Hodgkin LymphomaDr. Dipalee B. Borade

DNB Student, Radiotherapy Dept.Jupiter Hospital, Thane

Introduction

Hodgkin’s disease was initially described as an inflammatory disease (hence the term “disease”), but is clearly recognized and treated as a malignant lymphoma (hence the more accurate term Hodgkin’s lymphoma (HL) is used synonymously with Hodgkin’s disease).

The management of Hodgkin’s lymphoma has evolved from extended-field radiation alone as the main therapy to a combined-modality approach withchemotherapy and radiation, or chemotherapy alone.

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Epidemiology and Risk Factors

Always begins in lymph nodes

More than 80%- cervical lymph node >50% have mediastinal disease

Isolated extralymphatic involvement in the absence of nodal disease is rare

The reported incidence is less than 3 per 100,000 and 0.56% of all cancers

Male predominance (1.2:1)

Rare in children <10 years of age. Median age is 26 years, Bimodal peak- early peak 25 to 30 years and A second peak, from age 75 to 80 years

A relation between HD and previous infection with Epstein-Barr virus

(EBV4 Weiss et al.5 identified components of the EBV genome in the cellular DNA of Reed–Sternberg cells in lymph nodes involved by HD)

Mueller et al.6 identified elevated levels of immunoglobulin G and immunoglobulin A against the EBV capsid antigen and elevated levels of antibody against the EBV nuclear antigen and early antigen D in the serum of patients with Hodgkin lymphoma 3 to 156 months before the diagnosis of HD

The risk more in patinets with infectious mononucleosis; Several series demonstrated an association between EBV infection and mixed-cellularity Hodgkin lymphoma, especially in children in developing countries

increased risk for Hispanics (vs. Whites), or children from economically less developed (vs. more developed) regions, and young adult men (vs. women)

Natural History and ClinicalPresentation

Painles lymphadenopathy

Systemic symptoms- unexplained fevers, drenching night sweats, weight loss, generalize pruritus, fatigue, and alcohol-induced pain in tissues involved by HD

Mediastinal mass on a routine chest radiograph

90% of patients present with contiguous sites of involvement or Extension from adjacent lymph nodes

Hematogenous (liver or multiple bony sites) Involvement of the bones may cause blastic changes, especially in the vertebrae (creating the classic “ivory vertebra” on plain radiographs), pelvis, sternum, or ribs

Nearly all patients with hepatic or bone marrow involvement by Hodgkin lymphoma have extensive involvement of the spleen

Rare- Gut-associated lymphoid tissues such as Waldeyer ring and Peyer patches, Upper aerodigestive tract, Central nervous system, and Skin

B Symptoms

There are three “B symptoms”

One-third of patients present with one of these symptoms

Fever- Classic waxing-and-waning Pel- Ebstein pattern

Night sweats may be drenching and require a change of bedclothes

Significant weight loss

Occur even in patients with relatively limited disease (stage II) but uncommon in stage I disease

Diagnostic and Staging Procedures forHodgkin Lymphoma

History- Systemic B symptoms: unexplained fever, drenching night sweats, weight loss >10% of body weight in the last 6 months Other symptoms: alcohol intolerance, pruritus, respiratory problems, fatigue

Physical examination- Palpable nodes (note number, size, location, shape, consistency, mobility), Palpable viscera

Laboratory studies- Complete blood count, differential, platelets, Erythrocyte sedimentation rate, Serum albumin, lactate dehydrogenase, liver function studies, Blood urea nitrogen, creatinine, Pregnancy test in women of childbearing age

Radiographic studies- Chest radiographs: posteroanterior and lateral; Contrast-enhanced computed tomographic (CT ) scan of thorax, abdomen, and pelvis; Contrast-enhanced CT scan of neck (if neck irradiation is indicated); Integrated positron emission tomography-CT scan

Additional biopsies, if indicated- Bone marrow, needle biopsy (if subdiaphragmatic disease or B symptoms); Cytologic examination of effusions, if present; Percutaneous liver biopsy if abnormal liver function tests but normal CT

The Ann Arbor Staging Classification forHodgkin’s Disease

Stage I Involvement of a single lymph node region

Stage II Involvement of two or more lymph node regions on the same side of the diaphragm (II ), or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE )

Stage III Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (IIIS ) or by localized involvement of an extralymphatic organ or site (IIIE ) or by both (IIISE )

Stage IV Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement

The absence or presence of fever, night sweats, and/or unexplained loss of 10% or more of body weight in the 6 month before diagnosis is denoted by the suffix letter A or B, respectively

The Cotswolds modification of the Ann Arbor system employs the subscript “x” to designate large mediastinal adenopathy

Pathologic Classification

Reed– Sternberg cell- Binucleate, prominent centrally located nucleolus in each nucleus, a well-demarcated nuclear membrane, and eosinophilic cytoplasm with a perinuclear halo

