T1
Tumor limited to ipsilateral parietal pleura
T1a
No involvement of visceral pleura
T1b
Some scattered foci involving visceral pleura
T2
Tumor involving entire ipsilateral pleura, both visceral and parietal
Plus, invasion of diaphragmatic muscle
Or, confluent involvement of visceral pleura, including the fissures
Or, invasion from visceral pleura into pulmonary parenchyma
T3
Tumor locally advanced but potentially resectable
T4
Tumor locally advanced but technically unresectable
NX
Regional nodes cannot be assessed
N0
No lymph node metastasis
N1
Metastasis to ipsilateral bronchopulmonary or hilar lymph nodes
N2
Metastasis to subcarinal or ipsilateral mediastinal nodes
N3
Metastasis to contralateral mediastinal or internal mammary nods, or to any supraclavicular node
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis present
Stage
Description
Stage I
Ia
T1aN0M0
Ib
T1bN0M0
Stage II
T2N0M0
Stage III
Any T3M0
Any N1M0
Any N2M0
Stage IV
Any T4
Any N3
Any M1
EPP is a complex operation where the lung, pleura, pericardium, and diaphragm are resected en bloc [15]. It is performed via a single-extended posterolateral thoracotomy that is then followed by careful extrapleural dissection that is carried over up to the apex of the chest and peeled off the subclavian vessels around the hilum and down to the central tendon. On the left, the aorta is evaluated for possible invasion and care is taken while removing tumor from the aortopulmonary window by ensuring that the recurrent laryngeal nerve is preserved. On the right, care is taken to avoid avulsion of the azygos and injuring the thoracic duct, which can also be ligated to avoid getting a postoperative chyle leak. The phrenic nerve is typically visualized and preserved unless the tumor encases the nerve or the diaphragm is involved which would require its resection anyway, and hence preservation of the phrenic nerve is not necessary. Occasionally, the superior vena cava can have tumor involvement that can be resected and reconstructed with or without the assistance of a cardiovascular surgeon. Pulmonary vein and arterial dissection around the hilum is carried out carefully and if the hilum seems to be too difficult to dissect, an intrapericardial pneumonectomy may be warranted. The bronchus is divided and either sewn or stapled; the margins are checked intraoperatively. Once deemed clear of tumor, the bronchial stump is typically covered with either omentum, intercostal muscle harvested during the thoracotomy, or pleura.
A P/D, on the other hand, starts off with an extrapleural dissection but eventually requires entering the pleural space and carefully removing the parietal and visceral pleura [15]. If the pericardium or diaphragm is noted to be involved on either side, they are resected to achieve negative margins. In order to prevent cardiac herniation, a fenestrated prosthetic patch (Goretex, W.L. Gore and Associates, Flagstaff, AZ) is placed and anchored circumferentially to prevent pericardial effusion and tamponade. The diaphragm is also reconstructed with two pieces of prosthetic mesh that are overlapped to create a dynamic seam and prevent herniation of abdominal contents into the chest. The patch is then secured to the chest wall, central tendon, and pericardium circumferentially using 0-Ethibond sutures. Usually, if the institution offers intraoperative chemotherapy , the pericardial and diaphragmatic reconstruction is saved for after completion of intrapleural chemotherapy treatment (see below).
Because local recurrence limits patient survival in this disease, recent studies have studied and demonstrated that intrapleural heated chemotherapy administered at the time of surgery, can extend interval to recurrence (27.1 vs. 12.8 months), and patient survival (35.3 vs. 22.8 months) [16, 17]. This heated intraoperative chemotherapy (HIOC) protocol entails administering cisplatin as a 1-h lavage of the chest and/or abdomen, in case of diaphragmatic resection, at 42° after completion of EPP or P/D, when minimal tumor burden is present. The toxic effects of the drug are balanced with the administration of intravenous (IV) sodium thiosulfate and amifostine. Argon beam is used to ablate the chest wall, mediastinal wall, and diaphragm after the HIOC run to attain microscopic cytoreduction of any disease left behind.
