hodgkin's lymphoma | Hodgkin's lymphoma: current therapeutic strategies and FuturesHodgkin lymphoma: current and future therapeutic strategies

Hodgkin's lymphoma: current therapeutic strategies and FuturesHodgkin lymphoma: current and future therapeutic strategies



Summary
Hodgkin's lymphoma is a cancer of the young subject, in which the current therapeutic strategies, based on chemotherapy and radiotherapy, have yielded healing rates of more than 80%, all stages confounded. Survivors are exposed to long-term complications of treatment, including secondary cancers and cardiovascular diseases, whose mortality eventually exceeds that associated with the disease itself. The adaptation of treatment to initial risk factors is the result of major modern therapeutic trials conducted by major co-operative groups. More recently, therapeutic strategies guided by the early response to treatment, evaluated by toe-scanner, have been developed. Combined chemotherapy treatment followed by radiation therapy remains a standard in most localized forms SUS-diaphragmatic. Immune checkpoint inhibitors (including anti-PD1 antibodies), which have shown spectacular results in some serious forms of relapsing or refractory classical Hodgkin's lymphoma, with limited toxicity, could contribute to The future to the objective of reducing the toxicity of treatments.


Summary
Hodgkin lymphoma (HL) is a cancer that mostly affects young people, in which modern therapeutic strategies using chemotherapy and radiotherapy result in a cure rate exceeding 80%. Survivors are exposed to long-term consequences of treatments, such as secondary malignancies and cardiovascular diseases, whose mortality exceeds the one of the disease itself, with long-term follow-up. The current therapeutic strategy in HL, based on the assessment of initial risk factors, is the result of large clinical trials led by the main international cooperating groups. More recently, several groups have tried to develop treatment strategies adapted to the response to chemotherapy, evaluated by interim PET/CT scan. However to date, the combined treatment with chemotherapy followed by radiation therapy remains a standard in most of the above-diaphragmatic localized forms. Immune checkpoint inhibitors, and especially anti-PD1 antibodies, have shown dramatic results in some serious forms of relapsed or refractory HL, with limited toxicity, and may contribute in the future to reduce the toxicities of treatments.


Introduction
The term Hodgkin's lymphoma is a group of two distinct entities from the WHO 2008 classification of malignant hemic [1]; Classical Hodgkin's lymphoma (LHC), by far the most common, and nodular predominantly lymphocytic Hodgkin's lymphoma (LHNPL), or paragranulome of Poppema and Lennert, a rare disease that accounts for less than 5% of Hodgkin's lymphoma cases. The first Anatomo-clinical description of classical Hodgkin's lymphoma, from a autopsy series, dates back to 1832 [2], but the distinction of this entity within adult lymphomas still retains its current meaning, due to Singular clinical and histological characteristics, specific treatment regimens, high chemo-sensitivity and radiosensitivity, and a prognosis that remains better than that of most other lymphomas. High growth-free survival and overall survival rates (> 80% all stages) and the identification of long-term complications, some of which may be the consequences of treatments, have long led to the search for the conditions of therapeutic degrowth. It is currently based on the adaptation of treatments to initial risk factors and the early response evaluated by TEP-scanner, but also on the development of new modalities of radiotherapy or new medications, such as Immune checkpoint inhibitors.

Epidemiology
The estimated incidence of classical Hodgkin lymphoma for 2012 in France was 1880 new cases, a standardized incidence rate on the world population of 3.0 in humans, and 2.7 in women [3]. There is a slight male predominance with a sex ratio of 1:1. Two peaks of incidence were observed, the first at about 25 years of age, and the second, less pronounced, around 75 years. Although the incidence in humans appears to have increased from the years 2000, it remains overall stable between 1980 and 2012. In women, incidence increased steadily between 1980 and 2012 [3].