Usually account for <1%

The majority are lymphoid cells, eosinophils, plasma cells, and other normal cells. Reed–Sternberg cells probably originate from B-lineage cells at various stages of development, including pre–B-cell and germinal center B-cell origin

RS cells stain positively for CD30, PAX5, and with variable expression of the antigranulocyte monoclonal antibody CD15

CD20, a marker of mature B cells, may be expressed on a minority of tumor cells (40%)

They stain negatively with CD45, ALK, and J chain

World Health Organization modification of the Lukes and Butler system

There are five histologic subtypes of Hodgkin lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma and four subtypes of Classic Hodgkin lymphoma: nodular sclerosis, mixed cellularity, lymphocyte- rich, and lymphocyte-depleted

NLPHD is characterized by An abundance of normal-appearing lymphocytes and a scarcity of abnormal cells

The abnormal cells (“L and H cells” or “popcorn cells”) in nLPHD are strongly reactive for CD20, CD45, CD79a, and PAX5 and negative for CD15 and CD30

Young people

Early-stage disease, usually in a solitary peripheral nodal site, and systemic symptoms are uncommon (<10%)

The most favorable of the histologic subtypes

Classic Hodgkin lymphoma (cHD). The Reed– Sternberg cells in these cases are CD15+, CD30+, PAX5+, and

occasionally CD20+

Nodular sclerosis classical Hodgkin lymphoma (NSHD) is the most common histologic subtype

Involved nodes often have a thickened capsule and are traversed by broad bands of birefringent collagen that surround nodules of cells consisting of lymphocytes, eosinophils, plasma cells, and tissue histiocytes intermixed with a variable proportion of atypical mononuclear cells and Reed–Sternberg cells. These cells may be in empty(lacunar) spaces, which are artifacts of formalin fixation

The clinical presentation includes common mediastinal involvement, and one-third of patients have B symptoms

The natural history of NSHD is less favorable than that of nLPHD.

Mixed-cellularity classic Hodgkin lymphoma (MCHD)- Diffuse effacement of lymph nodes by lymphocytes, eosinophils, plasma cells, and relatively abundant atypical mononuclear and Reed–Sternberg cells

Advanced disease at presentation In older population Natural history of MCHD is less favorable than that of NSHD

Lymphocyte-rich classic Hodgkin lymphoma (LRHD)- It usually has a nodular growth pattern

Early stage, absence of B symptoms, and excellent prognosis

Lymphocyte-depleted classic Hodgkin lymphoma (LDHD)- Paucity of normal-appearing cells and an abundance of abnormal mononuclear cells, Reed–Sternberg cells, and Reed–Sternberg variants

Difficult to differentiate from anaplastic large-cell lymphoma Uncommon subtype of HD Older patients, advanced disease and B symptoms Worst prognosis of all histologic subtypes of Hodgkin lymphoma.

Prognostic Factors andTherapeutic Implications

Highly curable

prognostic factors are more important for defining therapy than for predicting outcome

International Prognostic Score for Advanced Hodgkin Lymphoma

Three or more adverse risk factors- An unfavorable prognostic group

Patients with stage I or II disease often have only one or two adverse factors based on this index

low (0–1), intermediate (2–3), or high (4–7) risk.

FactorUnfavorable Covariate

Serum albumin <4 g/dL

Hemoglobin <10.5 g/dL

Sex Male

Age ≥45 yr

Stage IV (Ann Arbor)

Leukocyte count ≥15,000/mm3

Lymphocyte count<600/mm3 or <8% of white count

Treatment Groups in Early Stage

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General guidelines for Hodgkin’s Lymphoma treatment

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General Management

Chemotherapy:

With the introduction of doxorubicin (Adriamycin), completely novel drug combinations were developed

The most successful of these is ABVD, which includes doxorubicin, bleomycin, vinblastine, and dacarbazine

ABVD has replaced MOPP as the gold standard of chemotherapy for Hodgkin lymphoma.

This is based largely on the results of an intergroup trial that compared MOPP, ABVD, and MOPP/ABVD.

Combination Chemotherapy Regimens

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The Milan trial was among the first and most influential in demonstrating the high cure rate of a brief course of ABVD (four cycles) combined with involved-field radiation therapy in limited-stage Hodgkin’s lymphoma

Subsequently, multiple trials have explored the questions of how many cycles of ABVD are needed and what radiation dose is needed to maintain these outstanding results.

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More recently, in an effort to reduce toxicity, the Stanford V regimen, which almost always includes a component of radiation, was developed as an alternative to ABVD

The German Hodgkin Study Group (GHSG) developed the BEACOPP regimen, which may be administered in a baseline, escalated, or 14-day schedules

Most recently, a completely new systemic agent has been approved by the FDA for the treatment of Hodgkin lymphoma. Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody linked to an antitubulin agent.

