Should all patients who have mesothelioma diagnosed by video-assisted thoracoscopic surgery have their intervention sites irradiated?

Summary

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether patients diagnosed with mesothelioma by video-assisted thoracoscopic surgery should have their intervention sites irradiated to prevent metastatic seeding. Altogether 334 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. There is no general consensus in the literature. Four studies recommend prophylactic irradiation therapy (PIT), while three studies stated that PIT was unnecessary. A systematic review identified only three suitable randomized controlled trials (RCTs) from the literature. One trial found that 23% of radiotherapy (RT) patients developed tract metastases compared to 10% of control patients (P=0.748) with an estimated hazard ratio (RT to control) of 1.28 (95% CI: 0.29–5.73). Time from procedure to tract metastases was in fact shorter in patients treated with RT (2.4 months RT vs. 6.4 months control, non-significant). Another trial found that seeding of metastatic tumour to the intervention site occurred in 7% of RT sites vs. 10% of control sites (P=0.53). Freedom from tract metastasis survival was also non-significant between RT and control arms (P=0.82). However, the third trial reported a significantly greater incidence of intervention site metastases in control vs. RT patients (40% vs. 0%, respectively, P<0.001). Non-randomised studies found mixed results. One reported that median survival between patients with and without local metastases was not significantly different (P=0.64) while another article described no local metastases in PIT sites. None of the studies reported significant skin or side reactions and treatment was generally well tolerated. Based on the available evidence, we conclude that PIT is not currently justified.

Mesothelioma, Radiotherapy, Video-assisted thoracoscopic surgery, Prophylaxis

1. Introduction

A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1].

2. Three-part question

In [patients with malignant pleural mesothelioma diagnosed by video-assisted thoracoscopic surgery] is [intervention site irradiation] superior to [conservative management] in terms of [survival and local recurrence].

3. Clinical scenario

You have diagnosed a patient with malignant pleural mesothelioma (MPM) using video-assisted thoracoscopic surgery (VATS). You think that irradiation of port sites would be advisable and refer the patient for it. The radiation oncologist suggests that there is no benefit of prophylactic irradiation therapy (PIT) as he has noted that patients develop subcutaneous nodules in any case and that moreover, these may often be asymptomatic. You resolve to check the literature yourself.

4. Search strategy

Medline 1948 to January 2011 using OVID interface

[exp VATS/OR exp mesothelioma/] AND [irrad$.mp OR exp radiotherapy/]

5. Search outcome

Three hundred and thirty-four papers were found using the reported Medline search. From the search nine papers were identified that provided the best evidence addressing the specific question. These are presented in Table 1 .

