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Eur J Cardiothorac Surg 2007;31:529-534. doi:10.1016/j.ejcts.2006.11.046
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

A phase II study of intrapleural immuno-chemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy and long-term sub-cutaneous IL-2 in stage II–III malignant pleural mesothelioma

Marco Lucchia,*, Antonio Chellab, Franca Melfia, Paolo Dinia, Marcello Ambrogia, Leonardo Finoa, Gabriella Fontaninic, Alfredo Mussia

a Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Pisa, Italy
b Division of Pneumology, Cardiac and Thoracic Department, University of Pisa, Pisa, Italy
c Division of Pathology, University of Pisa, Pisa, Italy

Received 23 August 2006; received in revised form 24 November 2006; accepted 28 November 2006.

* Corresponding author. Address: Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Via Paradisa 2, Pisa 56124, Italy. Tel.: +39 050 995226; fax: +39 050 577239. (Email: m.lucchi{at}med.unipi.it).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Conclusions
 Appendix A
 References
 
Objective: From therapeutic nihilism to extremely aggressive management, there is a wide range of possibilities in the treatment of malignant pleural mesothelioma (MPM). Unfortunately, there is little evidence as regards the best treatment to offer to the MPM patients. In 1999, we started a phase II study based on the multimodality treatment of stage II–III MPM, the results of which have been analysed and reported. Methods: From 1999 to 2004, 49 patients with IMIG stage II–III MPM underwent a multimodality treatment including: intrapleural pre-operative interleukin 2 (IL-2, 18 x 106 UI/day per 3 days), pleurectomy/decortication, intrapleural post-operative epidoxorubicin (25 mg/m2 per 3 days), IL-2 (18 x 106 UI/day per 3 days), adjuvant radiotherapy (30 Gy), systemic chemotherapy (cisplatin 80 mg/m2 day 1, gemcitabine 1250 mg/m2 day 1 and 8 up to 6 courses) and long-term sub-cutaneous IL-2 (3 x 106 UI/day 3 days per week). Results: There were 41 males and 8 females with a median age of 61 years (range 41–77). All the patients had a diagnosis of MPM by thoracoscopy before inclusion. We did not experience any post-operative mortality. The histology was: 39 epitheliomorf, 6 bifasic and 4 sarcomatous. According to the IMIG the post-operative staging was III in 40 cases and II in 9 cases. With a median follow-up of 59 months (range 14–81) 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stage II and III, respectively). Only the Performance Status at the diagnosis affected survival significantly. Conclusions: The multimodality treatment we adopted for stage II–III MPM was feasible, well tolerated by most of the patients and produced a favourable outcome. New targeted therapies are awaited for further improvements in the treatment of this disease.

Key Words: Mesothelioma • Multimodality treatments • Pleurectomy • Chemotherapy • Immunotherapy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Conclusions
 Appendix A
 References
 
Mesothelioma is a frightful disease which became more and more familiar to individuals, with professional asbestos exposure, who are aware of its aggressiveness and treatment resistance. Unfortunately, its incidence is expected to continue to increase for the next decade and, despite a lot of therapeutical attempts, there is still no cure or any evidence of the optimal treatment [1]. Even if a multimodality treatment is currently adopted in most of the centres [2] and prospective randomised trials have been advocated by most of the authors [3], physicians involved in the care of malignant pleural mesothelioma (MPM) look at the literature finding little or nothing at all.

Chemotherapy proved to be valuable for palliation with the combination of pemetrexed–cisplatin, as shown in a phase III study [4], able to produce a 41% objective response rate. Gencitabine plus cisplatin also offers a similar objective response rate [5], but the crucial question is if chemotherapy should be administered in a pre- or post-operative setting [6,7].

Surgery, both pleurectomy/decortication (PD) and extrapleural pneumonectomy (EPP) according to the policy of the surgeon, has been adopted in most of the multimodality protocols as a cytoreductive treatment [8,9]. There is no evidence of the superiority of EPP versus PD, but we must wait for the end of the ongoing MARS trial in the UK [10].

