pain regulate once 3six Gray in 4- Gray fractions were used. But pain recurred in a median of 69 days (de Graaf- Strukowska et al, 1999). In a review on that topic, pain relief is described for 50 to 70% of patients (Baldini 2004).

B. Role of surgery

There are mainly two surgical approaches to MPM. initial there is a very aggressive option, the extrapleural pleuropneumectomy (EPP) or a solely cytoreductive procedure: decortication and/ or pleurectomy. The latter can easily sometimes be performed via VATS. A case collection describing the trimodality approach of EPP plus consecutive chemoradiation showed a five-year survival fee of 22%. 
But this was a chosen group of patients and a regulate group was lacking (Sugarbaker and Norberto 1998). In yet another trial the two surgical procedures were compared, showing a benefit in progression free survival for EPP (319 vs. 197 days, p= 0.019) however only a non substantial benefit favouring EPP in overall survival (497 vs. 327 days, p=0.079) (Stewart et al, 2004). In both papers the involvement of mediastinal lymph nodes was a predictor of poor survival. To date a large randomized trial is ongoing to clarify the role of radical surgery in MPM (Treasure et al, 2006).

C. Role of medical therapy

1. “Older” Regimens

Numerous trials have actually been conducted in the 1980´s and 1990´s along with various cytotoxic agents in the treatment of MPM. Focussing on remission there were some agents along with moderate efficacy: the anthracyclines, platinum compounds, alkylating agents, mitomycin C and antimetabolites. However, these results were only based on small case series. No large randomized controlled trials were available and the impact on survival was not clarified (Ryan et al, 1998). There were likewise some case collection along with combination therapies however there was no clear evidence for superiority over monotherapies (Ryan et al, 1998).

2. Vinca-Alkaloids

Two modern vinca-alkaloids reveal promising activity in phase II-trials in MPM: Vinorelbine and vinflunine.
Vinorelbine was tested in a weekly infusion regimen in 29 patients. 24% of patients attained a partial response and 55% had constant disease. There was likewise some improvement in quality of life (Steele et al, 2000). But the patient number was small and phase III studies are clearly needed. 67 patients were enrolled in a phase- II study along with vinflunine. Response fee was 13.8% and median survival was 10.8 months (Talbot et al, 2007).

3. Gemcitabine

There are several Phase-II studies of either gemcitabine alone ore in combination along with cisplatin (Kindler et al, 2002). Monotherapy failed to reveal substantial activity in two trials (van Meerbeeck et al, 1999; Kindler et al, 2001). The combination attained up to 47.6% partial responses (Byrne et al, 1999). However, as along with vinorelbine, phase-III data are lacking.

4. Taxanes

There is only sparse data on paclitaxel in MPM. One trial showed only 9% remissions along with high-dose paclitaxel
(Vogelzang et al, 1999). Docetaxel likewise showed at most mildly efficacy as monotherapy (Vorobiof et al, 2002;
Belani et al, 2004). likewise in combination along with irinotecan, the results are disappointing (Knuutila et al, 2000).

5. Antifolates

Alpha folate receptor protein is overexpressed in MPM-Cells in approximately 70% of cases. This may explain the responsiveness to antifolate drugs (Bueno et al, 2001) as shown in a group of 60 patients receiving higher dose methotrexate. There were 37% responses along with one finish response (Solheim et al, 1992).
In the start of this century, a brand-new multi-targeted antifolate, pemetrexed, was evaluated for its efficacy in MPM. A phase II -trial including 64 patients showed an overall response fee of 14.1% for monotherapy along with the substance. Interestingly, overall survival (OS) was greater in those patients that were supplemented along with folic acid and vitamin B12 (13 months OS vs 8 months in the not supplemented group).
Moreover, neutropenia was lower in the supplemented group (4 grade ! neutropenias in the supplemented group vs. 11 in the non-supplemented group) (Scagliotti et al, 2003). However, due to the small subgroups no definite conclusion could be drawn on the impact of vitamin supplementation. A phase III trial along with 45six enrolled patients compared pemetrexed and cisplatin along with cisplatin alone (Vogelzang et al, 2003). This was the initial trial ever in MPM showing a substantial survival advantage for a chemotherapy regimen along with a median survival of 12.1 months for the cisplatin/ pemetrexed-arm vs 9.3 months for cisplatin alone (p=0.02). Again, toxicities were significantly reasonable after adding folic acid and vitamin B12 to the regimen.
The combination of cisplatin and pemetrexed can easily now be considered standard initial line therapy in MPM in those patients, that can easily tolerate this fairly toxic regimen. due to the considerably toxicity of cisplatin, it is sometimes replaced by carboplatin for patient comfort in this palliative setting (Figure 2). yet another combination along with an antifolate drug along with some efficacy in a phase II trial are oxaliplatin and ralitrexed. 70 patients were enrolled, the overall response fee was 20% and one year survival was 26% (Fizazi et al, 2003).
There is one case collection suggesting that pemetrexed likewise has actually efficacy in second-line treatment after a platinumcontaining doublet (mostly platinum/ vinorelbine). In patients treated along with carboplatin + pemetrexed (n=11) there were 18% responses along with a median time to progression of 32 weeks. In patients treated along with pemetrexed alone the numbers were 21% and 21 weeks respectively. Median survival was 39 weeks and 42 weeks respectively (Sorensen et al,2007).