Table 1

Best evidence papers

Author, date and country	Patient group	Outcomes	Key results	Comments
Study type
(level of evidence)
Lee et al., (2009),	Systematic review	Effectiveness of	Less tract metastases with	Underpowered trials
Lung Cancer, UK,	including 3 RCTs (144	prophylactic irradiation	prophylactic irradiation	with small sample
[2]	total patients) and seven	in reducing chest wall	(P<0.001) in only one of	sizes make drawing a
	non-randomised studies,	metastases	three RCTs	definitive conclusion
Systematic review	291 total patients)			difficult. Authors
(level 1b)		Risk of chest wall	Range from 9% to 40%	strongly recommend
		metastases after		that a more highly
		thoracoscopy without		powered RCT be
		PIT		carried out
				Authors also analysed
				UK practice by a
				survey sent to 54
				oncology centres. 75%
				of responding centres
				did use PIT and 78%
				expressed interest in
				carrying out a large-
				scale RCT into PIT
				effectiveness
Di Salvo et al., (2008),	32 patients from 2001	Development of	Zero after mean follow-up of	Radiotherapy shown
Acta Oncol, Italy,	to 2006 with a mean age	metastases at	13.6 months	to be safe and
[3]	at diagnosis of 64 years	intervention site		efficacious in this
	(range 44–84 years)			cohort. Authors
Retrospective cohort study		Tolerance of treatment	Well tolerated with no late	recommend
(level 2b)			effects	radiotherapy to
				prevent tract
			Temporary erythema in 34%	metastases
			of patients
				However, study did
		Survival rate	One year:	not include control
			68.9% (95% CI: 51.8–86)	group and sample
				size was small
			Two-year:
			30.3% (95% CI: 7.6–53%)
Metintas et al., (2008),	46 patients with	Presence of local	13% of patients	Authors conclude that
Lung Cancer, Turkey,	histological diagnosis of	metastases		general
[4]	MPM who underwent			recommendation for
	thoracoscopy from	Effect of local	Patients with local	PIT is not justified and
Retrospective cohort study	1990 to 2005 with no	metastases on survival	metastases:	should be considered
(level 2b)	prophylactic		Nine months (95% CI:	for select patient
	radiotherapy		8.0–10.0)	groups
			10 months (95% CI: 7.4–
			12.6) P=0.64	Incidence of
				metastases was higher
				in patients undergoing
				thoracotomy
				compared to
				thoracoscopy
O’Rourke et al., (2007),	61 patients with	Development of	7/31 XRT patients	Authors conclude that
Radiother Oncol, UK,	histological diagnosis of	metastases at	3/30 BSC patients	radiotherapy does not
[5]	MPM were recruited	intervention site	P=0.748	significantly reduce
	from two centres			incidence of tract
RCT	between 1998 and 2004		Hazard ratio (XRT/BSC): 1.28	metastases
(level 1b)			95% CI: 0.29–5.73
	Stratified by age,			Authors also note that
	performance status and	Time from procedure to	XRT – median 2.4 months	many patients with
	treatment centre	tract metastases	BSC – median 6.4 months	radiotherapy develop
	before randomisation to			metastases anyway
	either radiotherapy			and that smaller
	(XRT) or best			nodules are generally
	supportive care (BSC)			asymptomatic
West et al., (2006),	37 patients with	Development of	32/37 patients – no	Authors conclude that
Respir Med, UK,	diagnosis of MPM from	metastases at	metastases	early radiotherapy and
[6]	2000 to 2003	intervention site		accurate selection of
Retrospective cohort study			3/37 patients – metastases at	field is crucial as lower
(level 2b)			intervention site prior to	doses are received
			radiotherapy	towards field edge
			2/37 patients – metastases
			following radiotherapy
Bydder et al., (2004),	43 patients with	Development of	RT arm: 2/28 sites (7%)	Authors did not
Br J Cancer, Australia,	histological diagnosis of	metastases at	Control arm: 3/30 sites (10%)	demonstrate benefit
[7]	MPM from 1997 to	intervention site	P=0.53	from single dose
	2003			irradiation and they
RCT		Freedom from tract	Not significant between two	recommend triple dose
(level 1b)	There were a total of 58	metastasis survival	arms P=0.82	as prophylaxis
	intervention sites
	randomised to either			Randomisation of sites
	radiotherapy (RT) or			instead of patients is a
	control			potential weakness as
				multiple sites on the
				same patient may not
				behave independently
Boutin et al., (1995),	40 patients with	Development of	RT arm: 0/20 patients (0%)	The authors conclude
Chest, France, [8]	diagnosis of MPM and	metastases at	Control arm: 8/20 patients (40%)	that prophylactic
	life expectancy over three	intervention site	P<0.001	radiation therapy
RCT	months			should be administered
(level 1b)		Tolerance of treatment	Skin discolouration in all	no later than 10–15
	20 patients randomised		patients but no oedema or	days after
	to each arm: radiotherapy (RT)		inflammation	thoracoscopy
	or control
		Time from procedure to	Mean six months (range	Authors also
		tract metastases	1–13 months)	recommend grouping
				entry sites to enable
				irradiation within
				one or two fields
Low et al., (1995),	20 patients with	Development of	0/19 patients at treated sites (0%)	Authors emphasise
Clin Oncol (R Coll Radiol),	diagnosis of MPM	metastases at	4/19 patients at untreated	importance of not
UK, [9]	between 1990 and 1994.	intervention site	sites (21%)	delaying treatment as
	One patient’s notes could			established recurrent
Retrospective cohort study	not be traced and was	Tolerance of treatment	No side effects and minimal	nodules rarely
(level 3)	excluded		skin reactions	regressed completely
				even with treatment
	There were a total of 38
	intervention sites			Study is presented as a
				short report and lacks
				detail on
				characteristics of
				patients
Kara et al., (2010),	19 patients with	Development of	0/19 patients had tumour	Authors conclude that
Asia Pac J Clin Oncol,	diagnosis of MPM	metastases at	progression in treated area	PIT is effective but
Turkey, [10]	between 2006 and 2008	intervention site		acknowledge that a
				larger RCT would be
Retrospective cohort study	Follow-up for median	Tolerance of treatment	Generally well tolerated	advisable
(level 3b)	of 13 months
			Most common side effect	Small sample size and
			was grade 1 erythema	lack of a control group
			(RTOG scale)	are severe limitations
				to this study

RCT, randomized controlled trial; PIT, prophylactic irradiation therapy; MPM, malignant pleural mesothelioma.

