The Management of Malignant Pleural Mesothelioma Single Centre Experience in 10 Years
The Management of Malignant Pleural Mesothelioma Single Centre Experience in 10 Years
The Management of Malignant Pleural Mesothelioma Single Centre Experience in 10 Years
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Abstract
Background and Objectives: Malignant pleural mesothelioma (MPM) is an asbestos-related disease of the pleura with a survival time
without treatment ranging from 4 to 12 months. The objective of this study is to review our experience in selection of MPM patients for
various modalities of treatment. Methods: Between 1989 and 1998, 302 patients with MPM have been referred to our Centre for assessment.
Majority (191 patients, 61%) of them received no specific treatment. Forty-seven patients were treated by decortication/pleurectomy and 64
had a radical extra-pleural pneumonectomy (EPP). Intrapleural chemotherapy and systemic post-operative chemotherapy was employed only
in the last 51 patients following radical surgery. Results: The average survival was 8.9 months for those treated by palliative care only. The
average survival was 13 and 14 months for patients treated by radical surgery only or by decortication/pleurectomy, respectively. However,
survival has improved to a mean of 35 months for patients treated by radical surgery followed by systemic post-operative chemotherapy. In
this group, the survival prevalence was 90 and 70% for T1 patients and 85 and 36% for T2 patients at 1 and 3 years, respectively (P ¼ 0:002).
Survival was surprisingly, not affected by lymph node involvement (P ¼ 0:08) or pathological type of MPM (P ¼ 0:07). The operative
mortality was 9% for EPP and 0% for decortication/pleurectomy. Conclusion: In selected patients with MPM, complete surgical resection by
EPP represents an important initial step in their management. Systemic chemotherapy improves survival in surgically treated patients.
Further trials are needed to improve on the adjuvant treatment regimes. q 2002 Elsevier Science B.V. All rights reserved.
Keywords: Malignant pleural mesothelioma; Extra-pleural pneumonectomy; Chemotherapy
q
Presented at the joint 15th Annual Meeting of the European Association 2. Patients and methods
for Cardio-thoracic Surgery and the 9th Annual Meeting of the European
Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.
* Corresponding author. Tel.: 144-1355-584-661; fax: 144-1355-584- 2.1. Patient assessment
473.
E-mail address: [email protected] (D. Prakash). Between 1989 and 1999, 302 patients were observed at
1010-7940/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved.
PII: S10 10- 7940(02)0027 3-7
T. Aziz et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 298–305 299
this centre for diagnosis and where appropriate for treatment 3. No co-morbidity preventing major surgery.
of diffuse MPM. Assessment of the patients included clin- 4. Good function in opposite lung.
ical examination, full medical assessment, and computer- 5. No abdominal or distant metastasis.
aided tomography (CAT) scan of chest and abdomen. Pre- 6. Age less than 60 years.
operative tissue sampling of the affected pleura was
obtained by a small open pleural biopsy in all patients.
The pathologic diagnosis was always based on both histol- 2.3. Operative technique
ogy and immunohistochemistry. Pleural fluid cytology, fine EPP was performed as described by Butchart et al. in their
needle and trucut needle biopsies were rarely helpful in our classic paper in Thorax [6]. Briefly, The resected specimen
centre because of false negative and equivocal reports. includes the entire parietal and visceral pleura en bloc with
Magnetic resonance imaging was not used for pre-operative the underlying lung and the ipsilateral pericardium and
assessment in any patient in our series. diaphragm. Blunt dissection is used to separate the
Those who were considered for extra pleural pneumo- diaphragm from the peritoneum underneath, which is left
3. Results
3.1.4. Patients selected for radical surgery
3.1. Patients demography Sixty-four patients were clinically and radiologically in
stage I–II MPM and fulfilled the criteria set out above, and
3.1.1. All study population were treated by extra pleural pneumonectomy. The first 13
Between 1989 and 1999, 302 patients with MPM have patients did not receive systemic chemotherapy (Group I),
been refereed to our institution for assessment. The median while the remaining 51 patients did receive systemic
age was 57 years (range 34–77 years). Sixty-one patients chemotherapy (Group II).
(20%) were females and history of smoking was reported in Pre-operative CAT scan identified pleural thickening in
202 patients. Clear history of asbestos exposure was docu- all patients. Sub-diaphragmatic, chest wall and contralateral
mented in 288 patients and the median duration between pleural involvement was excluded prior to radical surgery.
asbestos exposure and development of MPM was 26 years According to IMIG staging system, 28 patients had T1
(range 19–37 years). The mode of presentation is shown in tumour, 30 patients had T2, and six had T3. Thirty-nine
Fig. 1. patients had nodal metastases of which 25 had only N1
and 14 patients had ipsilateral mediastinal lymph nodes
3.1.2. Patients for best supportive care (N2). None of our study population was proved to have
The majority of patients (191 patients, 63%) had locally N3 or M1 disease. The histological tumour type was epithe-
extensive or metastatic disease at the time of referral to us or lial in 35/64 patients (54%), fibrosarcomatous in 22/64
were in quite poor health. They tolerated an open pleural patients (35%) and mixed cellularity in 7/64 patients
biopsy to establish the diagnosis beyond doubt, thus (11%). Thirty-eight patients underwent right EPP while 26
strengthening their compensation claims. They were offered patients required a left-sided procedure.
