The conundrum of hodgkin lymphoma nodes: To be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines

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1 Radiotherapy and Oncology 88 (2008) Hodgkin guidelines The conundrum of hodgkin lymphoma nodes: To be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines Theodore Girinsky a, *, Lena Specht b, Mithra Ghalibafian a,1, Veronique Edeline c, Guillaume Bonniaud d, Richard Van Der Maazen e, Berthe Aleman f, Amaury Paumier a, Paul Meijnders g, Yolande Lievens h, Evert Noordijk i, Philip Poortmans j, on behalf of the EORTC-GELA Lymphoma Group a Department of Radiation Oncology, Institute Gustave Roussy, Villejuif, France, b The Finsen Centre Rigshospitalet, Copenhagen University Hospital, Denmark, c Department of Nuclear Medicine, Centre René Huguenin, Saint Cloud, France, d Department of Nuclear Medicine, Institut Gustave Roussy, Villejuif, France, e Department of Radiotherapy, Nijmegen, The Netherlands, f Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands, g Department of Radiotherapy, Antwerpen, Belgium, h Radiotherapy Department, Leuven, Belgium, i Department of Clinical Oncology, Leiden University Medical Center, The Netherlands, j Department of Radiotherapy, Dr. Bernard Verbeeten Institute, LA Tiburg, The Netherlands Abstract Purpose: To develop easily applicable guidelines for the determination of initially involved lymph nodes to be included in the radiation fields. Patients and methods: Patients with supra-diaphragmatic Hodgkin lymphoma. All the imaging procedures were carried out with patients in the treatment position. The prechemotherapy PET/CT was coregistered with the postchemotherapy CT simulation for planning purposes. Initially involved lymph nodes were determined on fused prechemotherapy CT and FDG-PET imaging data. The initial assessment was verified with the postchemotherapy CT scan. Results: The classic guidelines for determining the involvement of lymph nodes were not easily applicable and did not seem to reflect the exact extent of Hodgkin lymphoma. Three simple steps were used to pinpoint involved lymph nodes. First, FDG-PET scans were meticulously analysed to detect lymph nodes that were overlooked on CT imaging. Second, any morphological and/or functional asymmetry was sought on CT and FDG-PET scans. Third, a decrease in size or the disappearance of initially visible lymph nodes on the prechemotherapy CT scan as compared to the postchemotherapy CT scan was considered as surrogate proof of initial involvement. Conclusions: All the radiological procedures should be performed on patients in the treatment position for proper coregistration. It is highly advisable that all CT and/or CT/PET scans be performed with IV contrast. Using the abovementioned three simple guidelines, initially involved lymph nodes can be detected with very satisfactory accuracy. It is also emphasized that the classic guidelines (2, 3, 4) can always be used when deemed necessary. c 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 88 (2008) Keywords: Involved lymph nodes; Involved node radiotherapy; EORTC-GELA guidelines; Hodgkin lymphoma The new concepts and guidelines on involved node radiotherapy (INRT) were recently published by the EORTC-GELA group [1]. Proper implementation of these new concepts entails following simple and pragmatic guidelines so that initially involved lymph nodes can be accurately identified. Current definitions of involved lymph nodes in Hodgkin and non-hodgkin lymphoma patients are variable and a threshold of cm in the longest transverse diameter is usually 1 Present address: Department of Radiation Oncology, Mahak Hospital, Tehran, Iran. accepted [2 4]. These definitions may also be inaccurate because lymph node architecture can be modified without much change in the size of lymph nodes, as previously demonstrated with the use of lymphography [5 7]. Moreover, on transverse CT slices, cross-sectioned lymph nodes are shown in various directions, making the size criterion less reliable. The conundrum is compounded by two additional factors: interobserver variability in the detection of involved lymph nodes [8] and the frequent difficulty of measuring poorly defined tumour masses. Relying on its long experience, the EORTC lymphoma Group decided to set /$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi: /j.radonc