BV has demonstrated efficacy in CD30+ lymphomas, including Hodgkin lymphoma and anaplastic large-cell lymphoma.

It is approved for patients who have had disease recurrence after stem cell transplantation and is being introduced in clinical trials

Among favorable patients without risk factors, the GHSG evaluated two versus four cycles of ABVD and 20 versus 30 Gy involved-field irradiation.

The final results of this trial have not been published, but multiple presentations of the data to date have shown FFP rates in excess of 95% for all four treatment arms.

Thus, for the approximately 35% of limited-stage patients with very favorable presentations, as few as two cycles of chemotherapy combined with low-dose involved-field irradiation is sufficient for cure.

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For patients with unfavorable, limited-stage Hodgkin’s

The H9U trial conducted by the EORTC-GELA demonstrated that the less toxic ABVD regimen was as effective as the BEACOPP regimen and that four cycles of treatment were sufficient.

Similarly, the GHSG HD11 trial has shown no differencesin outcome thus far between ABVD and BEACOPP in limited-stage patients with risk factors.

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Randomized Clinical Trials in Limited-Stage Hodgkin’s Lymphoma

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The early CALGB study determined that ABVD-containing combinations were superior.

A second U.S. Intergroup trial comparing ABVD to the hybrid MOPP/ABV combination, concluded that the treatments were similarly efficacious but ABVD was less toxic.

On the basis of these trials, ABVD was widely adopted as the standard chemotherapy for advanced Hodgkin’slymphoma with an expected cure rate of about 70%.

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Randomized Clinical Trials in Advanced-Stage Hodgkin’s Lymphoma

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Radiation Therapy

The principal to treat involved nodes and regions at high risk for containing disease to a dose associated with a high likelihood of tumor eradication

This requires thoughtful evaluation of all imaging studies, especially

diagnostic CT and integrated PET-CT scans

A precise simulation with appropriate immobilization

Consideration of organ motion

Detailed treatment planning, and effective treatment delivery, including portal imaging and appropriate quality assurance measures

Three-dimensional conformal treatment planning and opposed-field treatment is appropriate

Occasionally intensity-modulated radiation therapy (IMRT)- Better dose conformality, improved dose–volume histogram (DVH) criteria for the heart, coronary arteries, esophagus, and lungs and less acute toxicity

At the expense of the low-dose “bath,” which may put larger volumes of normal tissue at risk for the development of secondary cancer, for example, the lungs, breasts (in women), and thyroid gland

Useful in situations of reirradiation

In the uncommon situations when radiation therapy alone is used for the treatment of Hodgkin lymphoma (primarily for nLPHD), the National Cancer Center Network (NCCN) guidelines recommend a dose of 30 to 36 Gy to involved and 25 to 30 Gy to uninvolved regions

Fractions of 1.5 to 1.8 Gy depending on field size and patient tolerance

More commonly, radiation therapy is used in the combined-modality setting

The NCCN guidelines is- 20 to 30 Gy for nonbulky and 30 to 36 Gy for bulky sites of disease

The classic fields for lymphoma by radiotherapy alone included the mantle and inverted-Y

Clinical trials have demonstrated an equivalence of “involved-field” treatment (IFRT) with “extended-field” or “subtotal-lymphoid” irradiation in the context of combined-modality therapy programs

Involved field irradiation has been adopted as the standard for combined-modality therapy

More recent trials- application of “involved-node radiotherapy” (INRT) or “involved-region” or “involved-site” irradiation

PET-CT “Simulation”

Integrated PET-CT- Part of the initial staging for all patients

Accurate information of the initial extent of disease

However, not usually obtained in the treatment position or on a flat couch

PET-CT scan is usually repeated After the completion of chemotherapy

After the radiation therapy simulation, the data from the initial staging PET-CT is merged with it in order to localize the initial sites of disease.

The accuracy of the registration will vary, depending on patient positioning for the two studies

This needs to be accounted for ultimate design of the treatment fields.

Supradiaphragmatic Fields

The classic mantle included all of the major lymph node regions above the diaphragm

The field extended from the inferior portion of the mandible almost to the level of the insertion of the diaphragm

With individually contoured lung blocks and conformed to the patient’s anatomy and tumor localization.

In addition to the lung blocks, blocks could be placed over the occipital region and spinal cord posteriorly, the larynx anteriorly, and the humeral heads both anteriorly and posteriorly.

The use of these blocks depended on total dose planned and proximity of the adenopathy.