Despite the fact that the results of radiotherapy in mesothelioma have been disappointing, it seems effective in the prevention of seeding along the surgical scars [11] and in the palliation of pain.

Immunotherapy, especially interleukin 2 (IL-2) and interferon {alpha} (IFN {alpha}) or IFN ß, has shown that it can induce MPM regression in animal models and in human beings [12–14]; moreover, it can be easily combined with other therapeutic modalities.

Because of the poor success rate of each single modality, a multimodality approach has been reported to improve survival and quality of life [2]. Particularly, Sugarbaker [6] identified a subset of patients with early stage disease, epithelial MPM with a notable survival rate. On this basis we always reserved the extrapleural pneumonectomy (EPP) for patients with epitheliomorf stage I MPM and optimal performance status, preferring the P/D in all the other cases.

In 1999, we started a phase II study on the multimodality treatment (immunotherapy-surgery-chemotherapy-radiotherapy) of stage II and III MPM, the results of which have been analysed and reported.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Conclusions
 Appendix A
 References
 
The objectives of this trial were as follows: (1) to determine the feasibility of the multimodality treatment we proposed; (2) to determine the patterns of local and distant recurrence after treatment; and (3) to determine overall survival.

The study design was approved by our local Ethics Committee and all patients gave written informed consent.

The eligibility criteria were:

- histologically documented stage II and III MPMs, with diagnosis obtained by thoracoscopy;
- patients under 75 years of age;
- no history of malignancy;
- no prior chemotherapy and/or radiotherapy;
- performance status (ECOG) 0–2;
- adequate bone marrow reserve (leukocyte count ≥3500/µl; platelet count ≥100.000/µl);
- adequate liver (bilirubin ≤1.5 mg/dl) and renal (serum creatinine ≤1.5 mg/dl with creatinine clearance >65 ml/min) function.

All patients were evaluated by means of anamnesis and physical examination, chest and upper abdomen CT, laboratory data, pulmonary function testing and echocardiography. Additional tests to exclude distant metastases were performed whenever clinically indicated.

A thin catheter (pig tail 12 Fr) was always positioned at the end of the thoracoscopy and of the pleurectomy/decortication for intrapleural drug administration.

Pre-operatively, 18 x 106 UI/day of interleukin-2 were administered through the pleural catheter per 3 days. Acetaminophen was administered throughout treatment whenever fever was higher than 38°. After 1 day of recovery all the patients underwent a thoracotomy. At the operation, if the disease was minimal and considered a stage I, the patient was excluded from the study and underwent a extrapleural pneumonectomy. In case of stage II or III MPM, we performed a pleurectomy/decortication consisting of the removal of the parietal and mediastinal pleura of the involved areas of the visceral pleura, with minimal resection of the lung if necessary. In case of minimal involvement of the pericardium and diaphragm, they were resected and sutured; however, they were never replaced with a mesh as for the radical pleurectomy/decortication (neither in case of a T3 tumour). At the end of the procedure a lymph node sampling was performed. Final pathologic staging was performed according to the International Mesothelioma Interest Group staging system [15].

Five to seven days after the P/D, patients underwent intrapleural chemotherapy with epidoxorubicin (25 mg/m2 per 3 days) and then post-operative IL-2 (18 x 106 UI/day per 3 days). One week following the last instillation, the pleural catheter was removed.

Post-operative radiation therapy started approximately 30–45 days after the operation. We used a hypo-fractionated schedule with 30 Gy delivered in three fractions. Radiation therapy was used in all patients aiming at treating all surgical scars while sparing the underlying lung parenchyma.

Chemotherapy began 1 month after radiotherapy and consisted of three to six courses of cisplatin (80 mg/m2 day 1) and gemcitabine (1250 mg/m2 day 1 and 8).

One month after chemotherapy, a long-term sub-cutaneous IL-2 (3 x 106 UI/day 3 days per week) administration began. Patients’ immunological profile was monitored with routinary serum samples and the therapy with subcutaneous IL-2 was stopped when the disease relapsed.

Toxicity of both chemotherapy and therapy with IL-2 were recorded and analysed using the World Health Organization (WHO) grading system.