2 T. Girinsky et al. / Radiotherapy and Oncology 88 (2008) practical guidelines to help radiation oncologists design INRT fields, notably in cervical and axillary areas. These practical guidelines are based on the coregistration of properly performed imaging procedures carried out before and after chemotherapy with patients in the treatment position. As mediastinal tumour masses are easier to define, we did not include this lymph node region in the manuscript which should be considered as an addendum to the guidelines reported earlier [1]. Patients and methods Patients Patients entered in the H10 trial. Methods All the radiological procedures were performed with patients in the treatment position and whenever possible using IV contrast. Lymph node involvement was determined by two radiation oncologists and a nuclear medicine physician (TG, MG and VE). The assistance of a radiologist was obtained when required. The prechemotherapy PET/CT was coregistered with the postchemotherapy CT simulation for planning purposes. Initially involved lymph nodes were first identified on the prechemotherapy CT scan. Initial involvement was verified, first, by adding the prechemotherapy FDG-PET, and second by using the CT simulation performed 2 3 weeks after the end of chemotherapy. A decrease in size or the disappearance of the contoured lymph nodes was considered as surrogate proof of initial involvement, bearing in mind that occasional lymph node enlargement due to benign causes might also be affected by chemotherapy. Results Fifteen patients with localized supra-diaphragmatic Hodgkin lymphoma were entered in the study. Not all the examples shown in the figures were contrastenhanced because we wanted to show how difficult it is to identify initially involved lymph nodes without IV contrast and we also wanted to display the most suitable examples. Lymph node measurements are not easily implementable or useful Measuring all the lymph nodes on each CT slice is extremely tedious, time consuming and therefore cannot be implemented on a daily basis. As shown in Fig. 1, measuring each lymph node [6] would have been unnecessary as all of them were initially involved (the left cervical area was in complete remission (CR) after chemotherapy). In addition, Fig. 1. (A) A few poorly identifiable lymph nodes in the left cervical area on an axial CT slice without IV contrast before chemotherapy. (B) FDG- PET image of the same area. (C) Measurements of the largest lymph nodes (3.7, 4.6 and 11.1 mm). (D) The left cervical area after chemotherapy.

3 204 Involved lymph nodes in Hodgkin lymphoma Fig. 2. (A) Poorly delimited tumour mass of the right supra-clavicular area on a prechemotherapy CT scan. (B) FDG-PET image of the same area. (C) The right supra-clavicular area after chemotherapy. Fig. 3. (A) A small lymph node in the left cervical area. (B) Measurement of the lymph node (4.5 mm). (C) FDG-PET image of the left cervical area demonstrating no suspicious PET avidity. (D) Left cervical area after chemotherapy with the disappearance of the lymph node. (This finding is highly suggestive of initial involvement). as mentioned before, lymph nodes may be cross-sectioned differently depending on their position relative to the CT slices. Moreover, measurements of poorly delimited tumour masses that are not easily distinguishable from normal tissues or organs can be extremely difficult (Fig. 2). It is noteworthy that even small non-avid lymph nodes (less than 1 cm) on PET may contain disease (Figs. 1 and 3). This might be explained by a modification of internal lymph node architecture caused by Hodgkin lymphoma without any increase in size.

4 T. Girinsky et al. / Radiotherapy and Oncology 88 (2008) Fig. 4. (A) An obvious involvement of the mediastinum on a prechemotherapy CT scan. (B) FDG-PET pinpointing involvement of an internal mammary lymph node. (C) The mediastinal area after chemotherapy. (D) A conspicuous mediastinal involvement on a prechemotherapy CT scan. (E) FDG-PET also showing axillary lymph nodes. (F) Postchemotherapy CT scan of the mediastinal area. Fig. 5. (A) Mediastinal involvement that is difficult to differentiate from large blood vessels. (B) FDG-PET demonstrates hilar and subcarinal lymph nodes. (C) Postchemotherapy CT scan. (D) Prechemotherapy CT scan of the thorax. (E) FDG-PET pinpoints a small left axillary lymph node. (F) The axillary area after chemotherapy.