The causes of Hodgkin's lymphoma remain largely unknown. If there is a probable genetic predisposition [4], [5] Other environmental factors such as tobacco have also been mentioned [6]. Epstein – Barr virus (EBV) infection also plays a role [7], as this virus can be detected up to nearly 100% of the cases of classical Hodgkin lymphoma in some tropical countries [1], and in HIV-infected patients. Moreover, his involvement in the physiopathogénie of the disease was also well demonstrated [8].

Overall survival in France, at all stages, was estimated at 81% between 2001 and 2004.

The main cause of death in patients diagnosed with Hodgkin lymphoma is lymphoma itself in the first 10 years of follow-up, but after 20 years of follow-up, lymphoma mortality is lower than that associated with toxicity Delayed treatment, including second cancers [9] and cardiovascular disease [10]. This relative risk is estimated to be between 6 and 14 for these two causes after 20 years of follow-up [11].

Predominantly lymphocytic Hodgkin's lymphoma is less than 5% of Hodgkin's lymphoma, and also affects young adults (median age 35 – 38 years) [12], [13], [14], [15], although there are pediatric cases, rather in children prepubescent [16]. The two incidence peaks described in classical Hodgkin lymphoma are not found here, and the distribution of cases by age follows a Gaussian curve [16]. Three-quarters of the patients are male [12], [17] [18]. The risk factors are not known, but the existence of family cases and a higher incidence in Finland than in other European countries causes genetic and/or environmental factors to be suspected [16]. Epstein – Barr virus is not involved. The clinical presentation of predominantly lymphocytic Hodgkin's lymphoma differs from that of classical Hodgkin's lymphoma, with a disease generally more localized to diagnosis, less frequency of mediastinal and Extraganglionnaires, and a often indolent evolution. The prognosis is generally better than that of classical Hodgkin lymphoma, marked, however by frequent relapses, and a risk of transformation into diffuse large-cell lymphoma B estimated at 1 – 2% per year. Tumor cell of origin and Lymphomagenesis
Hodgkin's lymphoma is characterized histologically by the presence within a polymorphic inflammatory infiltration, a small percentage of tumor cells, predominant lymphocyte cells (LP) or popcorn in Nodular Hodgkin's lymphoma at Lymphocyte predominance, and Reed – Sternberg, or Hodgkin cells (their mononuclear variant) in classical Hodgkin lymphoma.

In nodule-predominantly lymphocytic Hodgkin's lymphoma, LP cells express several markers of the germ centre, such as BCL6, AID, HGAL, and Centérine. They carry functional rearrangements of IGV genes, and often exhibit somatic hypermutation. Moreover, follicular architecture is generally preserved, which is an additional argument in favour of a centrogerminative origin of LP cells [19]. The study of gene expression profiles of microdissected cells of predominantly lymphocytic Hodgkin's lymphoma showed that these cells were derived from cells of the germ centre, at a transition stage to memory B lymphocytes [20 ].

In classical Hodgkin's lymphoma, Hodgkin/Reed – Sternberg (HRS) cells do not express most markers of the B lymphocyte line in immuno-Histochemistry, which has long made it difficult to identify their cell origin. The study of PCR-globulins genes in Hodgkin/Reed – Sternberg cells obtained by Microdissection showed that these genes were rearranged in a clonal manner, which is an argument for their B lymphocyte origin [ 21] These genes exhibit somatic hypermutation, which occurs only in the germ centre [22]. In addition, rearrangements of the globulins genes found are often non-functional, leading to the idea that Hodgkin/Reed – Sternberg cells are derived from germ center B lymphocytes that have escaped apoptosis because of secondary oncogenic events [23], [24].

Several signalling pathways are deregulated in the HRS cells. The NF-KB pathway is activated constitutively, either by inactivatrices mutations (genes NFKBIA, NFKBIE, TNFAIP3) or by gains or amplifications, particularly for the REL gene in 50% of cases [19]. Epstein – Barr virus may also play a role in activating this pathway through the LMP1a protein. The JAK/STAT pathway is also activated by inactivatrices mutations of SOCS1 (40% of cases), or gains or amplifications of the 9P24 region involving JAK2. The MEK/ERK and PI3K/AKT/MTOR pathways may also be deregulated, as well as other pathways or transcription factors not normally expressed in Lymphoid line B (NOTCH-1, GATA-3, ID2, CSF1R) [19].