All patients were followed up until death or to the final date of analysis for this report (December 2005).

As regards to the follow-up tests, a physical examination and CT scan of the chest and upper abdomen were performed 1 month after radiotherapy and then 3 months thereafter. Disease progression, according to the Response Evaluation Criteria in Solid Tumours Group (RECIST), was defined as at least 20% increase in the sum of the longest diametres of target lesions. Cytologic or histologic proof of disease progression was rarely obtained.

Survival was calculated from the date of the diagnosis until the date of death or of the last follow-up. The statistical analysis was performed by the Stat-Soft software. Results are expressed as mean ± standard deviation. Survival curves were estimated by the Kaplan–Meyer's product-limit method and were compared by using the log-rank test. The Chi-square test was used for comparison between proportions, whereas Fisher's exact test was used when the cell frequencies were small. In this study, a p-value less than 0.05 was considered significant in all comparisons.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Conclusions
 Appendix A
 References
 
From 1999 to 2004, 49 patients with IMIG stage II–III MPM were enrolled in our phase II study.

The demographic data of the patients as well as the tumour characteristics are shown in Table 1 . All patients had a diagnosis of MPM by thoracoscopy before inclusion. All patients received the intrapleural administration of IL-2 and epidoxorubicin without dose reduction or interruption. All patients experienced fever during treatment requiring antipyretic medication. Three patients had cutaneous complaints (mostly desquamation) which spontaneously stopped after treatment.


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  		Table 1 Patients’ characteristics
 
We did not experience any post-operative mortality. As regards the post-operative morbidity, we had one case of bleeding, three arrhythmias and six cases of prolonged air leakage. The reason for the classification as a stage III tumour was the N2 status in nine cases, and in the remaining cases it was due to a T3 tumour.

All patients underwent adjuvant chemotherapy. The total number of courses delivered was 259 (mean 5.3; range 2–6). Median granulocyte, platelet and haemoglobin nadirs were 712/mmc, 181000/mmc and 10.5 g/dl, respectively; neutropenic fever occurred in 52 courses (20.1%). The most common non-haematological toxicities were alopecia, nausea/vomiting, usually mild or moderate (Table 2 ).


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  		Table 2 Non-haematological toxicity of adjuvant chemotherapy by number of cycles
 
The adjuvant radiotherapy was performed in all the patients. Four patients, referred by centres where the radiotherapists refused the treatment, were excluded from the analysis. Radiation-related complications were mild with only actinic pneumonia, recorded in 38 cases (77.6%), but easily controlled by corticosteroids.

The subcutaneous IL-2 maintenance therapy lasted a median of 10 months (range 1–36) and was well tolerated. The only complications were eosinophilia, observed in 37% of the patients, and a mild fever, sometimes requiring paracetamol 500 mg.

With a median follow-up of 59 months (range 14–81), 13 patients were still alive. Five patients were radiologically disease-free, 37 had a local relapse and 7 had both a local and systemic relapse. The 2- and 5-year actuarial survivals were 60.2% and 23.3%, respectively (Fig. 1 ). The overall median actuarial survival was 26 months (31 and 21 months for stage II and III, respectively). There was a better survival in stage II MPM with respect to stage III but the difference was not statistically significant (Fig. 2 ). Only the Performance Status at the diagnosis affected survival significantly (p = 0.02) (Fig. 3 ).


Figure 1
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  		Fig. 1. Overall survival of 49 patients, with stage II–III MPMs, who underwent multimodality treatment.

 

Figure 2
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  		Fig. 2. Survival according to the stage of disease.

 

Figure 3
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  		Fig. 3. Survival according to the patients’ Performance Status at the diagnosis.

 

   4. Conclusions
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Conclusions
Appendix A
 References
 
Physicians looking at the medical literature for the treatment of MPM find a lot of conflicting data, ranging from mere palliation to really aggressive multimodality treatments, but there is no certainty [1]. It seems that nothing has changed in the early diagnosis and, more important, in the prognosis of MPM patients so that a person could rightly conclude: ‘little evidence, still time to do trials’ [3]. Lacking evidence about the best treatment to offer to MPM patients, in 1999 we thought of drawing up a multimodality treatment which would be aggressive, but not so much as to impact the quality of life of patients with an expected poor prognosis.

