Combined Modality Treatment in Mesothelioma

A Systemic Literature Review With Treatment Recommendations

Charlotte De Bondt; Ioannis Psallidas; Paul E. Y. Van Schil; Jan P. van Meerbeeck

Transl Lung Cancer Res. 2018;7(5)

PICO 2: What Is the Optimal Regimen Within Each Modality?

What Is the Optimal PORT-technique?

RT of the pleura is understandably challenging as there is a large surface area to irradiate, the shape is complex and there are vital organs and large vascular structures close to the pleura that need to be shielded from radiation as much as possible.^[33] The evolution towards lung sparing surgical techniques introduces additional difficulty as measures must be taken to avoid radiation pneumonitis or other complications in the spared ipsilateral as well as in the contralateral lung. The most frequently used radiation technique in multimodality treatment protocols for MPM are conventional 3-dimensional conformal RT and intensity modulated RT (IMRT). Conventional 3D hemithoracic RT has shown to be excessively toxic by Gupta et al. and Stahel et al. among others, both in the context of lung sparing surgery and after EPP.^[22,34] IMRT allows for a tailored approach wherein large doses of radiation are administered to the affected pleura and the underlying lung and surrounding tissue are spared.^[35] Helical tomotherapy or dynamic arc RT combines the precision of the IMRT technology with a megavoltage CT-scan. This allows for daily image-guided adjustments, which creates a more precise application of radiation. The fact that the radiation beam moves around the patient while the table moves through the arc enables irradiation of larger areas in a shorter time period.^[36] Sylvestre et al. applied this technique for MPM in 24 MPM patients after EPP and reported a median disease free survival of 24 months. Two patients died of radiation pneumonitis.^[36] Krayenbuehl et al. compared IMRT and 3D conformal RT in 39 MPM patients after EPP. They found a non-significantly longer median time to relapse in the IMRT group (16.2±3.1 versus 10.9±5.4 months with 3DRT). This did not however result in a longer overall survival (22.3±15.3 months for IMRT and 21.2±9.2 months for 3DCRT), probably because of a higher rate of distant relapse.^[33] Rimner et al. evaluated IMRT after CT and P/D and reported a median progression free survival of 12.4 months and a very promising median overall survival of 23.7 months. There were no treatment related deaths. There were 8 cases (30% of patients) of grade 2–3 pneumonitis which responded well to steroid treatment.^[35] In conclusion, IMRT techniques are hence likely to be preferable to 3DRT with regards to toxicity.

What Is the Optimal CT Regimen?

The standard CT regimen in multimodality treatment for MPM is a cisplatin-pemetrexed doublet. Pasello et al. performed a retrospective analysis of 51 patients who received neoadjuvant CT (pemetrexed plus cisplatin or carboplatin) as part of a multimodality treatment approach for MPM. Although they report a similar median progression free survival outcome in both groups (14.5 months in the carboplatin group versus 13.1 months in the cisplatin group), overall survival was significantly longer in the carboplatin group (25.5 versus 15.2 months in the cisplatin group). The authors attribute this to the patients' characteristics being more favorable in the carboplatin group. When they compared outcomes for only epithelioid-type mesothelioma in both groups, the difference was not statistically significant (26.9 months in the carboplatin group versus 18.9 months in the cisplatin group, P=0.054). As expected, cisplatin was tolerated more poorly and treatment with cisplatin resulted in higher numbers of anemia, nausea, vomiting and asthenia as opposed to carboplatin-based therapy.^[37] A Turkish series, in which patients were treated with a pemetrexed-carboplatin doublet similarly showed a better median survival than with a pemetrexed-cisplatin doublet.^[38]

In conclusion, these reports suggest that carboplatin containing regimens could be equally effective and less toxic and thus preferable in a combined modality approach already hampered by other toxicities.