6. Results

Lee et al. [2] performed a systematic review of articles assessing the effectiveness of PIT in reducing seeding at intervention sites in MPM patients. Three randomized controlled trials (RCTs) were identified with only the oldestone demonstrating a significant difference between radiotherapy (RT) and control groups. Seven non-randomised studies were also identified with a wide range of RT regimens and a general (though non-significant) trend towards PIT being effective in reducing seeding at intervention sites. Small sample sizes, heterogeneity in study designs and lack of statistical significance significantly weakens the conclusions that can be drawn from these papers.

Di Salvo et al. [3] performed a retrospective cohort study of 32 MPM patients who had received PIT. All surviving patients at a mean follow-up of 13.6 months had no detectable metastatic seeding at their intervention sites. They also noted that the treatment was well tolerated with only temporary and mild (grade I RTOG scale) erythema in 34% of patients. Conversely, Metintas et al. [4] performed a retrospective cohort study of 46 MPM patients who had not received PIT. Metastatic seeding to local intervention sites was detectable in 13% of patients who had undergone thoracoscopy. The authors concluded that the general recommendation for PIT was not justified, especially as the median survival between all patients with and without local metastases was not significantly different (P=0.64).

O’Rourke et al. [5] conducted a trial of 61 MPM patients randomised to either immediate RT treatment (XRT) or best supportive care (BSC). Less than 50% of patients completed the planned 12-month follow-up reducing the power of the study from the intended 80–60%. Seven of 31 XRT patients developed tract metastases compared to three of 30 BSC patients (P=0.748). The associated estimate of the hazard ratio (XRT to BSC) was 1.28 (95% CI: 0.29–5.73). Only two of seven patients completing a questionnaire about their nodule reported it as “uncomfortable a lot”. The authors concluded that PIT was unnecessary as many RT patients would develop nodules anyway and that often, these were asymptomatic.

West et al. [6] carried out a retrospective cohort study on 37 MPM patients. Two patients (5%) developed metastases at the edge of their RT field. A further three patients (8%) already had local metastases present at the interven-tion site prior to RT. There was no metastatic growth within the RT field of treated patients. The authors stress the importance of both early PIT and accurate selection of the RT field as lower doses are received towards the edge.

Bydder et al. [7] conducted a trial of 43 MPM patients with 58 intervention sites randomised to either RT or control. Seeding of metastatic tumour to the intervention site occurred in 7% of RT sites vs. 10% of control sites (P=0.53). This trial used single dose RT compared to the triple dose used in the majority of other studies and the authors recommend a triple dose as standard protocol. A potential weakness of this trial was the randomisation of sites instead of patients as multiple sites on the same patient may not have behaved independently.

Boutin et al. [8] conducted a similar trial in which 40 MPM patients were randomised to either RT or control. This is the classical trial that is often quoted in support of PIT for MPM patients. Eight of 20 patients (40%) in the control arm developed intervention site metastases compared to no patients in the RT arm (P<0.001). On average metastasis took six months to develop (range 1–13) and RT treatment was well tolerated with skin discolouration in all patients but no oedema or inflammation.

Low et al. [9] performed a retrospective analysis of 20 MPM patients with a total of 38 intervention sites that were treated with PIT. One patient was excluded from the analysis and none of the remaining 19 patients had developed metastatic seeding at their treated intervention sites. However, four patients (21%) had additional sites that were untreated and subsequently developed tumour deposits at only these sites.

7. Clinical bottom line

Broadly speaking, five studies recommend PIT [3, 6, 8–10], three studies state that PIT is unnecessary and one recent systematic review [2] concludes that there is a definite need for a high-powered RCT to assess the requirement for PIT as well as the optimum timing and dose. The existing RCTs have small sample sizes and were inadequately powered as they were based on an expected incidence of 40% tract metastases in the control arm. Recent data suggests this may be an overestimate [4]. Given the enthusiasm shown by UK oncology centres for performing a large-scale RCT [2], this would be a sensible step prior to forming further guidelines on the topic. In the meantime, assigning the greatest weight to the existing RCTs as well as considering the other available evidence, we conclude that PIT is not currently justified.