Epigenetic alterations have also been described in the HRS cells: methylation of tumor suppressor genes (CDKN2C, RASSF1A), or genes encoding transcription factors such as KLF4 or BOB1. Several genes of the PRC1 and PRC2 complexes, which regulate gene expression by histone modification, are also overexpressed in the HRS cells, such as BMI1 and EZH2 [25].

Finally, the interactions of the HRS cells with the tumor micro-environment play a major role in the Physiopathogénie of classical Hodgkin lymphoma. The signalling channels already mentioned (NF-KB, JAK/STAT) can be activated by different signals from the micro-environment. Hodgkin/Reed – Sternberg cells secrete different chemokines (CCL5, CCL17, CCL22) which lead to the recruitment of CD4 + T lymphocytes of the TH2 type and Treg. It is likely that they even induce the differentiation of CD4 + T lymphocytes into Treg. Other micro-environment cells are also important: the adverse prognostic value of tumor infiltration by M2-polarized macrophages has been demonstrated in several studies, using expression profile data Gene [26], [27].

The tumor micro-environment is, more generally, involved in tumor escape mechanisms to the immune response. The interaction of PD1, a surface protein expressed in particular by activated T lymphocytes, with its PD-L1 ligand is a well-known mechanism for regulating the immune response, based on the induction of a CD8 + t lymphocyte [28]. However, the chromosomal region 9p 24.1, where the PD-L1 and PD-L2 genes are located, is reworked recurrently in classical Hodgkin's lymphoma [29], resulting in overexpression of these genes, causing one of the major exhaust mechanisms at the Immune response for HRS cells.

Diagnosis

Clinical presentation

Classical Hodgkin lymphoma

The disease is revealed in most cases by the discovery of adenopathies superficial pains, of firm, unfixed consistency, preferentially affecting the lower or SUS-supraclavicular cervical areas [30], [31], [32]. Mediastinal damage is present in the diagnosis in the majority of patients. A quarter of the patients have general signs: fever, slimming of more than 10% of body weight in 6 months, profuse nocturnal sweats, constituting "B symptoms". Asthenia, pruritus, pains in the ingestion of alcohol, conventional, but rare are not part of the symptoms B. Medullary flooding is found in 5 to 8% of cases [31]. This invasion is rare in localized forms (less than 1% of cases).

The disease initially follows a node extension mode by adjacency, usually from a cervical or mediastinal ganglionic territory to the Supraclavicular and axillary ganglion areas. Sub-diaphragmatic ganglion territories can be achieved in more advanced forms [33], [34]. Visceral attacks, in disseminated forms, are explained by blood-borne diffusion, often from splenic impairment. Primitive diaphragmatic forms are exceptional.

Nodular predominantly lymphocytic Hodgkin's lymphoma

The disease is often revealed by a superficial cervical or axillary adenopathies. General signs are rare, as are mediastinal or abdominal impairment, and extraganglionnaires locations. Large tumor masses are also infrequent, with the presentation most often indolent, and localized [35].

Histology

The diagnosis is based on Anatomo-pathological analysis of tissue fixed and included in paraffin from a biopsy of good quality, preferably surgically performed. Cytological analysis (e.g., bronchial puncture-endoscopy of a mediastinal lymphadenopathy) may possibly guide the diagnosis, but must always be confirmed by histological examination. Diagnostic management is, at best, carried out in consultation with a hematology service [36].

