Treatment of intervention sites of malignant pleural mesothelioma with radiotherapy: a Dutch–Belgian survey

doi:10.1016/S0167-8140(03)00229-9

Radiotherapy and Oncology

Volume 68, Issue 3, September 2003, Pages 299-302

https://doi.org/10.1016/S0167-8140(03)00229-9 Get rights and content

Abstract

A survey was performed on the radiotherapy practice of malignant pleural mesothelioma in The Netherlands and Belgium in 2002. Thirty-eight out of 47 centres (81%) responded. Prophylactic radiotherapy to intervention sites is given by 32/38 (84%) centres, with all centres offering palliative radiation. For both prophylactic and palliative indications, all centres use hypo-fractionated schedules. The present study shows that in the radiotherapy community in The Netherlands and in Belgium, a de facto consensus exists that both prophylactic and symptomatic radiotherapy to intervention sites of malignant pleural mesothelioma are effective and that hypo-fractionated schedules should be used.

Introduction

Diffuse malignant pleural mesothelioma is a rare malignant tumour with an increased incidence rate in Europe [6]. Its natural history is characterised by local aggressiveness and invasion, which results in a median survival ranging between 4 and 12 months [6]. Even in very carefully selected patients, neither aggressive single-modality therapy (surgery, radiotherapy, chemotherapy) nor multimodality regimens have resulted in median survival rates consistently exceeding 18 months [2], [3], [4], [9], [10], [11]. Most patients are therefore treated with palliative purposes. Diagnosis is established either by thoracentesis with cytology, closed pleural biopsy, or open pleural biopsy via video-assisted thoracic surgery [2], [5]. Regardless of the procedure used, tumour cell seeding leading to metastases at the biopsy sites occur in about 20% of the patients, but the incidence may be as high as 50% [1]. These subcutaneous metastases are often painful and very difficult to treat with surgery, radiotherapy, or chemotherapy [6]. Prevention of malignant seeding along the tracts of diagnostic and therapeutic intervention procedures has therefore received much attention. One retrospective analysis [7] and two small randomised studies [1], [8], clearly suggest a role for prophylactic radiotherapy, but no firm evidence for its benefit is available.

Obviously, only a large phase III trial could definitively answer the question. In order to get insight into the current practice in The Netherlands and in Belgium as well as the feasibility of such a phase III study, we performed a survey in both countries.

Section snippets

Methods

In 2002, a questionnaire was sent to all radiotherapy departments in The Netherlands and in Belgium.

With regards to prophylactic radiotherapy, the following questions were asked: (1) Were patients suffering from malignant mesothelioma offered prophylactic radiotherapy to the intervention sites on a routine basis? (2) Which radiation schedule is used? (3) How many patients actually receive this treatment annually? (4) Were centres interested in participating in a phase III trial randomising

Response

All 21 radiotherapy centres in The Netherlands responded to the questionnaire and 17 of the 26 radiotherapy departments in Belgium (65%). Overall, 38 of the 47 centres (81%) answered.

Is prophylactic radiotherapy to the intervention sites offered in routine practice?

Prophylactic radiotherapy is offered to all patients in 15/21 (71%) Dutch centres and in 17/17 (100%) Belgian departments. Overall, 32/38 (84%) of the centres thus routinely offer prophylactic radiotherapy to the intervention sites.

What is the radiation schedule used?

Of the 30 centres that deliver radiation as prevention of recurrences and the

Discussion

As patients with malignant pleural mesothelioma have a high incidence of recurrences in diagnostic tracts that are difficult to treat, the role of prophylactic radiotherapy to intervention sites has received considerable attention. In a retrospective study of 20 patients with 38 drainage sites, all tracts were irradiated prophylactically and no in-field recurrences were observed [7]. A first phase III trial randomised 40 patients between radiotherapy to the intervention tracts to a dose of 21

Acknowledgements

All radiotherapy centres in The Netherlands and Belgium are greatly acknowledged for their contribution to this survey.