There are multiple potential complications that are associated with either surgical approach. The most common ones that we encounter are postoperative dysrhythmias, myocardial infarction, prolonged intubation secondary to air leak, aspiration, or acute respiratory distress syndrome, deep venous thrombosis and pulmonary embolism requiring either anticoagulation or inferior vena cava (IVC) filter placement, pulmonary hypertension, vocal cord paralysis, stroke, empyema, bronchopleural fistula, and patch dehiscence requiring a return trip to the operating room. Postoperative renal failure is another potential risk from the HIOC despite the pharmacologic protection.
The goal of surgery in the multimodality treatment of MPM is to dramatically reduce tumor burden such that tumor ablation with the argon beam and HIOC can potentially eradicate microscopic disease, and thereby decrease the incidence of tumor recurrence. Although surgery is offered to patients with MPM, clinicians should caution offering these surgeries to patients with poor prognostic features, advanced disease, and mediastinal node involvement, as these patients demonstrate poor long-term survival.
Radiation Therapy
Radiation therapy uses high-energy X-rays to kill cancer cells. More than 50 % of cancer patients receive radiation therapy as part as their overall treatment plan. Patients usually receive external-beam radiation therapy in daily treatment sessions (5 days a week) over the course of several weeks. The number of treatment sessions depends on the treatment intent, cancer type, stage, and patient’s performance status (PS).
Radiation is used in the treatment of MPM mainly for local control. It can be used for radical treatment, part of multimodality treatment after P/D or EPP as well as palliation. However, treatment with radiation therapy in MPM is hampered by the challenge to deliver tumoricidal doses while minimizing toxicity. This is owing to the large volume to be irradiated including the entire hemithorax with many adjacent critical radiosensitive structures (heart, lung, spinal cord).
The target volume of adjuvant radiation therapy after pleurectomy or EPP includes the entire visceral and parietal pleura of the side involved. This includes not only the outer lung surface but also along the fissures in cases of pleurectomy alone. Because the lung remains in place after pleurectomy, radiation doses must be lower than when EPP is performed [18]. Initial treatment of the hemithorax with radiation delivered using a photon/electron combination was developed at Memorial Sloan Kettering Cancer Center (MSKCC) in the 1980s [19]. In this technique, a radiation block is used to shield the central portion of the lung, heart, spinal cord, and liver, which limits the total dose to the pleural surfaces .
Even after oncologic surgical procedures, there is a high rate of local recurrences. There have been numerous reports of the use of adjuvant radiation therapy after pleurectomy using the photon/electron match technique in which areas of the target receive less than the prescribed dose . The largest study was published by Gupta where the mean radiation dose was 42.5–45 Gy [20]. Unfortunately, the median survival was only 13.5 months with 28 % of patients developing grade 3–4 toxicity after radiation therapy and a palliative surgical procedure. Radiation therapy after EPP is also complex, however, since the entire ipsilateral lung is removed; this does provide a certain advantage by decreasing the potential toxicity from pneumonitis. Using conventional radiation techniques with the photon/electron match technique, the MSKCC group showed promising results [21]. In a phase II trial of induction chemotherapy , EPP, and postoperative radiation therapy, median survival of 33.5 months was achieved, and there was no patient with grade 3 or higher toxicity [22].
Despite improvement in local control with adjuvant conventional radiation therapy, local control and toxicity rates were not ideal. The field of radiation therapy has advanced significantly over two decades with new technology and planning systems allowing for complicated treatment planning and delivery. Intensity-modulated radiation therapy (IMRT) improves the efficacy of higher radiation doses to the entire target volume while minimizing radiation dose to critical surrounding structures by creating a highly conformal radiation plan (Fig. 7.1) . Recent advances with image-guided radiation therapy (IGRT), have improved the accuracy of radiation delivery, and thus reduced the treatment margin leading to further decrease in the volume of normal tissues receiving high-dose radiation. The reduction of radiation dose to normal structures allows for decreased toxicity involving all critical organs, especially the lungs .