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Next Section

Abstract and Introduction
Methods
Results
PICO 1: Is Multimodality Treatment Better Than CT Alone?
PICO 2: What Is the Optimal Regimen Within Each Modality?
PICO 3: What Is the Optimal Sequence of Combined Modality?
Discussion
Conclusions & Recommendations
Recommendations
References

Table 1. Overview of current guidelines
Group	Published	Guidelines regarding multimodality treatment in MPM	Grade
ESMO	2015	The first- and second-line treatment of unresectable mesothelioma; patients in good condition should be recommended to join studies in second line	II, A
		RT can be given in an adjuvant setting after surgery or chemo-surgery to reduce the local failure rate. However, no evidence is available for its use as a standard treatment	II, A
		The indications for surgery are; to be part of a multimodality treatment, preferably as part of a study	II, A
		To perform a macroscopic complete resection by means of P/D or EPP	III, C
ERS/ESTS	2010	Pleurectomy/decortication should not be proposed in a curative intent but can be considered in patients to obtain symptom control, especially symptomatic patients with entrapped lung syndrome who cannot benefit from chemical pleurodesis. The VATS approach is preferred	IC
		Radical surgery (EPP) should only be performed in clinical trials, in specialized centres, as part of multimodal treatment	IA
		Radiotherapy should not be performed after pleurectomy or decortication. Post-operative irradiation after EPP should only be proposed in clinical trials, in specialized centres, as a part of multimodal treatment. Patients who are considered candidates for this multimodal approach should be included in a prospective randomized trial in specialized centres	IA
BTS	2018	Do not offer extra-pleural pneumonectomy (EPP) in MPM	B
		Do not offer extended pleurectomy decortication (EPD) outside of a clinical trial	D
		Offer patients with MPM with good PS (WHO 0–1) first line therapy with cisplatin and pemetrexed. Where licensed (not presently in the UK), bevacizumab should be added to this regime. Raltitrexed is an alternative to pemetrexed	A
		Where cisplatin is contraindicated, or has adverse risk, offer carboplatin in combination with pemetrexed. First-line clinical trials are an appropriate option for patients with good PS and are recommended above any other option for second-line treatment, providing the patient is of adequate PS. Do not offer preoperative or postoperative radiotherapy in MPM	A
		Do not offer hemithorax radiotherapy for MPM	D
ASCO	2018	Given the very limited activity of second-line chemotherapy in patients with mesothelioma, participation in clinical trials is recommended	Type of recommendation: evidence based; evidence quality: intermediate; strength of recommendation: strong
		Maximal surgical cytoreduction as a single modality treatment is generally insufficient; additional antineoplastic treatment (chemotherapy and/or radiation therapy) should be administered. It is recommended that this treatment decision should be made with multidisciplinary input involving thoracic surgeons, pulmonologists, medical and radiation oncologists	Type of recommendation: evidence based; evidence quality: intermediate; strength of recommendation: strong
		Patients with ipsilateral histologically confirmed mediastinal lymph node involvement should only undergo maximal surgical cytoreduction in the context of multimodality therapy (neoadjuvant or adjuvant chemotherapy). Optimally, these patients should be enrolled in clinical trials	Type of recommendation: evidence based; evidence quality: intermediate; strength of recommendation: strong
		A maximal cytoreduction (either lung sparing or non-lung sparing) should only be considered in patients who meet specific preoperative cardiopulmonary functional criteria, have no evidence of extrathoracic disease, and are able to receive multimodality treatment (adjuvant or neoadjuvant)	Type of recommendation: evidence based; evidence quality: intermediate; strength of recommendation: strong
		Since surgical cytoreduction is not expected to yield an R0 resection, it is strongly recommended that multimodality therapy with chemotherapy and/or radiation therapy should be administered	Type of recommendation: evidence based; evidence quality: intermediate; strength of recommendation: strong
		Chemotherapy may be given pre- or postoperatively in the context of multimodality treatment	Type of recommendation: evidence based; evidence quality: low; strength of recommendation: moderate
		In the context of multimodality treatment, four to six cycles of pemetrexed/platinum-based chemotherapy may be administered pre- or postoperatively	Type of recommendation: evidence based; evidence quality: intermediate; strength of recommendation: moderate