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The role of prophylactic irradiation of tracts (PIT) to prevent tumor seeding at the site of a diagnostic or therapeutic intervention in patients with malignant pleural mesothelioma (MPM) is controversial. This study aimed to determine the efficacy of PITs in preventing procedure tract metastases (PTM) after a chest wall procedure in MPM.
We searched various databases from inception date to April 2020 for randomized controlled trials (RCTs) comparing PIT with no PIT in patients who had a chest wall procedure for MPM. We assessed the risk of bias of individual RCT using the RoB2 tool. The primary outcome was the occurrence of PTM. Meta-analysis was performed using random-effects model. We employed the GRADE approach to assess the certainty of the evidence.
We identified five RCTs including 737 patients. Two RCTs had a low risk of bias. PIT was associated with a significant reduction in the odds of PTM (odd ratio, 0.55; 95 % confidence interval, 0.32 to 0.95; P-value = 0.03; I² = 13 %; GRADE: moderate certainty). One RCT reported no difference in overall survival outcome with the use of PIT. None of the RCTs performed subgroup analyses. Sensitivity analyses showed similar results when limited to RCTs with low risk of bias.
PIT significantly reduces the occurrence of PTM in patients with MPM who had a diagnostic or therapeutic chest wall procedure.
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Aiming to exclude palliative and prophylactic insertion tract irradiations from the treatment schemes, short series radiotherapy (1–10 fractions) was reported separately. This decision was supported by the findings from De Ruysscher and Slotman in 2003 [12]. Schedules and time-trends were studied for chemotherapy.
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, for which treatment is often limited to palliative combination chemotherapy. Multimodality-therapy, including radical surgery, is largely restricted to clinical trials, leaving its benefit currently unclear. This study aimed to get a comprehensive view on real-world MPM treatment at the Belgian population level, to assess survival and to identify prognostic factors.
The study period covered the incidence years 2004–2012 (N = 1453). Starting from the Belgian Cancer Registry, additional information regarding patient characteristics, diagnosis and treatment was retrieved from multiple data sources. Adjusted cox proportional-hazard regression models using time-dependent covariates were performed to assess survival in relation to treatment patterns and centre volume.
Sixty-nine percent of patients underwent tumour-directed treatment, mostly cisplatin-pemetrexed chemotherapy. Radical surgery was mainly performed in younger patients with epithelioid subtype. Centre volume, surgery and chemotherapy showed a positive relation with survival in univariable analyses, but only chemotherapy remained significantly relevant in multivariable analyses. Younger patients, females, and epithelioid subtypes also independently had a better survival.
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The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial.
We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336.
Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19–1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy.
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The high rates for Belgium and England are somewhat surprising because the value of radiotherapy for port-site prophylaxis has not yet been resolved [29]. Surveys previously suggested that the majority of clinicians in England [30], Belgium and the Netherlands [31] were inclined to prescribe prophylactic radiation of drain sites. However, randomized trials were inconclusive and the issue is currently being addressed in a nationwide randomized trial in the UK (NCT01604005).
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Para el diagnóstico de mesotelioma se requiere distinguir entre afectación mesotelial benigna y maligna, y entre mesotelioma maligno y carcinoma metastásico. Para ello son necesarias técnicas inmuno-histoquímicas realizadas sobre biopsias amplias. La toracoscopia es la técnica de elección, aunque la biopsia con aguja usando técnicas de imagen en tiempo real puede ser muy útil si hay marcado engrosamiento nodular. Es improbable que la cirugía radical (pleuroneumonectomía) sea realmente curativa, por lo que está ganando adeptos la reducción de masa tumoral mediante pleurectomía/decorticación, con asociación de quimioterapia y radioterapia a la cirugía (terapia multimodal). Cuando la resección no es factible se plantea quimioterapia, con pleurodesis o colocación de un catéter pleural tunelizado si se requiere el control del derrame pleural y se reserva la radioterapia para tratar la infiltración de la pared torácica. También es esencial un completo control del dolor (que adquiere particular protagonismo en esta neoplasia) en unidades especializadas.
Diagnosis of malignant pleural mesothelioma requires making the distinction between benign mesothelial hiperplasia and true mesothelioma, and between malignant mesothelioma and metastatic pleural adenocarcinoma. This involves immunohisto-chemical techniques applied on large biopsy specimens, and thoracoscopy is the best choice for obtaining them. Real-time image-guided needle biopsy can also be very helpful in presence of marked nodular pleural thickening. Radical surgery (ie, extrapleural pneumonectomy) is unlikely to cure completely the patient, and cyto-reduction surgery with preservation of the underlying lung (pleurectomy/decortication), with addition of chemo and radiation therapy (muiltimodal treatment) is gaining adepts in the last few years. When surgery is not feasible at all, early chemotherapy -with pleurodesis or placement of a indwelling pleural catheter (to control the effusion if necessary)- is advisable. Radiation therapy should be reserved to treat chest wall infiltration in those cases, and complete control of pain in specialized units is also essential in those patients.
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2015, Archivos de Bronconeumologia
El diagnóstico del mesotelioma pleural maligno presenta 3 importantes retos: es necesario distinguir entre hiperplasia mesotelial benigna y mesotelioma, entre mesotelioma maligno (con subtipos) y carcinoma metastásico, y también se requiere demostrar la invasión de estructuras vecinas a la pleura. Para aclarar los 2 primeros aspectos hay que basarse en un panel de anticuerpos monoclonales con adecuado estudio inmunohistoquímico —realizado por manos muy expertas— y para el tercero hay que apoyarse en biopsias suficientemente amplias y profundas, y la toracoscopia es la técnica de elección. La biopsia con aguja guiada con técnicas de imagen en tiempo real puede ser de gran ayuda cuando existe marcado engrosamiento nodular difuso y derrame pequeño o ausente. Dadas las dificultades de un diagnóstico precoz, es infrecuente que se consiga un tratamiento curativo mediante cirugía radical (pleuroneumonectomía), por lo que en los últimos años está ganando adeptos la liberación de masa tumoral mediante pleurectomía/decorticación, con asociación de quimio y radioterapia a las técnicas quirúrgicas (terapia multimodal). En los casos en que la cirugía no es factible se plantea la quimioterapia (combinando pemetrexed y compuestos de platino en la mayoría de los casos), con pleurodesis o colocación de un catéter pleural tunelizado si se requiere el control del derrame pleural, y se reserva la radioterapia para el tratamiento del dolor asociado a infiltración de la pared torácica o cualquier otra estructura vecina. En todo caso, es esencial un completo tratamiento de soporte para el control del dolor (que adquiere particular protagonismo en esta neoplasia) en unidades especializadas.
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Short communicationTreatment of intervention sites of malignant pleural mesothelioma with radiotherapy: a Dutch–Belgian survey

Abstract

Introduction

Section snippets

Methods

Response

Is prophylactic radiotherapy to the intervention sites offered in routine practice?

What is the radiation schedule used?

Discussion

Acknowledgements

Chest

Clin Oncol

Lung Cancer

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Short communication
Treatment of intervention sites of malignant pleural mesothelioma with radiotherapy: a Dutch–Belgian survey