Fig. 7.1
An example of IMRT treatment planning
Initial multimodality treatment using IMRT showed troubling result with increased pulmonary toxicity of the single lung. MD Anderson Cancer Center (MDACC) used IMRT by dose-escalating patients after EPP to 50 Gy with a boost to 60 Gy to positive margins. In an updated MDACC publication by Rice, the local recurrence rate for 63 patients treated with IMRT after EPP was only 13 %; however, early mortality was significant with 23 deaths within 6 months [23]. Another early study using IMRT supported lower recurrence rate of 14 % vs. 42 % for patients treated with conventional radiation therapy [24]. The Dana–Farber group also reported 46 % fatal pulmonary toxicity in patients treated with IMRT after EPP [25]. Due to the unexpectedly high pulmonary toxicity due to radiation dose to the contralateral intact lung, a toxicity analysis study found that the volume of lung receiving 20 Gy (V20) and the mean lung dose (MLD) must be kept as low as possible with recommendations of MLD < 8.5 Gy and V20 < 7 % [26, 27].
Recent studies from experienced centers have shown safe adjuvant IMRT delivery even in the presence of the intact lung [28−30]. A prospective Italian study involving 20 patients after radical pleurectomy, receiving high-dose radiation to 50 Gy with boost to 60 Gy, showed 3-year local control of 60 % without fatal toxicity. Only five patients had grade 2–3 pneumonitis [29]. Gomez also published results from an updated series from MDACC of 86 patients treated with IMRT after EPP. At 2 years, the rate of overall survival (OS) was 32 % with local control of 55 %. However, the grade 3 or higher pulmonary toxicity was 11.6 % [30]. Even in expert centers with improved techniques, expected rates of grade 3 or worse radiation pneumonitis are 12–20 %, and the rates of fatal pneumonitis are approximately 3–8 % [31].
Patients with advanced or recurrent disease suffer from symptoms of pain, dyspnea, and esophageal symptoms. Radiation therapy can be used to palliate both the local and distant symptoms as it is used in other cancers. Most of the literature, both retrospective and prospective, has reported a 50–70 % response rate of using palliative radiotherapy in MPM. Various palliative dose regimens have been used showing a dose response to pain control with individual doses greater than 4 Gy. Unfortunately, the pain control is short lived with median time to pain recurrence of 2 months [32].
Chemotherapy for MPM
A number of cytotoxic agents have modest single-agent activity against mesothelioma, including the platinum agents , antifolates such as pemetrexed and raltitrexed, anthracyclines, and the spindle toxin vinorelbine. Most agents that have been tested have relatively low response rates, generally between 10–20 %, when utilized as a single-agent except for cisplatin and the antifolates, and for that reason, combination cytotoxic therapy has been the primary chemotherapeutic strategy tested over the recent past [33].
Byrne and colleagues reported on a combination of cisplatin and gemcitabine [34]. The cisplatin was given at a dose of 100 mg/m2 on day 1, and the gemcitabine was administered 1000 mg/m2 IV on days 1, 8, and 15. Tolerance of the regimen was good, with the main toxicities being hematologic and gastrointestinal. Ten of 21 patients had objective responses (47.6 %) and an additional 9 patients had stable disease. While the trial was not designed to assess for quality of life, all responding patients reported an improvement in disease-related symptoms. The 1-year estimated survival was 41 %. Based on these promising results, a multicenter confirmatory trial was performed [35]. The partial response (PR) rate was 33 %, and 60 % of patients had stable disease; the median survival from initiation of chemotherapy was over 11 months. All responding patients had significant improvements in quality of life .
Pemetrexed is a multitargeted antifolate that has significant activity against mesothelioma [36]. In an early phase I study, where the study drug was partnered with cisplatin, there were four out of ten PRs in patients with MPM [37]. This eventually led to a phase 3 trial, comparing the combination of pemetrexed plus cisplatin to cisplatin alone, in patients with advanced MPM [38]. There were three early treatment-related deaths on the pemetrexed arm, and the protocol was modified so that B12 and folic acid supplementation were required after data suggested a significant decrease in toxicity. Two-thirds of the patients had epithelial histology and 78 % had stage III or IV disease. The median survival was significantly improved in the combination arm: 12.1 vs. 9.3 months, and the vitamin supplementation improved tolerance without adversely affecting efficacy. Based on this, pemetrexed and cisplatin became the standard of care for frontline therapy for patients with advanced disease .
