Lung Cancer (2004) 45S, S93—S96

Considerations for post-operative radiotherapyto the hemithorax following extrapleuralpneumonectomy in malignant pleuralmesothelioma

Suresh Senana,*, Marjan van de Polb

a Department of Radiation Oncology, Vu University Medical Center, De Boelelaan 1117,PO box 7057, 1007 MB Amsterdam, The Netherlandsb Department of Radiation Oncology, Erasmus MC–—Daniel den Hoed Cancer Center, Rotterdam,The Netherlands

KEYWORDSExtrapleuralpneumonectomy;Post-operativeradiotherapy;Early stage malignantpleural mesothelioma;Clinical target volume;Intensity-modulatedradiotherapy

Summary With growing interest in evaluating extrapleural pneumonectomy (EPP) andpost-operative in selected patients with early stage malignant pleural mesothelioma,it is essential that clinical trials should be conducted using a clear and reproducibleradiotherapy protocol. The considerations which have determined the policy of ra-diotherapy planning and treatment delivery for patients with mesothelioma in TheNetherlands are given. As well as general considerations such as patient selection, tar-get volume and critical organ delineation, a dose-fractionation scheme, constraintsrelating to normal tissue, treatment planning, the type of external beam equipment,treatment verification and radiation toxicity and scoring are all taken into account.© 2004 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Extrapleural pneumonectomy (EPP) appears to bea promising treatment approach in selected casesof malignant pleural mesothelioma (MPM), a dis-ease with an otherwise dismal prognosis. However,EPP alone has not been shown to improve survival;the efficacy of EPP is limited by residual tumour,local recurrence, and metastatic disease [1,2]. Asimilar picture was observed when EPP, followed bylow-dose hemithorax irradiation to 30Gy, was com-bined with a boost to sites of previous bulk disease

*Corresponding author. Tel.: +31-20-444-0414;fax: +31-20-444-0410.

E-mail address: s.senan@vumc.nl (S. Senan).

to 50Gy [3]. However, disease control was far supe-rior with loco-regional recurrences reported in only13% of patients after high-dose radiotherapy (54Gy)to the entire hemithorax [4]. The latter results wereachieved despite the use of electron fields in or-der to spare underlying critical structures [5]. Whentwo-dimensional (2D) radiotherapy planning tech-niques were used, most toxicities seen with irradi-ation after EPP were scored as Radiation TherapyOncology Group (RTOG) grades 1 and 2. The low in-cidence of grade 3 toxicities included fatigue, oe-sophagitis, skin reactions, nausea and vomiting, andpneumonitis [4].

There is growing interest in evaluating EPPand post-operative radiotherapy in selected pa-tients with early stage MPM [4—6]. Recently, ac-tive chemotherapy regimens have been identified

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S94 S. Senan, M. van de Pol

[7,8]. The encouraging, but uncontrolled, survivaldata reported in selected patients undergoingtri-modality therapy have led to two proposals forprospective trials. The first is an EORTC single-armstudy evaluating the feasibility of the trimodality(induction chemotherapy, EPP and post-operativehemithorax radiotherapy) approach. The secondis a British study, the mesothelioma and radicalsurgery trial, in which induction chemotherapyis followed by randomisation to either EPP plusradiotherapy or none of the two. An essential re-quirement for conducting these clinical trials is aclear and reproducible radiotherapy protocol. Thispaper summarises the considerations that have de-termined the approach to radiotherapy planningand treatment delivery for these patients in TheNetherlands.

2. General considerations

High-dose radiotherapy after EPP is technicallychallenging due to the proximity of dose-limitingadjacent organs such as the spinal cord, the heartand the liver. Only a few European centres haveexperience with this treatment. An essential pre-requisite for implementing three-dimensional (3D)treatment planning and delivery at an institution isa close multidisciplinary collaboration in relationto the following.

• Careful pre-operative selection of suitable pa-tients based upon performance score, co-morbi-dity and disease extent.

• The general inclusion criteria that includesbiopsy-proven malignant mesothelioma; theabsence of mediastinal nodal metastases; theabsence of distant metastases; normal liver andrenal function; no prior radiotherapy of the lowerneck, thorax or upper abdomen.

• Surgical procedures that can reduce the toxicityof radiotherapy should be routine. These includea low reconstruction of the diaphragm and thecreation of a neo-pericardium in order to limitthe volume of abdominal viscera and heart in thehigh-dose radiotherapy volume.

• The pleural cavity, in particular at the re-section margins that are difficult to identifypost-operatively (such as the anterior-medialpleural reflection, pericardial margins, and theoutline of the resected hemidiaphragm) shouldbe marked by the use of multiple radiopaque sur-gical clips to facilitate contouring of the targetvolume.

• On the basis of pathology or operative findings,a careful delineation of the boost volume to

indicate areas at risk for disease recurrence isnecessary. A joint review of the contoured targetvolumes together with the thoracic surgeon isrecommended.