Nodular predominantly lymphocytic Hodgkin's lymphoma

The normal ganglionic architecture is replaced in a variable proportion by a nodular, diffuse, or nodular infiltrate, composed of small lymphocytes, mixed with more or less numerous histiocytes, scattered or clustered, in which Detach large tumor cells, called LP cells or popcorn cells (formerly called "L&H"). Tumor cells are characterized by a large, often multilobé, nucleus with fine chromatin, containing several discrete nucleoli basophils. Their Nucleo-cytoplasmic ratio is high, and the cytoplasm is abundant and pale (figure 1a). Neutrophil and Eosinophilic Polynuclears, as well as plasma, are usually absent. Necrosis is not observed. Fibrosis is rarely present but can be identified during relapses of the disease. Diffuse territories can accompany the more characteristic nodular territories. The deletion of the whole ganglion by a proliferation of diffuse architecture is much rarer and must have a discussion of the diagnosis of diffuse lymphoma with large B cells rich in T/histiocytes cells. Partial involvement of the ganglion by predominantly lymphocytic Hodgkin's lymphoma may accompany the remaining parenchyma of follicular hyperplasia, and sometimes a gradual transformation of the germ centres.

Figure 1. Pathology of predominantly lymphocytic Hodgkin's lymphoma A: nodular architecture proliferation, no fibrosis (A) (HES X1). "LP" tumor cells say "Popcorn" (b) (HESX20). B: immunohistochemistry of LP Cells: CD20 expressed by LP cells in a small B-lymphocyte-rich background (HESX40). CD5 negative and EMA positive on LP (HESX20) cells. C: immunohistochemistry microenvironment nodular: CD21 + dendritic follicular cell network expansively subtending CD20 + B lymphocyte-rich nodules with rare follicular helper T lymphocytes (TFH) arranged in rosettes around LP cells.

The immuno-histochemical examination is instrumental in discriminating against the predominantly lymphocytic Hodgkin lymphoma and classical Hodgkin lymphoma. In the predominantly lymphocytic Hodgkin's lymphoma, tumor cells express CD45, as well as B markers: CD20, CD79a, and PAX5, in a diffuse and high intensity manner (Figure 1b). They are Bcl6 +, MUM1 −, and express EMA or IgD in about 50% and 30% of cases, respectively. They usually do not express CD15 or CD30 (10% of cases are CD30 +). LP cells Express Transcription factors OCT-2, BOB-1, and AID. The presence of the EBV virus, although rare, does not eliminate the diagnosis. Lymphoid cells are subtended by an expansive lattice of follicular dendritic cells CD21 −, CD23 +. The follicles mostly contain small B lymphocytes, associated with variable number CD4 + T lymphocytes, sometimes arranged in rosettes around LP cells, and expressing the CD10, CD57, PD-1, Bcl6, and C-MAF markers, characteristics of a subtype Germ Center (TFH) T lymphocytes (Figure 1c). The interfollicular zones are rich in T-lymphocytes CD3 +, CD57 −, PD1 −, CD4 +/CD8 +, TiA1 −, and CD30 + immuno-blasts are identified. Six immuno-architectural variants were reported by Fan et al. [37] (A: nodular classical, rich in B cells; B: Nodular serpiginosum or interconnected; C: Nodular with predominance of extranodulaires LP cells; D: T-cell-rich nodular; E: Form close to large B-cell diffuse lymphoma rich in T/histiocytes cells; F: Diffuse and raised rich in B cells, the prognostic value of which was recently demonstrated in a retrospective study of GHSG [38].

Classical Hodgkin lymphoma

It is characterized by the presence of Reed – Sternberg (RS) cells, or their mononucléé equivalent, Hodgkin cells (HRS), dispersed in a non-tumor background in which are mixed in varying proportions of polynuclears, Histiocytes, Plasma and fibroblasts. The WHO classification 2008 distinguishes four morphological variants specific to tumor cells (gap cells): Nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte depleted (Figure 2). The immuno-phenotyping of tumor cells is identical in morphological variants. Only the frequency of association with EBV virus varies. Macroscopically, the Nodular sclerosis variant may be in the form of an enlarged ganglion, a thickened capsule, and nodular at the cut. Reed – Sternberg cells are large cells (about 40 μm in diameter), with a slightly basophile abundant cytoplasm, containing at least two nuclear nuclei or lobes, with a nucleolus eosinophilic in a decondensed chromatin. Prominent, surrounded by a clear halo (Figure 2a). When their cytoplasm is condensed and their nucleus is pycnotic, they are called "mummified" cells.