5 206 Involved lymph nodes in Hodgkin lymphoma Fig. 6. (A) Three small lymph nodes (less than 1 cm) are visible in the right cervical area in contrast with the normal left area. (B) Measurements of two lymph nodes (7.4 mm and 9.4 mm). (C) Two of the lymph nodes are PET avid. (D) The total disappearance of the three lymph nodes strongly suggests their initial involvement. Fig. 7. (A) Small lymph node visible in the left retroclavicular area. (B) The measurement of the lymph node shows that its largest diameter is less than 1 cm (8.1 mm). (C) FDG-PET of the retroclavicular area showing the lymph node. (D) Disappearance of the lymph node after chemotherapy. Assessment of initial lymph node involvement: practical guidelines Assessment of initially involved lymph nodes should be carried out with the full knowledge of the extent and biology of the disease (for example: multiple small lymph nodes adjacent to an obviously involved area are very likely to be involved). Usefulness of FDG-PET CT assessment of lymph node involvement can be extremely difficult. A lymph node can be mistaken for a muscle or a blood vessel (especially if CT was performed without IV contrast) (Figs. 4 and 5). Fig. 4 demonstrates that obvious lymph node involvement can preclude the detection of other lesions in the vicinity. Fig. 5a c shows that FDG-PET can be particularly useful when CT is performed without IV contrast. Small lymph nodes (less than cm in their greatest diameter) are often considered disease-free on CT. Fig. 5d f, Figs. 6 8 demonstrate that such lymph nodes were actually involved initially and could easily have been overlooked without a proper FDG-PET examination in the treatment position. Asymmetry on CT and/or FDG-PET Comparing both sides on prechemotherapy CT and/or FDG-PET can be useful for cervical and/or axillary areas

6 T. Girinsky et al. / Radiotherapy and Oncology 88 (2008) Fig. 8. (A) Apparently normal hilar areas before chemotherapy. (B) FDG-PET showing a small right hilar lymph node. (C) An apparently normal precarinal area on CT without IV contrast before chemotherapy. (D) FDG-PET showing a small precarinal lymph node. Fig. 9. (A and B) Slight asymmetry which only exists in the left axillary area on CT and FDG-PET before chemotherapy. (C) Disappearance of the lymph node after chemotherapy. and/or internal mammary lymph nodes. Figs. 6, 9 and 10 demonstrate the diagnostic value of such asymmetry. Fig. 6 shows asymmetry between both cervical areas with small lymph nodes of less than 1 cm in the right area. Suspicion of initial involvement increased because most lymph nodes were PET avid. Initial involvement was confirmed when complete remission was observed on the postchemotherapy CT scan. Slight asymmetry existed in the left axillary area on CT and on FDG-PET (Fig. 9) and disappeared after chemotherapy. Fig. 10 shows asymmetry of the right internal mammary lymph node chain on CT and FDG-PET which regressed after chemotherapy. Comparison of pre- and postchemotherapy CT scans in the treatment position In a few cases, lymph node involvement could well prove persistently difficult to assess (the largest diameter of lymph nodes is less than cm and lymph nodes are not FDG-PET avid). In such cases, comparing pre- and postchemotherapy CT scans (or PET/CT) of the patient in the treatment position is of paramount importance. As mentioned above, not all the lymph nodes are necessarily FDG avid, and therefore the use of IV contrast is strongly recommended. Figs. 3 and 6 show small, non-avid lymph nodes on PET which disappeared after chemotherapy, strongly suggesting their initial involvement. The same reasoning can be applied to small, non-avid lymph nodes on PET located between larger nodes (Fig. 1). Design of an involved node field As shown in Fig. 12, the design of an involved node field should encompass the area in which the involved nodes are located. The entire area should be contoured on a