The combination of cisplatin with a different antifolate agent was also demonstrated to be active with raltitrexed—a quinazoline folate analog that acts as a pure and specific thrymidine synthetase inhibitor. In a randomized trial pairing raltitrexed with cisplatin vs. cisplatin monotherapy, there was a significant improvement in survival, 11.4 months to 8.8, similar in magnitude to the benefit seen with pemetrexed [39]. Stable disease was similar in both arms (54 and 53 %) and toxicity was manageable with no decreases in the health-related quality of life (HRQOL).
Because of the toxicities associated with cisplatin, such as nausea and vomiting, nephrotoxicity, and neuropathy, alternative agents to pair with pemetrexed were sought. Janne et al. reported on a combination of pemetrexed with gemcitabine using two different dosing schemes [40]. The results were disappointing, with the response rates less than those achieved with pemetrexed and cisplatin, and the median survivals being less as well than those achieved with single-agent pemetrexed. While the median age of patients were higher than on the Vogelzang trial, and more had stage IV disease, it still suggested that the gold standard was a platinum doublet with an antifolate .
Because of its more favorable toxicity profile, carboplatin has been studied in combination with pemetrexed. Ceresoli et al. reported on the results of a phase II study, giving pemetrexed at a standard dose of 500 mg/m2 along with carboplatin dosed to an area under the curve of 5 [41]. All patients received vitamin supplementation with B12 and folic acid. The response rate was 18.6 % and an additional 47 % had disease stabilization. The median survival compared favorably with that achieved with pemetrexed and cisplatin—12.7 months. Not surprisingly, the nonhematological toxicity was negligible, suggesting that this combination might be useful in older patients with MPM or those with significant comorbid conditions.
The development of vascular endothelial growth factor (VEGF) inhibitors offered a chance to add a targeted therapy to a chemotherapy doublet to see if response rates could be improved upon. Serum VEGF levels are higher in MPM than in many other solid tumors, and given the efficacy of adding bevacizumab to chemotherapy in non-small cell lung cancer it was hoped that a similar advantage would be seen in mesothelioma [42, 43]. Kindler et al. reported the results of a randomized phase II study of cisplatin and gemcitabine with bevacizumab vs. placebo in patients with advanced MPM [44]. Patients received six cycles of therapy and then continued on bevacizumab or placebo until progression. The PR rates were similar in both arms (24.5 % vs. 21.8 %). The estimated median OS was 15.6 months (95 % CI, 10.6–18.7 months) for the study arm and 14.7 months (95 % CI, 10.3–20.0 months) for the placebo . The OS curves were not significantly different. Not surprisingly, bevacizumab toxicities such as epistaxis, proteinuria, and hypertension were noticed more in the treatment arm.
Bevacizumab has also been paired with the oral small molecular inhibitor of thymidine kinase, erlotinib. Jackman et al. reported on a trial utilizing second-line therapy with erlotinib at a dose of 150 mg a day coupled with bevacizumab at 15 mg/kg every 3 weeks [45]. The results were disappointing; despite good tolerance of the therapy, there were no radiological responses, half the patients had stable disease for 6 weeks, and the median time to progression was 2.2 months.
With the emergence of pemetrexed and cisplatin as the frontline therapeutic treatment for advanced MPM, other studies have tried to assess strategies for salvage chemotherapy. Toyokawa recently published a second-line study in patients previously treated with pemetrexed and cisplatin [46]. Seventeen patients received vinorelbine and gemcitabine. The PR rate was 18 %, but 82 % had disease control while on therapy and median survival was 11.2 months. Toxicity was manageable. Clearly, patients continuing to exhibit a good PS after frontline therapy can benefit from second-line cytotoxics .
Other groups have looked at trying other targeted therapies . Nowak et al. gave patients progressing after frontline pemetrexed and cisplatin, a multitargeted thymidine kinase inhibitor, sunitinib [47]. Fifty-one patients were evaluated; 12 % had a radiological response, 65 % had stable disease, and 22 % progressed. Fatigue was the primary toxicity reported and 40 % of patients required a dose reduction. Correlative biomarkers were examined, including serum mesothelin and serum VEGF levels . The authors concluded that sunitinib has some activity in previously treated patients and that a further search for other dosing schedules and biomarkers should be pursued .
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