3. Target volume and critical organdelineation

Patients should undergo a planning computed to-mography (CT) scan and treatment simulation insupine position with the arms above the head, andan immobilisation device should be used to ensurea reproducible position for daily treatments. In-cision and drain sites should be marked using ra-diopaque material and the CT scan will extend tothe pelvic brim in order to include the total re-nal volume. The clinical target volume (CTV), theboost-CTV and the organs at risk are defined withoutlines on each transverse slice of the planning CT.All organs at risk such as contralateral lung, kidneys,spinal cord, liver, heart and oesophagus should becontoured.

The CTV includes the entire ipsilateral thoraciccavity from lung apex to insertion of the diaphragm,ipsilateral mediastinal pleura, ipsilateral pericar-dial surface, and full thickness of the thorax atthe site of the thoracotomy incisions and sites ofchest drains. The mediastinum will not be rou-tinely included except at sites of proven disease. Aboost-CTV (bCTV) that encompasses sites of grossor microscopic residual disease should be sepa-rately contoured. A planning target volume (PTV)will be generated from the CTV and bCTV by theaddition of a 3D margin of at least 1 cm in order toaccount for internal mobility and set-up variations.

4. Dose-fractionation scheme

The use of a dose of 54Gy was associated withgood loco-regional control, and this dose will bedelivered to these patients in 30 once-daily frac-tions (five fractions per week) of 1.8Gy to thePTV. The isodose curve representing 95% of theprescription dose should ideally encompass theentire planning target volume (guidelines of theInternational Commission on Radiation Units andMeasurements–—ICRU 50).

5. Normal tissues constraints

Dose volume histograms will be generated for thecontralateral lung, kidneys, liver, spinal cord, heart

Considerations for post-operative radiotherapy to the hemithorax S95

and oesophagus. The V20, which is the volume ofhealthy lung tissue receiving a total dose of ≥20Gy[9], will have to be 15% or less in order for thepatient to be eligible for full dose post-operativeradiotherapy. The dose to 80% of the contralateral(normally functioning) kidney should be less than15Gy. The maximum dose to the spinal cord shouldnot exceed 50Gy.

There are limited 3D data correlating the radi-ation dose to healthy liver with the risk of toxic-ity. In patients treated by radiotherapy combinedwith concurrent chemotherapy for unresectableintra-hepatic malignancies, no radiation-inducedliver disease was observed when the mean liverdose was lower than 31Gy [10]. The tolerance ofthe liver is likely to be higher with radiotherapyalone, and a mean dose of ≤35Gy will be accepted.No reliable dose-toxicity data is presently availablefor the heart and little is known about the toler-ance of the heart following EPP. Based on data de-rived in the era of 2D radiotherapy planning, it hasbeen recommended that 70% of the heart shouldreceive less than 45Gy, and that the maximumdose should not exceed 60Gy [11]. However, ifresidual disease is present in the cardiac region, itmay be acceptable to deliver a full dose of 54Gy tothe heart.

Underdosing a part of the PTV is considered to beacceptable if the dose to critical organs exceeds theabove-mentioned tolerable dose. The dose in thePTV, however, should be at least 45Gy. The minimalaccepted dose in the boost-PTV should be 54Gy.Chest-wall bolus will be used at incision sites for atleast a part of the treatment in order to ensure thata dose of at least 45Gy is delivered to this site.

6. Treatment planning

Only 3D radiotherapy, i.e. CT-based planning, willbe used and treatment plans will generally be eval-uated by reviewing dose—volume histograms. If thecardiac or hepatic dose constraints cannot be met,a two-phase treatment with a second plan using ad-ditional fields and a match-plane above the level ofthe organ at risk should be evaluated. One optionwould be to use wedged dorso-lateral photon fieldstogether with an anterior electron field. Anotheroption would be to incorporate a boost to only thebPTV, after a dose 45Gy has been delivered to theentire hemithorax.

Intensity-modulated radiotherapy (IMRT) is anadvanced form of conformal planning and deliverythat is based on the use of optimised non-uniformradiation beam intensities incident on the patient[12]. Early experience with IMRT for post-operative

radiotherapy in MPM has been published [6,13].However, this approach requires much additionaltime and effort from physicists and dosimetrists asIMRT planning and delivery systems do not as yetprovide totally automated solutions for all diseasesites [12]. Centres that have expertise with IMRTare encouraged to explore this technique for suchpatients.

7. External beam equipment

Megavoltage equipment will be used with photonenergies of 6—10MV, and electron energies suffi-cient to treat the full thickness of the chest-wall(generally 9—15MV). A multileaf collimator or stan-dard blocks will be used to shape the irradiationportal according to the target volume.

8. Treatment verification

In order to verify patient positioning, either portalimaging films or electronic portal images must beobtained during the course of treatment in accor-dance with standard department protocols.

9. Radiation toxicity and scoring

All acute and late toxicity should be recorded andcorrelated with the radiation dose-distributionin order to generate data for the design of fu-ture protocols. Toxicity will be scored accord-ing to the Common Terminology Criteria for Ad-verse Events version 3.0 (CTCAE v3.0) criteria(http://ctep.cancer.gov/reporting/ctc.html).

Patients are seen at 3-month intervals for thefirst year with a CT scan performed at each visit.In patients without evidence of disease, this willbe changed to 6-month intervals thereafter. Carefuldocumentation of late toxicity will be consideredto be just as important as documentation of sitesof recurrences.

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