Modified involved Field Involved site RT

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Classic two-dimensional Mantle field

Set up supine, with the head fully extended

The superior margin- bisect the mandible and passed through the mastoid process

The lateral margins- flash the axillae (with humeral head blocks if the arms were at sides)

The inferior axillary margins- level of the inferior tips of the scapulae

The inferior mediastinal border- at the level of the T10-11 interspace

The lung blocks- to provide 1-cm margin around the mediastinal contours and ∼also encompass the pulmonary hilar lymph nodes

The superior most point of the lung blocks was no higher than the inferior tip of the head of the clavicle with the tops of the lung blocks tapered laterally, often parallel to the projection of a posterior rib, in order to expose the high axillary/infraclavicular lymph nodes.

LYMPH NODAL REGIONSLymph Nodal Groups

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Radiotherapy Fields

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Fields for I F R T

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Unilateral Cervical/Supraclavicular Region

Arms position: Akimbo or at sidesUpper Border: 1 to 2 cm above the

lower tip of the mastoid process and midpoint through the chin.

Lower Border: 2 cm below the bottom of the clavicle.

Lateral Border: To include the medial two-thirds of the clavicle.

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Medial Border: (a) If the SCL nodes are not involved, the border is placed at the ipsilateral transverse processes except when medial nodes close to the vertebral bodies are seen on the initial staging neck CT scan. For medial nodes the entire vertebral body is included. (b) When the SCL nodes are involved, the border should be placed at the contralateral transverse processes

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Blocks: A posterior cervical cord block is required only if cord dose exceeds 40 Gy. Mid-neck calculations should be performed to determine the maximum cord dose, especially when the central axis is in the mediastinum. A laryngeal block should be used unless lymph nodes were present in that location. In that case the block should be added at 20 Gy.

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Bilateral Cervical/Supraclavicular Region

Both cervical and SCL regions should be treated as described in the preceding slide regardless of the extent of disease on each side.

Posterior cervical cord and larynx blocks should be used.

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Mediastinum

Arms position: Akimbo or at sides. The arms-up position is optional if the axillary nodes are involved.

Upper Border: C5-6 interspace. If SCL nodes are also involved, the upper border should be placed at the top of the larynx.

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Lower Border: The lower of: (a) 5 cm below the carina or (b) 2 cm below the pre-chemotherapy inferior border.

Lateral Border: The post-chemotherapy volume with 1.5-2 cm margin.

Hilar Area: To be included with 1 cm margin unless initially involved, in which case the margin should be 1.5 cm.

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Axillary Region

Arms position: Arms akimbo or arms up.

Upper Border: C5-6 interspace.

Lower Border: The lower of the two: (a) the tip of the scapula or (b) 2 cm below the lowest axillary node.

Medial Border: Ipsilateral cervical transverse process. Include the vertebral bodies only if the SCL are involved.

Lateral Border: Flash axilla.

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Abdomen (Para-Aortic Nodes)

Upper Border: Top of T11 and at least 2 cm above pre-chemotherapy volume.

Lower Border: Bottom of L4 and at least 2 cm below pre-chemotherapy volume.

Lateral Borders: The edge of the transverse processes and at least 2 cm from the post-chemotherapy volume.

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Example of a para-aortic–spleen field treated with respiratory gating. In thisexample there was a positron emission tomography+ node at the L1 level, and the inferiorportion of the para-aortic field was set at the bottom of L2. The para-aortic nodes are highlightedin light red and the spleen in dark red. Due to the complex shape of this field, it isdefined with a combination of multileaf collimators and Cerrobend blocks (shown in lightorange) to shield the base of the left lung and the upper half of the left kidney.

Inguinal/Femoral/External Iliac Region

Upper Border: Middle of the sacroiliac joint.

Lower Border: 5 cm below the lesser trochanter.

Lateral Border: The greater trochanter and 2 cm lateral to initially involved nodes.

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Medial Border: Medial border of the obturator foramen with at least 2 cm medial to involved nodes. If common iliac nodes are involved the field should extend to the L4-5 interspace and at least 2 cm above the initially involved nodal border.

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Mantle

bilateral cervical, SCV, infraclavicular, mediastinal, hilar, and axilla

Mini-mantle: mantle without mediastinum, hila

Modified mantle: mantle without axilla

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mini mantle modified mantle

Mantle Field

Simulate with Arms - up (to pull axillary LN from chest to allow for more lung blocking) or Arms akimbo (to shield humeral heads and minimize tissue in SCV folds)

Head extended this ensures the exclusion of the oral cavity and teeth from the RT fields, and decreases the dose to the mandible

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Borders: Lateral = beyond humeral heads; Inferior = bottom of diaphragm (T11/12); Superior = inferior mandibleBlocks: Larynx on AP field Humeral heads on AP and PA fields PA cord block (if dose >40 Gy) Lung block at top of fourth rib to cover IC LN If pericardial or mediastinal extension, include entire heart to 15 Gy, then block apex of heart. After 30 Gy, block heart beyond 5 cm inferior to carina (unless residual disease)

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Inverted Y Field

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STLI

TLI

With 3D treatment planning, the initially involved lymph nodes (gross tumor volume [GTV]) and adjacent “at-risk” lymph nodes (clinical target volume [CTV]) are outlined on cross-sectional images, and field design is completed to ensure a dose range of 95% to 105% of the prescribed dose to the planning target volume (PTV)

The CTV will generally extend 2 to 5 cm proximal and distal to initial PET- or CT-positive disease. The PTV expansion is then 1 cm∼

Although special techniques such as deep inspiration breath hold, active breathing control, and respiratory gating are infrequently used in treatment of Hodgkin lymphoma

They do demonstrate improvements in DVH criteria for the lungs and heart - useful in the setting of treatment for patients with large mediastinal masses.