7 208 Involved lymph nodes in Hodgkin lymphoma Fig. 10. (A and B) Asymmetry in the internal mammary lymph node chains on CT and FDG-PET. (C) Disappearance of asymmetry after chemotherapy. Fig. 11. Heterogeneous PET avidity of the bulky mediastinal tumour mass. prechemotherapy CT scan as it would be impossible to pinpoint the exact location of every single lymph node on a CT simulation performed after chemotherapy. Various examples will soon be available on the EORTC website: groups.eortc. be/lymphoma. Discussion Involved node radiotherapy (INRT) guidelines were recently published by the EORTC group [1]. The guidelines were based on the assumption that the current definitions of node involvement in patients with Hodgkin and non-hodgkin lymphoma (NHL) would suffice to design such fields. During the Costwolds meeting in 1989 [2], the international committee suggested that a cross-sectional diameter of more than 1.5 cm on a CT scan was unequivocally abnormal in patients with Hodgkin lymphoma. In 1999, an international workshop report [3] on response criteria in NHL patients stipulated that any lymph node exceeding 1 cm in its longest transverse diameter should be considered involved in the case of NHL. Devising INRT fields based on these definitions would be a daunting task chiefly because measurements should be performed on each CT slice before chemotherapy. Moreover, internal lymph node architecture can change in the absence of significant node enlargement [5 7] and lymph nodes might be cross-sectioned in manifold directions rendering measurement on CT slices less reliable.

8 T. Girinsky et al. / Radiotherapy and Oncology 88 (2008) A possible method for identifying initially involved lymph nodes would be to assess response after chemotherapy using the published guidelines. In 1999, the international workshop [3] also concluded that a lymph node with a cm cross-sectional diameter after treatment should be considered as normal. The recently published revised response criteria for malignant lymphoma [4] used the same lymph node size thresholds. Using these contouring criteria for radiotherapy would signify measuring every single lymph node before and after chemotherapy in patients with variably FDG-PET avid lymphomas or lesions of unknown avidity. The detection of initially involved nodes would then become extensively time consuming work, and more likely than not, would never be implemented in daily clinical practice. Moreover, these measurements would be of doubtful value since we demonstrated that lymph nodes smaller than 1 cm can be initially involved (Figs. 1,3, and 6). Owing to all these considerations, the EORTC group decided to develop a simple and practical methodology to help radiation oncologists devise INRT fields. All the patients should have a CT and FDG-PET examination in the treatment position prior to chemotherapy and a CT simulation after chemotherapy. All the imaging procedures should be carried out with IV contrast. It must be emphasized that the help of a radiologist and a nuclear medicine physician is strongly advised, although such an assistance is not always readily available in daily clinical practice. It must also be underlined that the classic guidelines [2 4] can always be used when deemed necessary. The diagnostic usefulness of FDG-PET was recently underlined by Valette et al. [9] who demonstrated a very close correlation between results obtained with FDG-PET and lymphography in patients with negative infradiaphragmatic CT scans. In Hodgkin lymphoma unlike that observed in non-hodgkin lymphoma, lymph node involvement can manifest itself either as enlargement or the node may exhibit a modified architecture which is visible only on lymphography [6,7]. However, under no circumstances whatsoever should volume delineation be performed on FDG-PET alone because small initially involved lymph nodes (Figs. 1, 3 and 6) might not be PET avid, large tumour masses might exhibit very heterogeneous PET avidity (Fig. 11) and finally because often, only a portion of Hodgkin tumour masses is PET avid [10,11] (Fig. 11). We propose the following practical steps for identifying initially involved lymph nodes: First, a meticulous analysis of FDG-PET scans to identify lymph nodes that were overlooked on CT imaging [10,11]. Second, in the absence of bilateral involvement, asymmetry should be sought on both CT and on PET.Although the first two steps are of paramount importance for proper determination of initially involved lymph nodes, interobserver variability in the detection of Hodgkin lymphoma is still a formidable obstacle. Fletcher et al. [8] demonstrated that in 59 patients with supra-diaphragmatic Hodgkin lymphoma, reviewers never reached total Fig. 12. (A) Cervical area on a CT scan. (B) Coregistration of the prechemotherapy CT and FDG-PET. (C) On the prechemotherapy CT scan, contouring of the involved node area where the initially involved lymph nodes are located. (D) Final design of the involved node field on the postchemotherapy CT scan. (E) Prechemotherapy axial CT slice (5 mm below the slice shown in A) showing multiple small lymph nodes that were involved.

