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Trimodality therapy for mesothelioma
Debating the benefits of surgery alongside radiation
and chemotherapy
by Marc de Perrot, MD, MSc, FRCSC and Christopher Lee, MD, FRCPC
Abstract
T
here are limited treatment options for malignant pleural
mesothelioma. Cisplatin-based chemotherapy has
shown some survival benefit, but results remain discouraging. Radiation has been used as a palliative measure.
Recent attempts to improve the effect of radiation with
surgical resection have shown some promise.
Dr. Marc de Perrot describes vastly
improved outcomes with the SMART
approach to trimodality therapy
Malignant pleural mesothelioma (MPM) remains a dreadful
cancer with limited therapeutic options and extremely poor
survival. Most patients die from local progression and
cachexia associated with unrelenting pain from the invasion
of the intercostal nerves, ribs, spine and brachial plexus.1
Despite the fact that the use of asbestos was banned in
most Western countries in the 1970s and early 1980s, the
incidence of MPM is still rapidly rising, with almost 500
new cases per year in Canada. Whether this epidemic will
plateau in the next decade remains speculative.
MPM can be differentiated into 3 subtypes based on
their histology: epithelial, biphasic and sarcomatoid. The
epithelial subtype is the most common, affecting about 70%
of patients. Median survival ranges between 6 and 12
months depending on the histologic subtype, performance
status, gender and presence of an abnormal blood count
such as anemia, elevated white cell count, elevated platelets
and/or elevated neutrophil-to-lymphocyte ratio.2,3 The
clinical staging system is often not a reliable prognostic factor since many patients with apparently early-stage disease
are up-staged on final pathologic staging.
Standard of care
Currently, the only recognized standard of care for MPM
is cisplatin combined with an antifolate agent such as pemetrexed or raltitrexed.4,5 This combination was shown to
improve median survival by about 3 months, from 9 to 12
months, in 2 large randomized controlled trials (RCTs).
In patients with good prognostic factors (such as epithelial
subtype, good performance status and minimal chest pain)
At the 8th annual Ontario Thoracic Cancer Conference,
Dr. Marc de Perrot presented a promising view of trimodality therapy with the evolution of mesothelioma surgery,
while Dr. Christopher Lee pointed to shortcomings in the
evidence supporting surgery in all but a very select patient
group. In this article, Drs. Lee and de Perrot provide the
key points of their debate.
treated with chemotherapy alone, median survival is approximately 18 months and the chance of 3-year survival is 15%.6
Hence, although chemotherapy with cisplatin-pemetrexed or
cisplatin-raltitrexed provides some survival benefit, the results
remain very discouraging and other strategies need to be
explored.
The alternatives to chemotherapy are surgery and radiation.
Surgery includes pleurectomy-decortication (PD), extended
pleurectomy-decortication (EPD) and extrapleural pneumonectomy (EPP). The term EPD was recently proposed to
encompass the group of patients undergoing PD with
resection-reconstruction of the diaphragm to achieve an R1
resection. EPD differs from PD, which would not necessarily
require resection of the diaphragm and would often be
associated with residual macroscopic disease after surgery.7
Indications for surgery vary by centres and expertise.
However, most investigators currently agree that surgical
macroscopic complete resection and control of micrometastatic disease play a vital role in the multimodality treatment
of MPM, as in the treatment of other solid malignancies.8
All patients with a diagnosis of MPM should be evaluated
in a multidisciplinary setting with medical oncology, radiation
oncology and surgery. Surgery should be offered if an R0
(complete resection with no microscopic residual tumour)
or R1 (surgical margins show microscopic evidence of
tumour cells) resection is deemed safely achievable. The
type of surgery depends on clinical factors and on individual surgical judgment and expertise.
Marc de Perrot, MD, MSc, FRCSC is a surgeon in the Division of
Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer
Centre, and Head of the Toronto Mesothelioma Research Program.
Christopher Lee, MD, FRCPC is a medical oncologist with the
British Columbia Cancer Agency Fraser Valley Cancer Centre.
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Feature
progress in surgery
Since the first surgical series for MPM were reported in the
1970s, considerable progress has been made in quality and
safety. Most series now describe an operative mortality of
5% or less after EPP or EPD. Despite progress, the longterm results of surgery alone have been discouraging and
emphasis has turned to combination therapy to see further
improvements in outcome.