Interleukin-2 is a lymphokine which enhances the cytotoxic response of activated T cells and whose low serum level correlates with poor survival in advanced disease [16].

From a therapeutic point of view, it proved to be effective in melanoma and metastatic renal cancer, but it was also tested, with or without chemotherapy, in the treatment of other solid tumours [16].

IL-2 also proved to be superior to IFN-{alpha} and IFN-ß in neoplastic pleural effusions and, in a recent review of the literature [16], whenever used intracavitarily in mesothelioma, IL-2 determines a 40% OR rate. The subcutaneous route has been used by few authors, mostly in combination with the i.v. route or systemic chemotherapy [17], obtaining a good rate of stable disease.

Our protocol, as regards the administration route of IL-2, is original; we decided to combine epidoxorubicin with IL-2 for the local treatment, and gemcitabine with s.c. IL-2 for the systemic treatment, aiming to induce an improvement of the immunological defences. Our rationale was derived from previous studies.

All advanced tumours, and particularly the MPM, produce a depletion of the endogen IL-2, and increase, directly or indirectly, cytokine (TGFß, IL-10, IL-6) serum levels which induce an inhibition of cell-mediated immunity, expressed by the decrease of circulating lymphocytes [16]. The serum lymphocyte count extensively proved to be a prognostic factor in most of the solid tumours, although they are only about 2% of the overall amount which is in the lymphatic compartment. Moreover, the immunological efficacy of IL-2 is tested by parametres of aspecific flogosis, such as PCR and VES. Furthermore, and also in our experience the lymphocyte count together with PCR and VES were useful in monitoring the therapy with s.c IL-2.

As regards the surgical arm, our policy was to reserve the extrapleural pneumonectomy to minimal disease (stage I), whenever the lung and cardiac function were acceptable. So for stage II and III disease, we preferred to perform a pleurectomy/decortication which, even less radical than EPP [9], results in lower morbidity and allows most patients to tolerate a complex multimodality treatment.

It is extremely suggestive and important that, recently, Australian authors [18] showed, in an animal model, that the persistence of tumoural antigens after incomplete debulking, in combination with chemotherapy and immunotherapy, is critical for the induction of long-term immunity. What emerges from the above-mentioned report is something that clearly supports our policy in the multimodality treatment of MPM.

The scheduling of adjuvant intrapleural chemotherapy with epidoxorubicin and systemic chemotherapy consisting of cisplatin and gemcitabine had been chosen on the basis of a high objective response rate with those drugs reported in the literature [5,19]. More recently, Nowak et al. [20], in a murine model, showed that gemcitabine does not appear to be detrimental to specific antitumour cellular immunity, and may be useful in combination with chemo-immunotherapy protocols.

Our experience supports the experimental results: the scheduling was well tolerated by all the patients and had a synergistic effect with the IL-2 s.c. Altogether, we observed a long survival and a good quality of life which, unfortunately, was not registered in the questionnaire.

Hemithoracic radiation therapy has been combined with surgery (both P/D and EPP) in MPM, obtaining a decrease of the relapse rate in the surgical scars as well as a good local control. The experience of the Memorial Sloan-Kettering Cancer Center (MSKCC) has been extensively reported and, recently, Gupta et al. [21] published the largest series of MPM patients treated with P/D and hemithoracic radiotherapy. He concluded that P/D plus adjuvant hemithoracic RT is not an effective treatment option on the basis of a median overall survival of 13.5 months in the P/D group compared with the 17–19 months in the EPP group. However, looking at the survival rate according to the stage of disease, he found a median survival of 13.9 months in stage III/IV that is worth mentioning. It is obvious that radiation toxicity in the lung is minor following EPP, but P/D in patients who cannot tolerate a major operation and with advanced stage disease should not be excluded but should rather be better integrated with adjuvant chemotherapy and immunotherapy.