T. Aziz et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 298–305 301
3.2. Operative outcome 10/13 patients died within 5 weeks (range 3 weeks to 6
months) following diagnosis of the recurrence.
3.2.1. Mortality
The 30 days operative mortality for EPP patients was 6/
3.3.2. Radical surgery 1 systemic and intrapleural
64 (9.1%). No significant differences in mortality were
chemotherapy
found with regard to patient sex, pre-operative forced
The median time to relapse for patients who received
expiratory volume (FEV1), mediastinal lymph node invol-
chemotherapy following their radical surgery was 37
vement, or pre-operative oxygen saturation. However,
months (14–42 months). There were 31 patients who
survival was inversely affected by patient age and right-
recurred at 33 sites, among the 51 evaluable patients
sided EPP. Five out of six patients died of adult respiratory
(60%). Thirty-two (88%) of the recurrences were confirmed
distress syndrome from 9 to 30 days after operation. One
by histological or cytological assessment [5]. Radiological
patient died of acute myocardial infarction on the third post-
imaging studies and physical examination determined the
operative day and significant coronary artery stenosis was
recurrence in the remaining case. The sites of the first recur-
revealed in his post-mortem examination.
3.2.3. Minor post-operative complications following EPP The median length of follow-up for all 302 patients was
Eighteen patients (28%) had minor complications includ- 16 months (range 0–71 months). The median survival with-
ing atrial dysrhythmia (eight), wound infection (four), out any treatment was 7 months (1–19 moths). Over-all
sputum retention needing bronchoscopy (three), and survival analysis did not show any significant difference
contralateral pneumothorax (one). The median length of between patients who underwent EPP without adjuvant
hospital stay was 17 days. The duration of hospital stay chemotherapy (13 months) when compared to patients
was not affected by the minor complications but was signif- who had a decortication/pleurectomy (14 months) (Fig. 2).
icantly increased with a major complications (29 days). Adjuvant chemotherapy appeared to significantly influ-
ence the survival after EPP. The 1 and 3 years survival
3.2.4. Post-operative chemotoxicity rates were 84 and 48%, respectively, and the median survi-
Including nausea (63%), hair loss (71%), anaemia (32%), val was 35 months (range 0–71 months) for patients who
leukopenia (21%), and thrombocytopenia (9%). Generally, received chemotherapy following EPP. This compared well
myelosuppression was mild to moderate mostly after the with survival rate of 49 and 0% at 1 and 3 years, and a
third or fourth cycle. Most patients with nausea and vomit- median survival of 13 months (range 0–23 months) for
ing responded well to orally administrated anti-emetics those who did not receive systemic chemotherapy following
particularly Ondansetron. Treatment was delayed at times
Table 2
but modification of chemotherapy dose was not needed in Site of recurrence in patients after extrapleural pneumonectomy
any patient.
Site of first recurrence No of patients Percentage
3.3. Recurrence rate Thorax ipsilateral 8 12
Thorax contralateral 5 8
3.3.1. Radical surgery without systemic chemotherapy Liver 8 12
(n ¼ 13) Abdomen/retroperitoneal nodes 7 10
Clinical recurrence was diagnosed after a median period Kidney 2 3
of 10 months (range 8–14 months) in the first 13 patients Adrenals 1 1.5
Brain/nervous system 1 1.5
who did not receive any adjuvuant systemic chemotherapy
Skin 1 1.5
following EPP. The recurrence pattern was aggressive and
302 T. Aziz et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 298–305
their radical surgery (P ¼ 0:001 and 0.0001 for 1 and 3 of the types. However, there was better trend of survival in
years differences, respectively). (Fig. 3). Eighteen percent favour of epithelial tumours (P ¼ 0:07 at 3 years interval)
(9/51) of our patients who were treated with radical surgery rather than sarcomatous tumours. There was no difference in
followed by systemic chemotherapy have achieved more survival according to differences in age, sex, period of
than 5 years of survival. The univariate analyses of survival asbestos exposure and pre-operative symptoms.
in patients treated with systemic chemotherapy according to
TN status and stages are shown in figures (Figs. 4 and 5).
Comparison of individual T status categories showed signif- 4. Discussion
icant difference in survival for T1 vs. T2, and also signifi-
cant difference was noted for T2 vs. T3. The median The management of MPM remains a subject of contro-
survival for T1 tumour was 42.8 months. This was signifi- versy because of incomplete understanding of its natural
cantly different from the median survival of 31 months and history and apparent resistance to standard forms of therapy.