Reference :

Volume Definitions for Planning RadiationTherapy for Lymphoma

These principles apply whether Involved Site Radiation Therapy (ISRT) or Involved Node Radiation Therapy (INRT) is applied

The difference between them is the quality and accuracy of the pre chemotherapy imaging

Determine the margins needed to allow for uncertainties in the contouring of the CTV

Volume of interest acquisition

3-dimensional (3D) simulation study using CT simulator PET/CT simulator Magnetic resonance imaging simulator

Imaging studies should be obtained with the patient in the treatment position and using the planned immobilization devices

Determination of Gross Tumor Volume

Pre chemotherapy (or pre surgery) GTV

No chemotherapy or post chemotherapy GTV

Determination of Clinical Target Volume

The CTV encompasses the original (before any intervention) GTV

Normal structures such as lungs, kidneys, and muscles that were clearly uninvolved should be excluded from the CTV based on clinical judgment

The following points should be considered:▪ Quality and accuracy of imaging▪ Concerns of changes in volume since imaging▪ Spread patterns of the disease▪ Potential subclinical involvement▪ Adjacent organs constraints

If separate nodal volumes are involved, they can potentially be encompassed in the same CTV

If the involved nodes are more than 5 cm apart, they can be treated with separate fields using the CTV-to-PTV expansion guidelines

Determination of Internal Target Volume

CTV plus a margin taking into account uncertainties in size, shape, and position of the CTV within the patient

ITV is mostly relevant when the target is moving, most commonly in the chest and upper abdomen with respiratory movements

ITV is calculated by :

4D CT simulation Fluoroscopy Estimated by an experienced clinician

In chest or upper abdomen: Margins of 1.5 to 2 cm in the superior-inferior direction

In sites that are unlikely to change shape or position during or between treatments : Outlining the ITV is not required

Determination of Planning Target Volume

Volume that takes into account the CTV (or ITV, when relevant) and accounts for setup uncertainties in patient positioning and

alignment of the beams during treatment planning and through all treatment sessions

PTV margins are based on : Institutional protocols Site of area being treated with the amount of setup

uncertainties expected

Determination of Organs At Risk

The organs at risk (OARs) are critical normal structures that, if irradiated, could experience significant morbidity and might influence treatment planning or the prescribed dose

They should be outlined on the simulation study

Dose volume histograms (DVH) and normal tissue complication probability (NTCP) should be calculated

Radiation Therapy Dose Considerations

Early-stage classic HL in CR after chemotherapy Dose to the CTV :

Determined on the basis of the results of the German Hodgkin Studies HD 10 and 11

Favourable characteristics : 20 Gy in 10 fractions Unfavourable characteristics : 30 Gy in 15 fractions

Early-stage LPHL :30 to 35 Gy in 1.8 to 2 Gy per fraction is the recommended dose to the CTVNo advantage has been shown for higher doses

Residual lymphoma after chemotherapy : 36 to 40 Gy in 18 to 20 fractions

Treatment techniques

In some situations, conventional AP-PA techniques may be preferred

In other situations, more conformal techniques such as IMRT, arc therapy, or tomotherapy may offer significantly better sparing of critical normal structures

Recommendations as to which technique to use in the individual case cannot be made

Careful consideration must be given to choosing the technique to offer the minimum risk of significant late toxicity for that patient with adequate coverage of the targets

Involved Site Radiation Therapy in Early-Stage HL

The concept of ISRT was developed on the basis of the INRT concept

ISRT accommodates cases in which optimal pre chemotherapy imaging is not available

It is not possible to reduce the CTV to the same extent as with INRT because the pre chemotherapy GTV information may not be optimal

In ISRT, clinical judgment in conjunction with the best available imaging is used to contour a larger CTV that will accommodate the uncertainties in defining the pre chemotherapy GTV

If pre chemotherapy imaging is available, but image fusion with the post chemotherapy planning CT scan is not possible

To contour the pre chemotherapy target volume on the planning CT scan

Allowance should be made for the uncertainty of the contouring and differences in positioning by including a larger volume in the CTV

If no pre chemotherapy imaging is available To gather description of :