Figure 2. Pathology of classical Hodgkin lymphoma A: Classical Hodgkin's lymphoma. Collagen fibrosis surrounding tumor nodules (a) whose cellularity is polymorphic (b) with cells of Reed Sternberg (c). B: Cells of Reed Sternberg and immunohistochemistry. Membrane tagging with golgien (paranuclear dot) reinforcement (X40) C: Cells RS and immunohistochemistry: no expression of CD20 by Rs cells scattered in a background rich in small T-lymphocytes CD3 + arranged in rosettes. Expression of PAX5 by RS cells with lower intensity than on the small residual B-lymphocyte (X40) contingent.

Tumour cells do not express CD45, but usually express CD30 and CD15, with a slightly lower frequency, varying from 75% to 85% of cases. In addition, the expression of CD15 is heterogeneous, which can be limited to a minority of tumor cells, unlike the CD30, which is expressed in a diffuse manner. Finally, the expression of the CD15 can sometimes be confined to a golgi localization, or to reveal itself as the CD30, membrane with a golgien reinforcement (Figure 2b).

Usually, RS cells do not express CD20, and are dispersed in a background rich in small, mature T lymphocytes (CD3 + or CD5 +), arranged in rosettes around tumor cells (Figure 2c).

In a third of the cases, an expression of the CD20 is observed. However, its expression by tumor cells is always heterogeneous and of lower intensity than that observed on residual B lymphocytes. Immuno-tagging with CD79A is often more heterogeneous than with CD20. PAX5 is expressed in a diffuse manner by all tumor cells with moderate intensity (lower than on the small residual cell B lymphocyte component). Finally, MUM1/IR is constantly expressed by tumor cells, whereas EMA is not.

In a very unusual way, an aberrant expression of T markers by tumor cells is observed. This one is always heterogeneous.

Finally, the transcription factors BOB1 and OCT2 are generally not expressed. Infection with the EBV virus can be objective by immuno-histochemical techniques, using LMP1 and EBNA1 antibodies, or by in situ hybridization (detection of EBER RNA) at varying frequencies depending on the morphological variant.

Extension balance and pretherapeutic balance

The pet-scanner is the reference examination for the classification of the stage of the disease to the diagnosis [39]. The conventional scanner with injection remains indispensable for the precise measurement of the targets, because it allows to make finer cuts. It can also be more effective in detecting abdominal or pelvic sites, particularly in the context of necrotic ganglia [40]. The rib face in the upright position remains important for calculating the Médiastino-thoracic ratio (M/T), between the largest width of the mediastinal mass, and the thoracic diameter measured between the T5 and T6 vertebrae (Figure 3). The excellent sensitivity of the pet-scanner for the detection of medullary injury makes it unnecessary to perform a bone marrow biopsy in the majority of cases [39], [41], [42]. In the absence of arguments for a disseminated disease, the pet-scanner must be ideally planned in cooperation with the radiation therapy team, after making a restraint mask and in a treatment position, with a view to achieving a Nodal type radiotherapy (involved-nodes).

Figure 3. Impaired mediastinal voluminous. Definition of the ratio M/T: maximal measurement of the tumor mass reported to the thoracic diameter between T5/T6. A ratio of M/T ≥ 0.33 is a decision risk factor for treatment. NB = This M/T ratio should be measured on a face X-ray shot in the upright position, as the size of the mediastinum may indeed be artificially increased by the reclining position, if measured on the scanner Scout. Figure after closed and Reman, adult Hodgkin's lymphoma. EMC Hematology, 2011. Copyright © 2016 Elsevier Masson SAS. All rights reserved ".