Surgery following chemotherapy and
radiation
Following the demonstration by Weder et al9 that induction
chemotherapy followed by EPP was safe, and the study by
Rusch et al10 showing that high-dose hemithoracic radiation
provided excellent local control, several groups adopted a
trimodality approach with induction chemotherapy followed
by EPP and adjuvant hemithoracic radiation. In our experience at the Princess Margaret Cancer Centre, this approach
led to excellent local control with only 25% of patients
experiencing local recurrence and a 3-year survival of 53%
in patients who completed the radiation and did not present
mediastinal node involvement.11 Radiation was safely delivered
using intensity-modulated radiation therapy (IMRT).
Based on this experience, we developed the SMART
(Surgery for Mesothelioma After Radiation Therapy) concept
to optimize the quality of radiation. This approach offers
the advantage of short accelerated radiation treatment with
an hypofractionated regimen delivering 25 Gy in 5 daily
fractions over 1 week to the entire ipsilateral hemithorax
by IMRT, with a concomitant boost of 5 Gy to volumes at
high risk based on computed tomography (CT) and positron
emission tomography (PET) scan findings. EPP is performed
within 1 week after the end of radiation to prevent the
development of pneumonitis.
Implementing the SMART protocol
This protocol was implemented at Princess Margaret Cancer
Centre in November 2008 for patients with histologically
proven, previously untreated, resectable cT1-3N0M0 MPM.
It includes the possibility of adjuvant chemotherapy after
surgery with cisplatin-pemetrexed or cisplatin-raltitrexed for
patients with ypN2 disease on final pathology. The results
have been extremely encouraging since for the first time,
we are reaching a 3-year survival rate of about 80% in patients
with epithelial subtype.12 Hence, this protocol has now become
our treatment of choice for patients with resectable epithelial
disease. Current research in our laboratory has shown that
the benefit obtained with high-dose hypofractionated radiation followed by extended surgery is likely related to the net
positive effect on cancer immunity. In future, this protocol
could potentially be refined through the use of new immunomodulating compounds entering the clinical arena.
The difficulty with surgery and radiation is that, in contrast
to chemotherapy, both techniques are extremely difficult to
standardize and results are highly dependent on the expertise of individuals providing care. Hence, the performance
of a RCT to demonstrate the benefit of surgery and/or
radiation will very likely be impossible in MPM. The MARS
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VOL. 12, No. 3, august 2013
trial was an attempt to perform a large RCT to compare
EPP and radiation to no surgery.13 Considering that an estimated 670 patients would have been required to demonstrate
a difference between the surgical and nonsurgical arms, the
investigators started with a feasibility trial to see if 50 patients
could be randomized in 1 year. This was not achieved as it
took 3 years to randomize 50 patients. In addition, a third
of the patients scheduled for surgery did not undergo EPP
and 20% of the patients in the control arm eventually underwent surgery. This trial demonstrates the difficulty of randomizing patients to surgery vs no surgery in MPM and highlights
high variability in the delivery of surgery, since the authors
observed an operative mortality of 18% after EPP in the study.14
Thus, surgery and high-dose hemithoracic radiation for MPM
should only be done in centres with the required expertise
to limit risk and obtain the greatest benefit. Denying patients
access to such treatment due to the lack of a RCT, however,
could be detrimental for them and to efforts to refine therapeutic strategies in mesothelioma.
In conclusion, while cisplatin-based chemotherapy with
pemetrexed or raltitrexed is the only standard of care for
patients with MPM, the results remain very disappointing
even in the best group of patients. Additional strategies such
as surgery and radiation must be considered. Currently, the
SMART approach with a short course of high-dose hypofractionated hemithoracic radiation followed by surgery
provides the best outcome, with a 3-year survival of approximately 80% in patients with epithelial subtypes. Ongoing
research in our laboratory suggests that this approach could
potentially be optimized with the use of immunodulating
compounds to target the immune system at the time of
radiation or following radiation. Patients with mesothelioma should be strongly encouraged to participate in clinical
trials for their own potential benefit and to further refine the
therapeutic armamentarium against this challenging disease.