Table 2. PICO
Variable	1: CMT > 1T	2: optimal regimen	3: sequencing
Population	'Resectable' mesothelioma	'Resectable' mesothelioma	'Resectable' mesothelioma
Intervention	Bimodality, trimodality	EPP, 3D conformal TRT, cisplatin-pemetrexed	Postoperative
Comparison	Single modality (resection)	e-P/D, IMRT, non-cisplatin-pemetrexed	Pre-operative
Outcome	Outcome, toxicity/complications/mortality/QoL/PROM, compliance, recurrence

CMT, combined modality treatment; 1T, single modality treatment; EPP, extrapleural pneumonectomy; TRT, thoracic radiotherapy; e-P/D, extended pleurectomy decortication; IMRT, intensity modulated radiotherapy; QoL, quality of life; PROM, patient reported outcome measures.

Table 3. Type and number of fatal toxicities by treatment group in prospective combined modality treatment trials for MPM
Trial	Treatment protocol	Grade 5 toxicity
EORTC 2010	NA CT + EPP + HTRT	Pulmonary embolism [1], combined lung edema and pneumonia [1], pneumonia [2]
MARS 2011	NA CT + EPP + HTRT vs. CT	Aortic rupture during EPP [1], bronchopneumonia [1], unknown cause [1]
SAKK 2015	NA CT + EPP +/− HTRT	Pneumonitis [1], pulmonary embolism and right heart failure [2], cardiac arrest [1], diaphragmatic patch failure [1], septic multiorgan failure [1]
Bille 2012	NA CT + EPP + HTRT	Aortic rupture during EPP [1], pulmonary embolism [1], pneumonia [1], sepsis [1]
JMIG 0601 trial	NA CT + EPP + HTRT	ARDS [3], cardiac herniation and hemothorax [1]
Minatel 2015 (30)	P/D + IMRT	Pneumonitis [1]
Krug 2009 (31)	NA CT + EPP + HTRT	Pneumonitis [1], bronchopleural fistula [1], sepsis [1]
De Perrot 2009	NA CT + EPP + HTRT	Cardiac herniation [1], cardiac arrhythmia [1], bronchopleural fistula with empyema [1]
De Perrot 2016 SMART	IMRT + EPP +/− CT	Empyema [2], cardiac arrest [1]
Federico 2013	NA CT + EPP + HTRT	Cardiopulmonary [2], empyema [1], cardiac arrest [1], sepsis [2]

NA, neo-adjuvant; CT, chemotherapy; EPP, extrapleural pneumonectomy; HTRT, hemithoracic radiotherapy; IMRT, intensity modulated radiotherapy.