The initial biological balance includes at least one NFS, a sedimentation velocity (VS), a albumin and an evaluation of renal and hepatic functions. Screening for HIV, HBV and HCV virus infection must be systematic. An assessment of cardiac function (LVEF) in anticipation of administration of anthracyclines, and respiratory functional explorations with measurement of free diffusion of CO (DLCO) before treatment with bleomycin, are necessary. A cryopreservation of sperm or oocytes is to be offered systematically to patients, in the framework of a specialized consultation of onco-fertility.

Extension stage – prognostic and therapeutic groups

The modified ANN Arbor classification according to the Cotswolds (table I) defines the stage of extension. The letters "A" (absence), or "B" (presence) are used to signify that there are general signs or not. A large mediastinal impairment is indicated by the letter "X", and a splenic hit by an "S". The letters "a" or "B", frequently used to indicate the absence or presence of a biological inflammatory syndrome, are not retained in international classifications.

Table I. Modified Ann Arbor Classification by Cotswolds

Ann Arbor Stadium

 I attaining a single ganglionic area or a single lymphoid structure

 II with 2 or more ganglion areas on the same side of the diaphragm

 III ganglion on both sides of the diaphragm

 IV Extraganglionnaire with distinct extraganglionnaire contiguous location

Changing features

 Has no signs B

 b presence of signs B defined by: fever greater than 38 °c for more than one week without documented infection; and/or slimming by more than 10% of the body weight in the last six months; and/or nocturnal sweats, forcing the patient to change clothes

 X ' bulky ' disease: mediastinal mass with a diameter equal to or greater than one-third of the cross-rib diameter at the intervertebral disc T5 – T6 (ratio M/T > 0.33 on a thoracic face shot); or ganglionic mass equal to or greater than 10 cm

 (E) reaching a single contiguous viscera or located near a Ganglionic territory reached

The ANN Arbor classification is the basis for the definition of prognostic groups, on which the treatment regimens are based. The risk factors retained by LySA and EORTC for localized stages are age ≥ 50 years, the number of ganglion areas invaded ≥ 4, a high VS (≥ 50 mm at the first hour, or ≥ 30 mm in the presence of B symptoms), and the presence of a volumin ganglionic mass (≥ 10 cm or defined by a ratio of M/T ≥ 0.33). They distinguish between favourable (no risk factor) and unfavourable (presence of at least one risk factor) localized stages [43]. The risk factors retained by the German group (GHSG) differ slightly from the GELA/LySA and EORTC criteria and are detailed in table II. They define early stages (localized stages without risk factor) and intermediate stages, which include stages IA, IB and IIA with risk factors, as well as stages IIB without voluminous mediastinal mass or impairment Extraganglionnaire. Stages IIB with voluminous mediastinal mass and/or extraganglionnaire impairment are classified with stages III/IV in stages advanced by GHSG. Stages IIB with voluminous mediastinal mass were also included in the recent LySA AHL 2011 trial for advanced stages.

III – IV Advanced stages advanced Stages

EORTC: European Organisation for Research and treatment of Cancer; GELA: Adult lymphoma Study Group became the LySA in 2011; LySA: Lymphoma Study Association; GHSG: German Hodgkin Study Group; VS: sedimentation velocity; Voluminous mediastinal mass: mediastinal Mass with a diameter equal to or greater than one-third of the cross-rib diameter at the intervertebral disc T5-T6 (ratio M/T > 0.33, measured on a rib-face shot) or ganglionic mass equal or Greater than 10 cm.

First line treatment

Classical Hodgkin lymphoma

Localized stadiums SUS-diaphragmatic

The reference treatment involves chemotherapy with ABVD (doxorubicin, bleomycin, Vinblastine, dacarbazine), followed by radiation therapy [45], [46]. The scheme adopted by the EORTC and the LySA includes:

•

In forms without risk factors: 3 cycles of ABVD followed by radiotherapy at a dose of 30 Gy;

•

In the forms with risk factor (s): 4 ABVD cycles followed by radiotherapy at a dose of 30 Gy.