The pre chemotherapy physical examination of the patient The location of scars and scar tissue on the post chemotherapy

planning CT scan The patient’s and the family’s recollections of the location of the

presenting lymph node(s)

The CTV should be contoured taking into account all of this information, making generous allowance for the many uncertainties in the process

Involved-Node/Involved-Site Radiotherapy

Combined-modality therapy and the recognition that late effects may be reduced by using smaller radiation fields, and the introduction of sensitive functional imaging techniques- helped to reduce radiation field size

INRT requires prechemotherapy diagnostic CT and PET-CT imaging with the patient in the treatment position, postchemotherapy contrast-enhanced CT simulation, and fusion of the prechemotherapy and postchemotherapy images

The fields are designed to treat only the initially involved nodes with modification to avoid OARs

This GTV then becomes the CTV, and a 1-cm expansion of the CTV defines the PTV

It may be risky – when the pretreatment PET-CT scan was not done in the treatment position, there is poor registration between scans, or the CT simulation scan was done without intravenous contrast

So the concept of involved-site” irradiation is introduced

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Involved Node Radiation Therapy inEarly-Stage Classic HL

The concept of INRT for early-stage classic HL was developed and implemented by the EORTC

Reduces the treated volume to a minimum, but to be safe limit

Optimal imaging both before and after chemotherapy is needed

PET/CT is the most accurate imaging method for determining disease extent in HL, and thus up-front PET/CT is mandatory for INRT design

The pre chemotherapy PET/CT scan should be acquired with the patient in the treatment position and using the same breathing instructions that will be used later for RT

After the completion of chemotherapy, a response assessment using PET/CT or contrast-enhanced CT should be performed

INRT should be commenced 3 to 4 week after the completion of chemotherapy

The contouring process is as follows: 1. The CT images of the pre chemotherapy PET/CT are used

to delineate the initially involved lymphoma volume, the GTV-CT as determined by morphology on CT

2. The PET images of the pre chemotherapy PET/CT are used to delineate the initially involved lymphoma volume, the GTV-PET as determined by FDG uptake

3. The pre chemotherapy PET/CT is fused with the post chemotherapy planning CT scan, and the GTV-CT and GTV-PET are imported to the planning CT images

4. The post chemotherapy tissue volume, which contained the initially involved lymphoma tissue, is contoured using information from both pre chemotherapy PET and pre chemotherapy CT, taking into account tumor shrinkage and other anatomic changes.

The CTV Encompasses all of the initial lymphoma volume Still respecting normal structures that were never involved by

lymphoma, such as lungs, chest wall, muscles, and mediastinal normal structures

Irradiation of Residual Mass After FullChemotherapy for Advanced Disease

Advanced disease (classic HL and LPHL) Many centres treat patients with chemotherapy alone

(especially in the absence of bulky disease) Only if a CR is not achieved will RT is used

Target in this situation is the residual mass (GTV) after chemotherapy

Irradiation of Early-Stage LPHL

When RT is used as the only treatment modality, the CTV must be designed to encompass suspected subclinical disease

No advantage has been demonstrated with EFRT as opposed to more limited treatment fields

CTV should incorporate the GTV and include as a minimum adjacent lymph nodes in that site and a generous margin dictated by the clinical situation

Larger Field RT

Role of larger field RT is now limited essentially to salvage treatment in patients in whom chemotherapy is unsuccessful and who are unable to embark on more intensive salvage treatment schedules

Usually addressed on a case-to-case basis and it is not feasible to produce guidelines

No data to support the use of extended fields that can cause toxicity and compromise the safety of subsequent therapy such as stem cell transplantation

Refractory and Relapsed HL

Salvage RT Important role in local control for patients who have

primary refractory disease dominated by a local site Important for patients who experience relapse after

achieving a CR with initial therapy

RT should also be considered as a salvage option in the setting of ASCT failure, after relapse, or after progression

Salvage RT yields high response rates and high local control rates in refractory and relapsed HL and in relapses after ASCT

Systemic failures remain the commonest problem in this setting, underlining the need for improved systemic therapy in combination with salvage RT

Organs at Risk

The dose range used for Hodgkin lymphoma (20 to 36 Gy) is below the threshold tolerance for many organs, including the spinal cord

However, intrathoracic structures may be affected by these doses, and careful review of DVH is warranted to minimize both acute and late effects

The risk for pneumonitis is related to volume of lung irradiated, total dose, and fraction size

The relationship between mean lung dose or Vx and pneumonitis is complex and may vary for different diseases and depend on patient age, smoking history, presence of intercurrent disease, prior chemotherapy, prior surgery

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The likelihood of radiation-related pulmonary complications may be increased by the use of bleomycin

A guideline followed at Stanford is not to exceed a mean lung dose of 15 Gy after treatment with ABVD or 17 Gy after treatment with Stanford V, treating with 1.5-Gy fractions