9 210 Involved lymph nodes in Hodgkin lymphoma agreement regarding any involved site and agreement remained moderate in approximately two-thirds of the sites. Third, interobserver variability can be mitigated by carefully comparing the pre- and postchemotherapy CT scans (Figs. 1 7 and 10). This underscores the need to systematically perform all the imaging procedures in the treatment position and with IV contrast. The quality and accuracy of the design of involved node fields could be vastly improved by using a web-based imaging network which would allow the implementation of a real-time quality assurance program. Such a program is currently being organized in Europe. Conclusions Involved node radiotherapy cannot be properly carried out without careful identification of initially involved lymph nodes obtained from contrast-enhanced imaging with the patient in the treatment position Three steps are imperative to achieve a high degree of accuracy. First, FDG-PET scans should be carefully analysed to detect involved lymph nodes that were overlooked on CT imaging. Second, any morphological and/or functional asymmetry should be sought on CT and FDG-PET scans. Third, any decrease in size or the disappearance of lymph nodes that were initially visible should also be sought on the prechemotherapy CT scan as compared to the postchemotherapy CT scan. Further improvement in the design of involved node radiation fields could be achieved by developing prospective web-based image exchanges. Acknowledgements The authors are grateful to Lorna Saint Ange for editing and to the Association pour la Recherche contre le Cancer (grant # 3154), to the Ligue Française contre le Cancer comité de l Essonne, and to the Fondation Clarence Westbury. * Corresponding author. Theodore Girinsky, Department of Radiation Oncology, Institute Gustave Roussy, Villejuif, France. address: girinsky@igr.fr Received 20 April 2008; accepted 1 May 2008; Available online 12 June 2008 References [1] Girinsky T, van der Maazen R, Specht L, et al. Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines. Radiother Oncol 2006;79: [2] Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin s disease. J Clin Oncol 1989;7: [3] Cheson BD, Horning SJ, Coiffier B, et al. Report of an International Workshop to standardize response criteria for non-hodgkins lymphoma. J Clin Oncol 1999;17: [4] Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25: [5] Guermazi A. Is it wise to eliminate lymphography from the staging of Hodgkin s disease? Leuk Lymphoma 2001;42: [6] Hanna SL, Fletcher BD, Boulden TF, et al. MR imaging of infradiaphragmatic lymphadenopathy in children and adolescents with Hodgkin disease: comparison with lymphography and CT. JMRI 1993;3: [7] Castellino RA, Hoppe RT, Blank N, et al. Computed tomography, lymphography and staging laparotomy: correlations in initial staging of Hodgkin disease. AJR 1984;14: [8] Fletcher BD, Glicksman AS, Gieser P. Interobserver variability in the detection of cervical thoracic Hodgkin s disease by computed tomography. J Clin Oncol 1999;17: [9] Valette F, Querellou S, Oudoux A, et al. Comparison of positron emission tomography and lymphangiography in the diagnosis of infradiaphragmatic Hodgkin s disease. Acta Radiol 2007;48: [10] Girinsky T, Ghalibafian M, Bonniaud G, et al. Is FDG-Pet scan in patients with early stage Hodgkin lymphoma of any value in the implementation of the involved-node radiotherapy concept and dose painting? Radiother Oncol 2007;85: [11] Specht L. 2-[18] Fluoro-2-deoxyglucose positron-emission tomography in staging, response, evaluation, and treatment planning of lymphomas. Sem Rad Oncol 2007;17:190 7.

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