GHSG showed in the early stages that treatment with 2 cycles of ABVD followed by radiotherapy at the 20 Gy dose on the initially affected territories (involved-field [IF]) was as effective and less toxic as 4 ABVD cycles followed by a Radiotherapy 30 Gy [47]. This treatment became the new standard of the German group for the early stages.

The conventional volumes of radiotherapy, which once took into account all the ganglion areas (involved-field radiotherapy [IFRT]), are now tending to be replaced by techniques targeting only the lymph nodes achieved, detected by the combination of all available imaging exams (especially injected scanner and pet-scanner at FDG). The rationale for this change in concept is the need to reduce irradiated volumes in order to limit the morbidity of radiotherapy (heart disease, secondary cancer) as well as the finding that recidivism occurs mainly in Adenopathies present for diagnosis in unirradiated patients [48]. The irradiation of the initially affected ganglia (involved-node radiation therapy [INRT]) is the technique that was retained in the EORTC/GELA/FIL Intergroup test H10. This technique involves the diagnosis of a pet-scanner in the position of radiotherapy treatment (arm along the body, head slightly bent, mask of restraint to guarantee the reproducibility of the position) in order to spot with Accuracy of adenopathies diagnosed (Figure 4). These volumes are then carried over to the centring scanner carried out in preparation for radiotherapy and then adapted to the anatomy of the patient after chemotherapy (tumor response) [49]. The basic input of the pet-scanner for the determination of the affected ganglia, for radiotherapy according to the INRT technique, has been demonstrated in a prospective study which covered 135 patients included in the H10 test, treated in 18 French centres. In this study, the pet-scanner identified at least one additional ganglion in 95 patients (70%), and at least one additional ganglionic territory in 55 patients (41%) [50]. When the whole of the imaging examinations could not be carried out under optimum conditions (in particular, toe-scanner in the treatment position), the "standard" proposed by the International Lymphoma Radiation Oncology Group (ILROG) is a Radiotherapy on the "sites" ganglion initially reached (involved-site radiotreatment [ISRT]) [51]. The idea remains to treat only the lymph nodes initially invaded, by applying margins to take into account the uncertainties associated with their identification (absence of toe in the treatment position, poor quality of the mergers), rather than using a Radiotherapy type IFRT. INRT is considered an optimum form of ISRT. The application of these new concepts coupled with the use of modern radiotherapy techniques such as conformational radiation therapy with intensity modulation, radiation therapy with breathing or protonation, allows Greatly reduce the doses delivered to healthy local organs (mammary glands, heart, coronary, lungs...). The long-term gain on morbidity has not yet been assessed, since the decline has not been sufficient to date.

Figure 4. Impaired mediastinal voluminous. Definition of the ratio M/T: maximal measurement of the tumor mass reported to the thoracic diameter between T5/T6. A ratio of M/T ≥ 0.33 is a decision risk factor for treatment. NB = This M/T ratio should be measured on a face X-ray shot in the upright position, as the size of the mediastinum may indeed be artificially increased by the reclining position, if measured on the scanner Scout. Figure after closed and Reman, adult Hodgkin's lymphoma. EMC Hematology, 2011. Copyright © 2016 Elsevier Masson SAS. All rights reserved ".

Combined treatment (chemotherapy followed by radiation therapy) yields response rates of more than 90%, but at the cost of significant toxicity attributable largely to radiation therapy [51]. In addition, several studies have shown that patients who did not obtain a complete remission evaluated by toe-scanner after 2 cycles of ABVD had a prognosis lower than that of patients TEP2 − [52], [53]. This has led several groups to develop treatment strategies guided by the early response evaluated by TEP-scanner to FDG.