When followed, the risk for radiation pneumonitis is negligible

Data indicate that lung cancer risk may be increased after doses as low as 5 Gy, it is reasonable to define the lung V5 and try to minimize it

The criteria for cardiac dose tolerance are not well defined; tolerances will be affected by comorbidities, family history, and prior treatment with cardiotoxic drugs such as doxorubicin

Acute effects (pericarditis) - keeping the mean pericardial dose to <26 to 27 Gy and the V30 to <46%; Data for late cardiac events are less reliable

Treatment techniques such as IMRT may succeed in reducing the cardiac dose but increase the V5 to the lungs or V4 to the breasts, resulting in a higher risk for secondary cancer in those organs

The excess risk of secondary breast cancer that exists for doses as low as 4 Gy, it is reasonable to track the breast V4 and keep that volume as small as possible, especially for women <30 years of age

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Color-wash dose distributions for three different plans for treating mediastinal Hodgkin lymphoma: axial sections (top) and sagittalsections (bottom) for conventional photon three-dimensional conformal anteroposterior/posteroanterior fields (left), intensity-modulated radiationtherapy photon (middle), and anterior proton field (right). Green outline, esophagus; red outline, heart; pink outline, breasts; blue outline, clinicaltarget volume.

Gonadal toxicity

Ovaries normally overlie the iliac lymph nodes. To avoid irradiation-induced amenorrhea, an oophoropexy must be performed. Medial or lateral transposition of the ovaries via laparoscopy

Radiopaque sutures or clips over ovaries and relocate them medially and as low as possible behind the uterine body

A double-thickness (10 halfvalue layers) midline block is then used; its location is guided by the position of the opacified nodes and transposed ovaries

When the ovaries are at least 2 cm from the edge of this block, the dose is decreased to 8% of that delivered to the iliac nodes

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In men, if no special blocking is provided for the testes, the testicular dose may be as high as 10% of the dose delivered to the inguinal-femoral nodes

Use of a double-thickness midline block and a specially

constructed testicular shield can reduce this dose to 0.75% to 3.0%, most of which results from internal scatter. The precise dose depends on the position of the testes in relation to the inferior margin of the inguinal-femoral field

Typical anteroposterior/posteroanterior field for treating unilateral pelvicnodes, in this case for a 34-year-old man with stage IIA lymphocyte-predominant Hodgkinlymphoma. T he initial positron emission tomography+ nodes are shown in blue. T he fieldincludes margins of at least 2 cm medial and lateral to the nodes and a field width of at least6 cm.

Proton Beam Therapy

The potential dosimetric advantage of treatment with protons, as opposed to photons is well established

The use of proton beam therapy can be associated with decreased dose to the gut, bone marrow, and other organs

Especially advantageous with respect to mediastinal treatment

Conventional 3DCRT with opposed fields minimizes lung exposure, but portions of the heart, especially the coronary arteries and valves, as well as of the esophagus, cannot be spared

IMRT plans can be quite conformal and spare those structures but at the expense of a low-dose “bath”

With proton there can be maximal sparing of the esophagus, lungs, and cardiac subunits, thereby minimizing risk to those organs, while at the same time avoiding low-dose exposure to the breasts and lungs

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Advanced disease

A general conclusion regarding the role of combined-modality therapy compared with chemotherapy alone for patients with stage III to IV disease

Patients who achieve a complete response to a full course of conventional chemotherapy have no proven benefit from the addition of chemotherapy

Nevertheless, irradiation is often added to such programs on a selected basis, especially for bulky disease

In addition, programs of attenuated chemotherapy may realize a benefit from the addition of irradiation

Patients who achieve only a partial response to chemotherapy may have an improved outcome by the addition of irradiation

Ultimately, improved imaging and evaluation of early response to chemotherapy with FDG-PET imaging may help to identify a subset of patients who would truly benefit from consolidative irradiation

Pediatric Patients

Most contemporary programs for the management of pediatric Hodgkin lymphoma are based on clinical staging and use chemotherapy alone or combined-modality therapy with low dose irradiation

Because higher doses of irradiation are associated with unacceptable risks for growth impairment and late effects

To limit growth effects, irradiation doses should not exceed 15 to 25 Gy

Children treated with these programs, all stages combined, are reported to achieve 5-year OS rates of approximately 90% and relapse-free rates of at least 80%

Older Adult Patients

The treatment of Hodgkin lymphoma in older patients (>60 years) also poses a challenge

They often have less favorable histology, worse performance status, intercurrent disease compromising the aggressive management programs used for younger people

Chemotherapy programs may often be modified to minimize cardiac or pulmonary toxicity, and the hematologic reserve in elderly patients more often results in dose reductions or premature discontinuation compared with younger patients

Drug combinations that seem to be more tolerable for older adults include ChlVPP procarbazine, Alkeran, and vinblastine, and vinblastine, bleomycin, and methotrexate (used primarily for stage I to II)

With respect to the radiation therapy, patients may need to be treated with slower fractionation programs and observed carefully for signs of weight loss or general decline in performance status

Extended fields are more difficult to tolerate than more limited fields.