References on page 45
Dr. Christopher Lee regards patient
selection, not trimodality therapy,
as the key determinant of outcome
Routine management of malignant pleural mesothelioma
(MPM) includes assessing the suitability of the patient for
systemic therapy while ensuring adequate symptom control
with other palliative measures. Radical surgery with the
goal of improving long-term survival outcomes is an option
in only a select subset of patients.
Results with extrapleural pneumonectomy
The first report of extrapleural pneumonectomy (EPP) for
pleural mesothelioma was a small series published in 1976.1
Since that time, a number of institutions have established
expertise in performing the procedure, with contemporary
perioperative morbidity and mortality rates between 2% and 5%.
Current treatment programs based on EPP incorporate
postoperative hemithorax radiotherapy plus neoadjuvant or
Feature
adjuvant chemotherapy: trimodality therapy. Removal of
the pleura, pericardium, diaphragm and lung by EPP used to
be performed to accomplish en bloc resection of the tumour.
However, it was soon recognized that R0 resection was rarely
achieved, prompting the addition of hemithorax radiotherapy
to improve local disease control. Chemotherapy was then
added to try to reduce distant as well as local recurrence rates.
Institutional case series of EPP have been published and
updated over the years, with a detailed review of these data
in 2008 by Flores and colleagues.2 Among 385 patients
treated with EPP, the 1- and 2-year survival rates were 50%
and 25%, respectively. However, the degree to which the
long-term survival outcomes seen with trimodality therapy
represent a real benefit is uncertain.
Chemotherapy
In the last decade, chemotherapy has been accepted as a
standard treatment option in the management of MPM,
with evidence that it is associated with a modest survival
benefit.3 Typical 1- and 2-year survival rates for treated
patients are around 40% and 20%, respectively.
Based on population data from British Columbia and
Ontario, 40% to 50% of individuals with MPM are not suitable candidates for chemotherapy or decline treatment.4,5
Among those who receive chemotherapy, only 15% to 20%
are reasonable candidates for radical surgery. This represents
no more than 10% of all patients with MPM.
The process of determining the most suitable candidates
for trimodality therapy necessarily focuses on younger
patients with good performance status and less comorbidity.
Another factor is the selection of patients with epithelial
mesothelioma, which is associated with a better prognosis
compared to those with sarcomatoid or mixed histology. As
well, institutions that employ neoadjuvant chemotherapy
require response after several cycles of treatment before
scheduling surgery.
The effect of selection is seen in Figure 1, which shows
the survival of patients treated with platinum-based combination chemotherapy in British Columbia from 1999 to 2005
(only one of whom was referred for EPP). For all patients,
the 1- and 2-year survival rates are 42% and 21%, respectively.
Selecting a subgroup of patients under age 70 years with
good performance status, epithelial histology, and who survived 100 days after the start of chemotherapy (equivalent
to completion of a neoadjuvant course), the 1- and 2-year
survival rates improve to 56% and 40%.
The best level of evidence supporting a role for EPP in
managing MPM comes from institutional case series, summarized in the review by Flores and colleagues.2 However,
a case-control study from Western Australia raises concerns
about selection bias accounting for any apparent survival
benefit of EPP.6 The study looked at 36 patients who were
referred for trimodality therapy; only half agreed to surgery
or were deemed suitable candidates after further workup.
Prognostic factors such as histology favoured the EPP
group, but overall survival was the same for those who
ended up not undergoing trimodality therapy. The 1- and
2-year survival rates for groups with and without EPP were
Figure 1. Overall survival for patients treated with platinum-based
combination chemotherapy; all treated patients (blue line), and
selected subgroup (black line).
around 75% and 40%, respectively.
Supporting the argument against EPP as part of trimodality therapy are the results of the MARS trial,7 a feasibility
study to assess enrolment in a randomized controlled trial
(RCT) comparing EPP to less aggressive management.
The basic trial design and survival analysis have been criticized
for being underpowered.8 Nevertheless, the MARS trial is
the only RCT of EPP vs no EPP, and 1-year survival was
inferior in the EPP arm: 52% vs 73% with no EPP.
Long-term survival outcomes reported for trimodality
therapy may be primarily a function of selection bias. The
benefit of EPP in the management of MPM is uncertain,
and the evolution to trimodality therapy has been driven
both by the limited ability of radical surgery to achieve
local disease control and persistent concerns regarding distant relapse.