Looking at the survival end-point, the first acceptable results were experienced by Sugarbaker [6] who pioneered a trimodality therapy (EPP-CT-RT), achieving in 176 patients alive after surgery a median survival of 19 months and, still better, selecting epithelial MPMs at stage I.

A neoadjuvant approach, similar to what happened with advanced NSCLC, has been investigated primarily by Weder [7] in 19 patients, and then in a multicentre setting in Switzerland in 61 patients, the final analysis of the results of which are pending [22]. It is an extremely aggressive approach, and the response rate to neoadjuvant chemotherapy (cisplatin–gemcitabine) was 32%, with the median survival time being 23 months in 16 of the 19 patients who underwent EPP.

This study, which was extended in a multicentre setting and with a larger number of patients, was completed in only 29 out of 61 patients, but it achieved, at a preliminary analysis, an amazing 26.3 months median survival [22]. Although the survival results are satisfying, the observed post-operative complication rate was quite high (62%) [23], and that prompted many authors to question about the level of risk of such procedures [24].

While most of the authors were moving towards very aggressive multimodality treatments for MPM, we decided to ‘swim against the stream’, choosing a four-modality treatment which introduced an intrapleural and long-term subcutaneous immunotherapy with IL-2.

Intraoperative intracavitary hyperthermic chemotherapy has been combined with P/D in a phase I/II study [25], determining a 26-month median survival in 20 patients with epithelial MPMs. This is further evidence that by enhancing local control of MPM without deterioring the performance status of the patients, an optimal survival rate may be achieved even in patients who are not candidates for EPP.

Our study supports these results, and adding the local and systemic immunotherapy to the multimodality treatment of MPM we achieved a 26-month median survival in advanced stage MPM, which is exceptional. Moving from a utopistic concept of care for MPM to a more realistic hope of good palliation, we feel that it is important to avoid being too aggressive in each single modality of the treatment. If we can complete the planned treatment in the totality of patients and consider MPM as an advanced disease at the diagnosis, the use of lymphokine (IL-2), capable of stimulating the growth and cytotoxic response of activated T lymphocytes, may lend further value to the integration of conventional therapies.

The dosages and administration routes of immunotherapy with IL-2 showed a good compliance with P/D, chemotherapy and RT. Overall, our four-modality treatment deserves further studies in MPM patients, perhaps taking into consideration the use of intraoperative intracavitary hyperthermic chemotherapy and new drugs.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Conclusions
 Appendix A
References
 
Conference discussion

Dr H. Batirel (Istanbul, Turkey): What's your technique for pleurectomy and decortication? Do you remove the diaphragm and the pericardium?

Dr Lucchi: It was not a radical pleurectomy/decortication. We removed a piece of diaphragm or pericardium only when it was strictly necessary, otherwise we left some tumour on the field. It is our opinion that extrapleural pneumonectomy, as well as a pleurectomy/decortication with diaphragm or pericardium replacement, may be too aggressive for a pleural mesothelioma.

Dr B. Passlick (Freiburg, Germany): At the very end of your presentation you mentioned the quality of life of these patients, and, as far as I know, at least from the patients who have renal cancer, the immunotherapy often has some problems with the long-term regimen. So what was the quality of life with these patients when they had continuous interleukin-2?

Dr Lucchi: Unfortunately we did not give a questionnaire to the patients. My impression during the study was that the quality of life was better, at least for the beginning, than that after aggressive treatments including extrapleural pneumonectomy. The patients accepted what we proposed more easily and during the follow-up, after the progression of the tumour, we balanced the chemotherapy and the immunotherapy. When there was tumour progression and the PCR was high and lymphocyte count was low, we did the immunotherapy. When there was tumour progression and the lymphocyte count and PCR were normal, we performed only chemotherapy. So I suppose that we had good results because the patients were also well followed during the follow-up period.


   Acknowledgments
 
The authors wish to acknowledge that some patients included in this study were operated on by Professor Carlo Alberto Angeletti, now retired.


   Footnotes
 
\#9734; Presented at the joint 20th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 14th Annual Meeting of the European Society of Thoracic Surgeons, Stockholm, Sweden, September 10–13, 2006.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Conclusions
 Appendix A
 References
 

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