Treatment for Relapse

Treatment for relapse must be individualized; Initial disease characteristics, initial treatment and response duration, relapse sites, and general patient status must be considered

In general, patients who were treated initially with irradiation alone for stage I to II disease (now a relatively infrequent occurrence) should receive chemotherapy as the primary salvage treatment

The efficacy of combination chemotherapy in this setting is similar to that achieved when chemotherapy is used in the primary management of advanced disease (rate of long-term freedom from relapse of 60% or better)

The role of irradiation in combination with salvage chemotherapy has not been defined but is quite reasonable to consider if relapse is in a previously unirradiated site

Patients who present initially with stage I to II disease and are treated with chemotherapy alone, In these patients, relapse may be restricted to initial sites of disease and be quite limited.

It is possible that in this situation programs using irradiation alone, or at least emphasizing the use of radiation, may be safe and effective

For patients who present initially with stage III to IV disease and relapse after achieving a complete response to chemotherapy or combined-modality therapy, the standard salvage therapy is high-dose chemotherapy with autologous hematopoietic cell rescue.

The long-term PFS rate for these patients is expected to be approximately 50%

Favorable prognostic factors in this group include a longer duration of response to primary therapy and absence of extranodal disease

Allotransplantation is not used often for relapsed Hodgkin lymphoma but may be considered in situations of an unsuccessful autotransplant.

Reduced-intensity conditioning regimens appear to be safer than myeloablative regimens

The Role of Radiation Therapy in HematopoieticCell Transplantation

Radiation therapy may be incorporated into high-dose therapy programs such as IFRT, TLI, or total-body irradiation (TBI)

Fractionated TBI is incorporated into a number of transplantation programs.

TBI is probably not the most efficacious way to use irradiation in these patients.

Recurrent Hodgkin lymphoma is often a locoregional problem rather than a systemic one.

In addition, data suggest that irradiation doses in the range used in TBI programs (12 to 15 Gy) are likely to eradicate disease in only about 20% of treated sites.

It is more logical to limit irradiation to sites of failure or those at high risk for disease, that is, initial sites of disease, especially bulky sites.

At Memorial Sloan-Kettering Cancer Center, an intensive program that incorporates pretransplant TLI has been used

Patients who had not received previous irradiation were treated with IFRT to 18 Gy and TLI to 18 Gy (both with twice-daily fractionation)

Patients who had prior irradiation were treated with IFRT only, if organ tolerance would not be exceeded, to a dose of 18 to 36 Gy in 5 to 10 days (twice-daily fractionation), depending on the prior doses received by the involved sites

The 10-year OS was 56%, and EFS was 56

Follow-Up

Follow-up is important to monitor for complications of therapy and late effects and to ensure health maintenance

As a rule of thumb, all studies that initially gave abnormal results (e.g., chest radiograph, CT scan, PET scan) should be repeated at the time of completion of therapy to document the completeness of response

The subsequent follow-up interval is typically every 2 to 4 months during the first 2 years, every 4 to 6 months during the third and fourth years, and annually thereafter.

The most important component of follow-up is an interim history and physical examination

The frequency with which imaging studies should be repeated after the completion of therapy is not well defined

The value of more extensive imaging evaluation in the absence of symptoms or abnormalities is questionable.

The ESR, serum albumin, or other serum marker studies may be followed if these markers were abnormal at presentation

Serum thyroxine (T4) and sensitive thyroid-stimulating hormone (TSH) levels should be obtained at least annually in patients who received irradiation to the neck, to detect subclinical hypothyroidism

In almost every case, the first episode of relapse should be documented by biopsy

Inflammatory disease, progressive transformation of germinal centers, or the rebound growth of the thymus in young patients are other reactive processes that can be confused with recurrent Hodgkin lymphoma. All of these processes may be FDG-avid on PET scanning.

A challenging problem in follow-up evaluation in the past was the interpretation of residual mediastinal abnormality on chest radiograph or chest CT scan. However, this problem has been obviated by the introduction of FDG-PET scanning as a posttreatment assessment tool

Conclusion

The newly defined fields of ISRT represent a significant reduction in the volume included in the previously used IFRT

Radiation oncologists treating HL should be involved as part of the multidisciplinary team in the initial management plan and attempt to introduce imaging procedures up front before the initiation of chemotherapy

Integrated multidisciplinary approach will enable the optimal outcome for patients with HL

Conclusion

Modern RT for HL is a highly individualized treatment restricted to limited treatment volumes

Modern imaging and RT techniques should be used to limit the amount of normal tissue being irradiated, thus minimizing the risk of long-term complications