References
1. Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneumonectomy in
the management of diffuse malignant mesothelioma of the pleura. Experience
with 29 patients. Thorax 1976;31:15-24.
2. Flores RM, Pass HI, Seshan VE et al. Extrapleural pneumonectomy versus
pleurectomy/decortication in the surgical management of malignant pleural
mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620-6.
3. Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant pleural mesothelioma.
J Clin Oncol 2009;27:2081-90.
4. Lee CW, Murray N, Anderson H et al. Outcomes with first-line platinum-based
combination chemotherapy for malignant pleural mesothelioma: a review of
practice in British Columbia. Lung Cancer 2009;64:308-13.
5. Hasani A, Sun B, Liu G et al. Systemic therapy usage and outcomes for patients
diagnosed with malignant pleural mesothelioma (MPM) between 2005 and 2010
in Ontario, Canada. J Clin Oncol 2011;29 ( suppl):Abstract 7085.
6. Hasani A, Alvarez JM, Wyatt JM et al. Outcome for patients with malignant
pleural mesothelioma referred for trimodality therapy in Western Australia.
J Thorac Oncol 2009;4:1010-6.
7. Treasure T, Lang-Lazdunski L, Waller D et al. Extra-pleural pneumonectomy
versus no extra-pleural pneumonectomy for patients with malignant pleural
mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery
(MARS) randomised feasibility study. Lancet Oncol 2011;12:763-2.
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supported by data. Lancet Oncol 2011;12:1093-4.
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References from Dr. Marc de Perrot, page 22
1. Finn RS, Brims FJ, Gandhi A et al. Postmortem findings of malignant pleural
mesothelioma: a two-center study of 318 patients. Chest 2012;142:1267-73.
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mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring
systems. Thorax 2000;55:731-5.
3. Kao SC, Pavlakis N, Harvie R et al. High blood neutrophil-to-lymphocyte ratio is an
indicator of poor prognosis in malignant mesothelioma patients undergoing
systemic therapy. Clin Cancer Res 2010;16:5805-13.
4. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed
in combination with cisplatin versus cisplatin alone in patients with malignant
pleural mesothelioma. J Clin Oncol 2003;21:2636-44.
5. van Meerbeeck JP, Gaafar R, Manegold C et al. Randomized phase III study of
cisplatin with or without raltitrexed in patients with malignant pleural
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Canada. J Clin Oncol 2005;23:6881-9.
6. Bottomley A, Coens C, Efficace F et al. Symptoms and patient-reported wellbeing: do they predict survival in malignant pleural mesothelioma? A prognostic
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7. Rice D, Rusch V, Pass H et al. Recommendations for uniform definitions of surgical
techniques for malignant pleural mesothelioma: a consensus report of the
international association for the study of lung cancer international staging
committee and the international mesothelioma interest group. J Thorac Oncol
2011;6:1304-12.
8. Rusch V, Baldini EH, Bueno R et al. The role of surgical cytoreduction in the
treatment of malignant pleural mesothelioma: meeting summary of the
International Mesothelioma Interest Group Congress, September 11-14, 2012,
Boston, Mass. J Thorac Cardiovasc Surg 2013;145:909-10.
9. Weder W, Kestenholz P, Taverna C et al. Neoadjuvant chemotherapy followed by
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10.Rusch VW, Rosenzweig K, Venkatraman E et al. A phase II trial of surgical
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11.de Perrot M, Feld R, Cho BC et al. Trimodality therapy with induction
chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose
hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol
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12.de Perrot M, Feld R, Leighl NB et al. Accelerated hypofractionated hemithoracic
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(EPP) for malignant pleural mesothelioma (MPM): Results of a phase I/II study.
J Clin Oncol 2013;31(suppl):Abstract 7526.
13.Treasure T, Lang-Lazdunski L, Waller D et al. Extra-pleural pneumonectomy versus
no extra-pleural pneumonectomy for patients with malignant pleural
mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery
(MARS) randomised feasibility study. Lancet Oncol 2011;12:763-2.
14.Weder W, Stahel RA, Baas P et al. The MARS feasibility trial: conclusions not
supported by data. Lancet Oncol 2011;12:1093-4.
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