14 months for T2 and T3, respectively. The survival preva- The treatment of MPM has gained importance because the
lence was 90 and 70% for T1 patients, and 85 and 36% for disease is becoming more prevalent worldwide [3]. The
T2 patients, and 49 and 0% for T3 patients at 1 and 3 years, perceived high operative mortality after EPP was the main
respectively (P ¼ 0:007, 0.002, respectively). reason for reluctance to operate, as early experience from
However, in variance to others’ experience, no significant Butchart et al. [9] cited hospital mortality of 31% (9 out of
difference in survival was noted between N0 and patients 29). Bamler and MaaBeen [10] found a similarly high rate
who had nodal spread (P ¼ 0:08 at 3 years interval). of 24% (4 out of 17). Operative mortality as high as this is
Univariate analysis of survival according to the histological bound to reduce any potential therapeutic effect. Recent
type demonstrated no significant difference between either experience [11–13] confirms that the operative mortality
of EPP although still higher than for a decortication/pleur-
ectomy, is not dissimilar to that for a standard pneumonect-
omy in the hands of surgeons or single institutions that both Rusch et al. [8,10] and Sugarbaker et al. [22,23], our
perform this operation regularly. In our experience, the results confirm that T1 and T2 patients have a much more
operative mortality was 9.1% (6 out of 64) and continues favourable survival outcome when radical surgery and thus
to improve with only a single mortality in the last 21 patients post-operative chemotherapy has been used. Our data also
and it is comparable with the operative mortality of standard shows that T1 tumour exhibits better long-term survival
pneumonectomy in our centre. outcome than T2 disease. T3 tumour has a poor prognosis
We did not find much difference in survival between even when radical surgical resection was achieved and
patients who underwent decortication/pleurectomy hence, we need to identify these patients before surgery
compared to patients without any surgical intervention. It and avoid operating on them. Tumour T stage does seem
is almost impossible to achieve reasonable degree of surgi- to be an important selection criteria.
cal clearance without radical surgery. Although the pallia- The negative significance of lymph node involvement on
tive effect could not be assessed in this retrospective study, survival following EPP has been illustrated in some bigger
it was not impressive and it was clear that more radical series [25]. The negative influence of lymph node involve-
was significant by its absence except for occasional post [9] Delaria GA, Jensik R, Faber LP. Surgical management of malignant
thoracotomy pain for which analgesics were not needed mesothelioma. Ann Thorac Surg 1978;26:375–383.
[10] Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneu-
and rarely prescribed. monectomy in malignant pleural mesothelioma. J Thorac Cardiovasc
Surg 1991;102:1–9.
[11] Chahinian AP. Therapeutic modalities in malignant mesothelioma.
6. Conclusions In: Chretien J, Hirsch A, editors. Disease of the pleura, New York,
NY: Masson, 1983. pp. 24–36.
[12] Allen KB, Faber LP, Warren WH. Malignant pleural mesothelioma.
The question of surgery in MPM is a subject that has Extrapleural pneumonectomy and pleurectomy. Chest Surg Clin N
already been aired by many others. We have tried to find Am 1994;4:113–126.
a way to separate patients who are unsuitable for any treat- [13] Rice TW, Adelstein DJ, Kirby TJ. Aggressive multimodality therapy
ment from those who may benefit from a palliative proce- formalignant pleural mesothelioma. Ann Thorac Surg 1994;58:24–29.
[14] Worn AH. Moglichkeiten und Ergbnisse der chirurgischen Behandlung
dure and those who deserve the best chance for a good
des malignen pleuramesotheliomas. Thoraxchirurgie 1974:391–393.
outcome by being offered a radical resection (EPP) [15] Davalle MJ, Faber LP, Kittle JF, Jensik RJ. Extrapleural pneumonect-
recurrence, when it occurred, was very vigorous, aggressive, and some of were operated by extrapleural pneumonectomy or did you have long-term
the patients died within weeks of recurrence occurring. In the second group survivors in other categories?
of patients, we do have long-term survivors, and although 31 patients had Dr Prakash: I didn’t get your second question.
recurrence, the recurrence was still treatable, we gave them a further course Dr Ris: The second question was, in these long-term survivors, were
of chemotherapy, which seemed to control the disease for a short period of these all patients who were treated by extrapleural pneumonectomy?
time, for a few months, before they died. Dr Prakash: Yes. Our long-term survivors was 9, not the figure you
Dr Toomes: The treatment of mesothelioma is also a question of selec- mentioned. I corrected myself. The long-term survival was 18%, or 9
tion, and, as you said, Sugarbaker has selected subgroups, and in subgroups patients, in the group with chemotherapy. And there were no special char-
with epithelial mesothelioma with only surgical treatment, he achieves a acteristics in these 9 patients that we were able to pick up: some of them did
46% five-year survival. Do you want to comment on this? have nodal involvement and some of them were sarcomatous.
Dr Prakash: We have not been as selective, we have not ruled out Dr D. Dougenis (Patras, Greece): Why do you consider a contraindica-
surgery for sarcomatous patients at this stage. In the future, one may tion to a radical extrapleural pneumonectomy the invasion of the
want to consider that. But I think we do have sarcomatous patients surviv- diaphragm? Do you remove the diaphragm along with the entire lung
ing long term, and we felt we should not deprive them of surgical treat- during the procedure?
ment. Dr Prakash: Yes, we do remove the diaphragm. We do preserve the
Dr H. Aebert: (Tubingen, Germany): I have a question relating to your underlying diaphragmatic peritoneum wherever possible. We feel that if