The EORTC/GELA/FIL Intergroup test H10 thus posed 2 questions:

•
Is it possible to do without radiation therapy in patients who obtain a complete metabolic remission from 2 cycles of ABVD?

•
Is there a benefit to be treated by BEACOPP strengthened patients considered "bad responders" on the data of the intermediate toe-scanner (TEP2 +)?

Regarding the first point, the evidence of a greater number of events in patients treated without radiotherapy (9 events vs. 1 in the favorable group, 16 events vs. 7 in the adverse group) led the independent committee of Data monitoring to recommend the premature closure of the experimental arms of the study [54].

On the other hand, results presented at the Congress of ICML 2015 in Lugano showed that the early increase in the intensity of treatment, by the transition to BEACOPP strengthened from the third cycle of chemotherapy in patients who do not get a remission After 2 cycles of ABVD, it was possible to obtain a better PFS at 5 years (91%, compared with 77%, HR: 0.42; 95% CI: 0.23 – 0.74; p = 0.002), certainly at the cost of increased toxicity, on haematological and infectious levels [55].

The English group's RAPID test, published in 2015, showed similar results on the issue of radiotherapy [56], and these data were confirmed by a meta-analysis [57], which focused on 1480 patients, and which found a PFS significantly Lower for patients treated with a pet-scanner guided strategy, without radiotherapy, compared to patients treated in a standard way (HR: 2.38; 95% CI: 1,62 – 3.50; P < 0.0001).

Radiotherapy remains a standard of treatment after chemotherapy in the localized forms SUS-diaphragmatic.

The use of Brentuximab Vedotin, an anti-CD30 antibody conjugated to a spindle poison (MMAE), in association with chemotherapy is currently being evaluated in the therapeutic first line, as part of the LYSA BREACH trial clinic identifier: NCT02292979). The selected combination is BV-AVD (without bleomycin), with phase I data showing too much toxicity to the BV-ABVD Association, particularly in the pulmonary plane [58].

Localized stadiums sub-diaphragmatic
There is no real standard of treatment for these forms whose presentation is rare. The options are either chemotherapy by ABVD X4 Cycles, followed by radiotherapy (inguinal and localized iliac), or chemotherapy alone by ABVD X6 Cycles.

Advanced Stages
The treatment is based on chemotherapy, with either 6 to 8 ABVD cycles or enhanced BEACOPP in patients under 60 years of age [44]. Additional radiotherapy on residual lesions greater than 1.5 cm after ABVD, or on residual lesions greater than 2.5 cm, hypermetabolic to the toe-scanner after BEACOPP reinforced can be proposed [44].

In fact, the German group's HD9 test showed that treatment with 6 cures of enhanced BEACOPP significantly increased the safe survival rate and overall survival compared to COPP/ABVD and standard dose BEACOPP [59], [60]. The safe survival rates for 10-year treatment were 64% for the COPP/ABVD arm, 70% for the standard-dose BEACOPP, and 82% for the enhanced BEACOPP, with overall survival rates of 75%, 80%, and 86%, respectively. However, these results have not been confirmed in other studies and remain controversial, since they show better initial tumor control, but no benefit in terms of overall survival [61], [62]. Event-free survival was similar between the 2 groups of the EORTC 20012 test, comparing 8 ABVD cycles and 4 enhanced BEACOPP cycles followed by 4 BEACOPP cycles [63].

Above all, they are obtained at the cost of an increase in the cumulative incidence of secondary cancers, although this only appears to be significant for myélodysplasies and acute leukemias. A solution could still be given by the treatment regimens guided by the toe-scanner with a decrease in ABVD treatment in "good responder" patients after 2 cycles of reinforced BEACOPP [64].

Brentuximab Vedotin in association with AVD chemotherapy is also evaluated in the first line in disseminated forms in the framework of the international phase III Therapeutic Trial ECHELON-1 (clinicaltrial.gov identifier: NCT01712490).

Figure 5 summarizes the management of Hodgkin's lymphoma in therapeutic first line