GOECP/SEOR clinical guidelines on radiotherapy for malignant pleural mesothelioma

Table 1 Infectious Diseases Society of America levels of evidence and grades of recommendation and European Society of Medical Oncology adaptation

IDSA United States Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines		ESMO adaptation of IDSA Grading System
Category, grade	Definition	Category, grade	Definition
Strength of recommendation		Grades of recommendation
A	Good evidence to support recommendation for use	A	Strong evidence for efficacy with a substantial clinical benefit, strongly recommended, strongly recommended
B	Moderate evidence to support recommendation for use	B	Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
C	Poor evidence to support a recommendation	C	Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.), optional
D	Moderate evidence to support a recommendation against use	D	Moderate evidence against efficacy or for adverse outcome, generally not recommended
E	Good evidence to support a recommendation against use	E	Strong evidence against efficacy or for adverse outcome, never recommended
Quality of evidence		Levels of evidence
I	Evidence from > 1 properly randomized, controlled trial	I	Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity
II	Evidence from > 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from > 1 center); from multiple time series; or from dramatic results from uncontrolled experiments	II	Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
III	Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees	III	Prospective cohort studies
		IV	Retrospective cohort studies or case-control studies
		V	Studies without control group, case reports, experts opinions

ESMO: European society for medical oncology; IDSA: Infectious Diseases Society of America.

Table 2 Recommendations for the treatment of malignant pleural mesothelioma using the European Society of Medical Oncology levels of evidence and grades of recommendation adapted from the Infectious Diseases Society of America

Surgery	Chemotherapy	Radiotherapy
For palliation of pleural effusions when patients cannot benefit from chest tube drainage or chemical pleurodesis or when these are not successful (II, A)	The anti-folate/platinum doublet is the only approved standard of care for the first- and second-line treatment of unresectable mesothelioma (I, A); If available, bevacizumab, could be added to the standard treatment in selected patients (II, B)	For palliation of pain related to tumor growth radiotherapy can be considered (II, A)
To obtain diagnostic samples of tumor tissue and to stage the patient (II, A)	Maintenance therapy (switch or continuation) has not yet improved overall survival and patients should be included in these studies (II, A)	The use of radiotherapy to prevent growth in drainage tracts is not proved to be useful (III, A)
To be part of a multimodality treatment, preferably as part of a study (II, A)	Patients in good condition should be recommended to join studies in second line (II, A)	Radiotherapy 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)
To perform a macroscopic complete resection by means of pleurectomy/decortication (III, C)		When postoperative radiotherapy is applied, strict constraints must be adhered to in order to avoid toxicity to neighboring organs, and special, tissue sparing, techniques should be used (II, A)

ESMO: European Society for Medical Oncology; IDSA: Infectious Diseases Society of America.

Table 3 Eighth edition of the tumor, node, metastasis classification for mesothelioma

T	Primary tumor	N	Regional lymph nodes
Tx	Primary tumor cannot be assessed	Nx	Regional lymph nodes cannot be assessed
T0	No evidence of primary tumor	N0	No regional lymphnodemetastases
T1	Tumor limited to the ipsilateral parietal pleura with or without involvement of visceral pleuralmediastinal pleuradiaphragmatic pleura	N1	Metastases in the ipsilateral bronchopulmonary, hilar or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad or intercostal lymph nodes) lymph node)
T2	Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral pleura) with at least one of the following features: Involvement of diaphragmatic muscle. Extension of tumor from visceral pleura into the underlying pulmonary parenchyma	N2	Metastases in the contralateral mediastinal, ipsilateral or contralateral supraclavicular lymph nodes
T3	Locally advanced but potentially resectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, visceral pleura) with at least one of the following features: Involvement of endothoracic fascia; Extension into the mediastinal fat; Non-transmural involvement of the pericardium; Solitary, completely resectable focus of Tumor extending into the soft tissues of the chest wall	M	Distant metastasis
T4	Locally advanced technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral pleura) with at least one of the following features: Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction; Direct transdiaphragmatic extension of tumor to peritoneum; Direct extension of tumor to the contralateral pleura; Direct extension of tumor to mediastinal organs; Tumor extending through to the internal surface of the pericardium with or without pericardial effusion, or tumor involving the myocardium	M0	No distant metastasis
		M1	Distant metastasis present

Table 4 Eighth edition of the tumor lymph nodes metastasis classification for mesothelioma

	T	N	M
Stage IA	T1	N0	M0
Stage IB	T2-T3	N0	M0
Stage II	T1-T2	N1	M0
Stage IIIA	T3	N1	M0
Stage IIIB	T1-T3	N2	M0
	T4	Any N
Stage IV	Any T	Any N	M1

Table 5 Dose constraints in organs at risk

Organs at risk	Dose constraints
Lungs-GTV	V20 < 37%, Mean dose < 20 Gy
Contralateral lung-PTV	V20 < 20%, V5 < 17%, Mean dose < 8 Gy
Ipsilateral lung	V40 < 67%, Mean dose < 36 Gy
Heart defined as pericardial sac	Right mesothelioma V40 < 25%; Left mesothelioma V40 < 35%
Brachial plexus	Maximum dose < 65 Gy
Esophagus	V55 Gy < 30%; Mean dose < 34 Gy
Stomach minus including PTV	Mean dose < 30 Gy
Bowel	Maximum dose < maximum PTV < 55 Gy; D5 cc < 50 Gy
Spinal cord	Maximum dose < 50 Gy
Liver minus GTV	V30 < 45%; Mean dose < 30 Gy
Kidneys evaluated separately	V18 < 33% (or V18 < 50%, if cannot be achieved at ≤ 33%)
Ipsilateral kidney; Contralateral kidney	V25 < 40%; V10 < 10%

GTV: Gross tumor volume; PTV: Planning treatment volume; V: Percent volume of organ permitted to receive specified dose.

Table 6 Dose constraints in organs at risk in mesothelioma radiotherapy treatment

Structure	Heart	Contralateral lung	Ipsilateral lung	Esophagus	Spinal cord
Dose constraints	V40: 0 (< 35%)	V20: 1.5 (< 20%); Mean dose 7 Gy (< 8)	V40: 57 (< 67%); Mean dose: 35 Gy (< 36 Gy)	V55: 0 (< 30%); Mean dose 26 (< 34 Gy)	Maximum dose: 43.7 (< 50 Gy)

In parentheses recommended limit values in relation to those reflected in Table 5 and those recommended by Gómez et al[116].