Table S1. Results of systematic review of literature
Reference	Design	Other type of trial: define in words	Date of publication	Number of patients	Type of intervention (define in words)	Results description according to the endpoint	Attrition bias?	Reporting bias?	Overall
(9)	4	Phase I clinical study	2015	36	(NA chemotherapy) + lung sparing surgery + IMRT or NA chemotherapy + IMRT	Acceptable toxicity	No	No	Better survival in + IMRT group as opposed to IMRT alone
(10)	4	ERS-ESTS Guidelines	2010	–	–	–	–	–	See Table 2. To be updated in 2018
(11)	4	ESMO clinical Guidelines	2015	–	–	–	–	–	See Table 2
(12)	4	ASCO Guidelines	2018	–	–	–	–	–	See Table 2. Conservative position regarding role of surgery and radiotherapy, based on low quality evidence
(13)	4	BTS Guidelines	2018	–	–	–	–	–	See Table 2. Strong recommendation to avoid monotherapy with surgery, based on intermediate quality evidence
(15)	1	Not applicable	2017	19,134	–	Best survival outcomes in patients treated with combined modality approach	–	–	Large database analysis supporting implementation of combined modality treatment. 40% of patients did not receive any MPM specific treatment
(16)	1	Not applicable	2017	20,561	–	2.6% of patients received trimodality therapy. Patients treated at an academic centre or who travel >26 miles for treatment were more likely to undergo trimodality therapy. Younger age, satisfactory overall condition and presence of private insurance also increased likelihood of multimodality treatment	–	–	Large database analysis reporting low numbers of patients treated with surgery-based multimodality therapy. Use of combined modality treatment is stable over time
(18)	1	Not applicable	2016	229	True adjuvant therapy vs. neo-adjuvant therapy vs. therapy reserved until disease progression vs. conservative in those unfit for chemotherapy	True adjuvant chemotherapy may be beneficial in those with a poorer prognosis based on cell type and nodal stage	No	Yes	Overall survival similar in all chemotherapy groups, even when calculated from time of diagnosis
(19)	3	Not applicable	2011	112	Chemotherapy followed by EPP and radiotherapy or no EPP	Hazard ratio for overall survival after factor adjustments was 2.75, P=0.016)	No	No	Good quality clinical trial showed high mortality on EPP group
(20)	2	Not applicable	2012	25	EPP, neoadjuvant chemotherapy and adjuvant radiotherapy	18.2 treatment mortality, 81% completed trimodality treatment, median survival of 12.8 months	Yes	No	Moderate case series report with shows similar survival with chemotherapy only
(21)	4	Systematic review	2017	–	Radical surgery and debulking surgery	More RCTs required	–	Yes	Author was co-investigator on the MARS1 trial and is part of ongoing MARS2 trial
(22)	3	Not applicable	2015	151	Neoadjuvant chemotherapy followed by EPP and control/treatment group of radiotherapy	Median locoregional relapse free survival was 7.6 months in the no radiotherapy group and 9.4 months in the radiotherapy group showing no support use of radiotherapy after chemotherapy + EPP	No	No	Study terminated earlier than expected due to slow accrual. Good quality study showing no clinical benefit of post-surgery radiotherapy and an overall survival of 20 months - less than other retrospective studies
(23)	2	–	2015	42	Induction chemotherapy, EPP and adjuvant radiation	Macroscopic complete resection of 71% and mortality of 9.5%	No	No	Prospective cohort that shows trimodality treatment is feasible in Japan
(24)	4	Systematic review	2018	–	Radical surgery ± radical RT ± photodynamic therapy ± systemic therapy vs. each other or vs. palliative care	Not enough evidence supporting routine implementation of multimodality treatment	No	No	Systematic review based on two multimodality treatment trials, including the already heavily cited MARS1trial. Limited added benefit
(25)	2	–	2010	36	Neoadjuvant chemotherapy	Significant improvement in FEV1 (0.13±0.30 L; P=0.01), in VO2 peak (1.76±2.91 mL kg−1 min−1; P=0.005), in PaO2 at rest (4.76±9.84 mmHg; P=0.03) and in PaO2 at peak exercise (6.26±12.72 mmHg; P=0.04) was detected. Diffusion capacity was increased but non-significantly	No	No	Most significant lung function improvement in patients who showed response to chemotherapy, effect of overall better condition or true chemotherapy effect?
(26)	3	Phase II clinical study- no control group	2010	59	Induction chemotherapy followed by EPP followed by radiotherapy	Trimodality treatment completed in 64.9% of patients. 24/42.1% patients met success of treatment (primary end point) and median overall survival was 18.4 months	No	No	Good quality clinical study showed that TMT is feasible but did not met the definition of success as per primary endpoint