6. “Biologicals”

Although endothelial-growth factor-receptor (EGFR) is overexpressed in the majority of MPM (Dazzi et al,
1990), the inhibition of the downstream signalling of EGFR by means of erlotinib does not seem to work. In a study along with 64 patients along with MPM, 75% of tumours showed higher expression of EGFR. But treatment along with erlotinib did not result in any sort of target remission (Garland et al, 2007). The need may be, that easy overexpression of EGFR is not predictive of response to erlotinib in Various other cancers. Only EGFR-mutations seem to have actually some predictive value.
The antisense-oligonucleotide ranpirnase blocks the 30S-subunit of the ribosome and interferes along with protein
synthesis. In a phase-II trial a median survival time of 18.5 months was observed (Mikulski et al, 2002). These results encouraged to perform a phase-III study comparing doxorubicin and ranpirase along with doxorubicin alone. The recruitment was finished recently and the results are pending.

D. Multimodality treatment

As described above, multimodality treatment approaches seem to be promising in a chosen group of MPM patients, those in a good performance status (Sugarbaker and Norberto, 1998). In yet another case collection focussing on prognostic factors in MPM, the data suggest that surgery within a multimodality approach improves survival much more compared to surgery alone (pleurectomy or EPP: 10.3 months median survival; pleurectomy or EPP plus chemotherapy and external beam radiotherapy: 20.1 substantial difference between pleurectomy and EPP in terms of survival once used as a single-modality (median survival 15.8 vs. 14.3 months) (Flores et al, 2007). In a phase-II trial the combination of hyperthermia (41.8° Celsius physique temperature) along with chemotherapy (ifosfamide, carboplatin and etoposide) resulted in a response fee of 20% and a two-year survival of 20% (Bakhshandeh et al, 2003). But to date, no phase-III
data were present to support this approach.

E. Palliative Treatment

Because of the devastating path of the disease almost all patients reason sufficient palliative care. Main symptoms are
pain and dyspnoea. Pain can easily be either neuropathic as a result of infiltration of intercostal nerves or somatic as a result of chestwall involvement. regularly there is a combination of both. Somatic pain responds to non-steroidal analgesic drugs and opiates. Neuropathic pain need to be managed along with opiates and co-analgesics enjoy antidepressants (i.e. amitryptiline) or anticonvulsants (i.e. carbamazepine, pregabaline; Doyle et al. 2004).
Dyspnoea results from pleural effusion as well as entrapment of the lung by the pleural tumor. Pleurodesis
either by VATS or pleuroscopy need to be done in the former case. But the latter calls for symptomatic
treatment along with opioids (Lee, YC, 2002).

IV. Summary

MPM is notoriously resistant to therapy. Moreover the natural path can easily vary widely from only a few months of survival to several years. due to the diffuse growth pattern, treatment response is not simple to evaluate and inter-observer differences can easily be great.

All these factors make good clinical trials difficult to perform and lots of troubles continue to be unanswered. As a handy approach we recommend to establish the diagnosis via VATS in patients along with adequate performance status or via pleuroscopy. along with the former, pleurectomy/ decortication can easily be done. The role of radical surgery (EPP) has to be clarified. Afterwards chemotherapy along with platinum and pemetrexed need to be made.
Radiotherapy is indicated for palliative reasons (i.e. pain control) however not for tumour reduction. In patients along with poor performance status monotherapy along with pemetrexed is a reasonable option. However, these tips lack clear evidence which will certainly hopefully come along with further clinical trials. David F. Heigener

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