(27)	4	Phase I/II clinical study	2016	62	IMRT followed by EPP and adjuvant chemotherapy (SMART protocol)	Ongoing phase II study—SMART protocol is feasible and 39% developed 3 + complications, 4.8% developed grade 5 complications and died	No	No	Moderate quality study suggesting a protocol with high complications to a selective population
(28)	4	Phase II clinical study- no control group	2013	56	Chemotherapy followed by EPP followed by radiotherapy	Median event free survival (EFS) was 6.9 months, 33% achieved 1 year EFS and 24% 2 years EFS. Median PFS was 8.6 months and 1 year PFS 40.7%	No	No	Good quality phase II study shows trimodality treatment is feasible in highly selective population
(29)	1	Not applicable	2009	60	Chemotherapy followed by EPP followed by radiotherapy	50% patients completed protocol, 5-year survival 53% of those completed the protocol-median survival of all patients included was 14 months	No	No	High selective population-retrospective study with 6.7% mortality of EPP
(32)	4	Systematic review	2012	16 studies, 744 patients	Radical pleurectomy followed by chemotherapy (Cis-Pem) and radiotherapy	Inconsistent results of long term survival from current studies	No	No	Good quality systematic review shows inconsistent results between prospective/retrospective and 1 randomized trial no allowing definitive conclusions to be drawn for the surgical procedures
(33)	1	Not applicable	2014	39	Postoperative highly conformal versus 3D conformal radiotherapy	Better local control in treatment group, problematic distant relapsing affecting overall survival	No	Yes	The more conformal, the lesser toxicity
(35)	4	Phase II clinical study- no control group	2016	45	Chemotherapy followed by PD followed by hemithoracic intensity modulated pleural radiation therapy (IMPRINT)		Less than 50% of enrolled patients did not undergo surgery	No	Moderate quality clinical study which showed the safety of IMPRINT but not established any clinical use
(36)	1	Not applicable	2011	24	Helical tomotherapy radiotherapy after chemotherapy and EPP or chemotherapy only	HT had comparable toxicity compared to IMRT	No	No	Retrospective study which suggests that HT is safe based on a retrospective study
(37)	1	Not applicable	2012	51	Induction chemotherapy (carboplatin or cisplatin) followed by EPP or PD and radiotherapy	Response rate of 22% (carboplatin) versus 17 (cisplatin). Higher grade 3 anaemia on the carboplatin group	No	No	Moderate quality retrospective study with selection bias not clear conclusions to be drawn
(39)	3	Not applicable	2014	25	IMRT followed by EPP and adjuvant chemotherapy (SMART protocol)	Feasibility study with 25 patients completed trial with no grade 3–5 toxicities	No	No	82% of patients screened were not eligible for the study. Selective population only conclusion that can be drawn is that IMRT followed by EPP is feasible on a selective population
(42)	1	Not applicable	2017	20,561	–	Cancer-directed surgery, chemotherapy, and radiation therapy were associated with improved survival (hazard ratio, 0.77, 0.74, and 0.88, respectively)	No	Yes	Immortal time bias
(30)	2	Not applicable	2015	69	PD or extended P/D, chemotherapy and radiotherapy (IMRT)	OS, PFS and locoregional control no different between groups	No	Not clearly demonstrated results	Moderate quality prospective study showing a high OS post PD and no toxicities post radiotherapy
(31)	4	Phase II clinical study- no control group	2009	77	Chemotherapy followed by EPP followed by radiotherapy	median survival of 16.8 months, 5% of EPP pathological complete response was observed	No	No	Clinical study that showed feasibility of TMT on a selective population
(43)	1	Not applicable	2015	169	Extrapleural pneumonectomy (EPP) and chemotherapy and radiotherapy	75% of patients developed recurrent disease with multimodality treatment	No	Yes	Poor quality retrospective analysis with variabilities on chemotherapy and radiotherapy among patients
(44)	1	Not applicable	2102	530	Extrapleural pneumonectomy and chemotherapy and radiotherapy	Median survival of multimodality group 317 days	No	No	Poor quality retrospective analysis, no control group for comparison, relative risk of death between multimodality treatment and untreated 0.57 and 0.61 respectively
(45)	1	Not applicable	2015	53	Adjuvant radiotherapy following EPP	18.7 months follow up survival	No	Yes	Poor quality retrospective analysis, no control group for comparison, selection bias and no regular reporting of CT scans
(46)	2	Not applicable	2012	25	EPP, neoadjuvant chemotherapy and adjuvant radiotherapy	28% average increase in FVC and 23.9% increase in FEV1	Yes (9 patients excluded)	No	Moderate case series report which shows improvement of FVC/FEV1 post trimodality treatment with high mortality rates and poor design
(47)	2	Not applicable	2011	102	Radical pleurectomy (RP) followed by chemotherapy (Cis/Pem) and radiotherapy	Surgical morbidity and mortality were 20% and 2.9%. Trimodality mortality was 5.8%	Yes	Yes from the initial 102 patients only 35 included in the analysis and not clear why the rest were not included	Moderate case series showing a lower mortality-morbidity rate with RP
(48)	1	Not applicable	2009	55	Induction chemotherapy, EPP and adjuvant radiation	Overall mortality after EPP 4.3%	Yes	No	Poor quality case series with selection bias, most aggressive cases were excluded from the cohort
(49)	2	Not applicable	2015	24	Intensity modulated radiation therapy after pleurectomy/decortication (PD) or EPP	IMRT post PD produced high grade toxicity but better overall survival compared to IMRT post EPP	No	Yes-minimal information for the matched control group	Poor quality study
(50)	4	Phase I clinical study	2012	3	EPP followed by hemithoracic IMRT	1 patient had grade 2 complication, 1 developed recurrence	No	No	Phase I feasibility study
(51)	1	Not applicable	2012	41	Chemotherapy followed by EPP followed by radiotherapy	1 year survival was 45% (overall) and patients with trimodality therapy showed significantly better survival rates after 1, 2, 5 years	No	No	Good quality retrospective study suggests that trimodality treatment should be considered in highly selected patients
(52)	3	Not applicable	2011	38	PD and photodynamic therapy	Median progression free survival (PFS) 9.6 months and median survival of 31.7 months	No	No	Retrospective study with selection bias suggesting the safety of lung sparing surgical approach
(53)	1	Not applicable	2009	36	EPP, adjuvant chemotherapy and radiotherapy	Mortality of 11%, PFS was 19 months	No	No	Retrospective study with selection bias, total mortality of 11%
(54)	1	Not applicable	2015	17	Induction chemotherapy, EPP and adjuvant radiation using volumetric modulated arc therapy (VMAT)	1 year overall survival and progression free survival of 43.1% and 55.7 respectively	No	No	Retrospective study which shows suggests that VMAT is safe
(55)	2	Not applicable	2016	210	Registry-no interventions planned	Differences on population treated with MTM compared to chemotherapy or best supportive care	No	No	Registry that shows patients who were treated with MTM were significantly younger, fitter and with better PS
(56)	1	Not applicable	2009	26	Chemotherapy followed by EPP followed by radiotherapy (IMRT)	1 patient died from intracranial hemorrhage, 4 patients had grade 5 toxicities	No	No	Retrospective study focusing on toxicities post radiotherapy
(57)	2	Not applicable	2015	186	Induction chemotherapy followed by EPP	Prognostication score based on database results proposed	No	No	No validation cohort to assess prognostication score-limited use at this stage
(58)	1	Not applicable	2013	103	Hyperthermic intraoperative pleural cisplatin chemotherapy	Patient on treatment group exhibited a significantly longer interval to recurrence (27.1 vs. 12.8) and overall survival (35.3 vs. 22.8) compared to control	No	No	Poor quality retrospective study with highly heterogenous groups
(59)	2	Not applicable	2015	62	Chemotherapy followed by EPP followed by radiotherapy	Overall survival was 20.4 months, no grade 4 toxicities with radiotherapy	No	No	Retrospective study of moderate quality
(60)	2	Not applicable	2009	83	Chemotherapy followed by EPP (or EPP followed by chemotherapy) followed by radiotherapy	Overall survival of 14.9 months, 4.8% mortality rates	No	No	Retrospective study showed site experience on trimodality treatment

Design: 1= retrospective series; 2= prospective observational cohort; 3 =randomised controlled trial; 4= other. CT, chemotherapy; EPP, extrapleural pneumonectomy; HT, helical tomotherapy; IMRT, intensity modulated radiotherapy; MCR, macroscopic complete resection; NA, neo-adjuvant; OS, overall survival; PD, pleurectomy decortication; PFS, progression free survival; RP, radical pleurectomy.

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Combined Modality Treatment in Mesothelioma

A Systemic Literature Review With Treatment Recommendations

PICO 2: What Is the Optimal Regimen Within Each Modality?

What Is the Optimal PORT-technique?

What Is the Optimal CT Regimen?

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Combined Modality Treatment in Mesothelioma

A Systemic Literature Review With Treatment Recommendations

PICO 2: What Is the Optimal Regimen Within Each Modality?

What Is the Optimal PORT-technique?

What Is the Optimal CT Regimen?

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