Childhood Hodgkin Lymphoma Treatment (PDQ®) 3/6 —Health Professional Version - National Cancer Institute

Childhood Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Diagnosis and Staging Information for Childhood Hodgkin Lymphoma

In This Section

• Diagnostic and Staging Evaluation
  • Systemic symptoms
  • Physical examination
  • Laboratory studies
  • Anatomic imaging
  • Functional imaging
• Establishing the Diagnosis of Hodgkin Lymphoma
• Ann Arbor Staging Classification for Hodgkin Lymphoma
• Risk Stratification
• Response Assessment
  • Interim response assessment
  • End of chemotherapy response assessment

Staging and evaluation of disease status is undertaken at diagnosis and performed again early in the course of chemotherapy and at the end of chemotherapy.

Diagnostic and Staging Evaluation

The diagnostic and staging evaluation is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:

• History of systemic symptoms (detailed).
• Physical examination.
• Laboratory studies, including complete blood count, chemistry panel with albumin, and erythrocyte sedimentation rate.
• Anatomic imaging, including chest x-ray and computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, chest, abdomen, and pelvis. MRI and positron emission tomography (PET)–MRI provide the advantage of limiting radiation exposure.[1]
• Functional imaging, including PET scan.

Systemic symptoms

The following three specific constitutional symptoms (B symptoms) correlate with prognosis and are considered in assignment of stage:

• Unexplained fever with temperatures above 38.0°C orally.
• Unexplained weight loss of 10% within the 6 months preceding diagnosis.
• Drenching night sweats.

Additional Hodgkin-associated constitutional symptoms without prognostic significance include the following:

• Pruritus.
• Alcohol-induced nodal pain.

Physical examination

• All node-bearing areas, including the Waldeyer ring, should be assessed by careful physical examination.
• Enlarged nodes should be measured to establish a baseline for evaluation of therapy response.

Laboratory studies

• Hematological and chemical blood parameters (e.g., albumin) show nonspecific changes that may correlate with disease extent.
• Abnormalities of peripheral blood counts may include neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis.
• Acute-phase reactants such as the erythrocyte sedimentation rate and C-reactive protein, if abnormal at diagnosis, may be useful in follow-up evaluation.[2]

Anatomic imaging

Anatomic information from CT or MRI is complemented by PET functional imaging, which is sensitive in determining initial sites of involvement, particularly in sites too small to be considered clearly involved by CT or MRI criteria. Collaboration across international groups to harmonize definitions is ongoing.[3]

Definition of bulky disease

Historically, the presence of bulky disease, especially mediastinal bulk, predicted an increased risk of local failure and resulted in the incorporation of bulk as an important factor in treatment assignment. The definition of bulk has varied across pediatric protocols and evolved over time with advances in diagnostic imaging technology.[3]

The criteria for bulky mediastinal and nonmediastinal disease are as follows:

• Mediastinal. In North American protocols, the posteroanterior chest radiograph remains important because the criterion for bulky mediastinal lymphadenopathy is defined by the ratio of the diameter of the mediastinal lymph node mass to the maximal diameter of the rib cage on an upright chest radiograph; a ratio of 33% or higher is considered bulky. In contrast, the EuroNet-Pediatric Hodgkin Lymphoma Group defines mediastinal bulk by the volume of the largest contiguous lymph node mass being 200 mL or more on CT. These two definitions differ from the recently published consensus guidelines from the International Conference on Malignant Lymphomas Imaging Group (Lugano), where bulk is described as a mass 10 cm or larger unidimensionally on CT.[4]
• Nonmediastinal. The criteria for bulky peripheral, nonmediastinal lymphadenopathy have also varied over the years in cooperative group study protocols, and this disease characteristic has not been consistently used for treatment stratification. In contemporary U.S. protocols, bulky peripheral lymphadenopathy is defined as greater than 6 cm, with aggregates measured transversely or cranial-caudal. In EuroNet protocols, peripheral adenopathy is again defined as a volume of greater than 200 mL, which is generally larger than a 6 cm unidimensional mass.

Criteria for lymphomatous involvement by CT or MRI

Defining strict CT or MRI size criteria for lymphomatous nodal involvement is complicated by several factors, such as size overlap between what proves to be benign reactive hyperplasia versus malignant lymphadenopathy, the implication of nodal clusters, and obliquity of node orientation to the scan plane. Additional difficulties more specific to children include greater variability of normal nodal size and the frequent occurrence of reactive hyperplasia.

General concepts to consider in regard to defining lymphomatous involvement by CT or MRI include the following:

• Contiguous nodal clustering or matting is highly suggestive of lymphomatous involvement.
• Any focal mass lesion large enough to characterize in a visceral organ is considered lymphomatous involvement unless the imaging characteristics indicate an alternative etiology.
• Criteria for nodal involvement may vary by cooperative group or protocol.[3]
  • Children's Oncology Group (COG) and EuroNet protocols consider lymph nodes abnormal if the long axis is greater than 2 cm, regardless of the short axis and PET avidity. Lymph nodes with a long axis measuring between 1 cm and 2 cm are only considered abnormal if they are part of a conglomerate of nodes and are fluorine F 18-fludeoxyglucose (18F-FDG) PET positive.
  • In the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) GPOH-HD-2002 study, nodal involvement was defined as node size greater than 2 cm in largest diameter. The node was not involved if it was less than 1 cm and was considered questionable if it was between 1 cm and 2 cm. The decision on involvement was then made on the basis of additional clinical evidence.[5]
  • In an analysis of 47,828 imaging measurements from 2,983 individual patients with adult and pediatric lymphoma enrolled in ten multicenter clinical trials, a single dimension measurement of 15 mm or more constituted involvement.[6]

Functional imaging

The recommended functional imaging procedure for initial staging is PET, using the radioactive glucose analog, 18F-FDG.[7,8] 18F-FDG PET identifies areas of tumor with increased metabolic activity, specifically anaerobic glycolysis. PET-CT, which integrates functional and anatomic tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent 18F-FDG avidity has been correlated with poor prognosis and the need for additional therapy in posttreatment evaluation.[9-12]

General concepts to consider in regard to defining lymphomatous involvement by 18F-FDG PET include the following:

• Concordance between PET and CT data is generally high for nodal regions, but may be significantly lower for extranodal sites. In one study specifically analyzing pediatric Hodgkin lymphoma patients, assessment of initial staging comparing PET and CT data demonstrated concordance of approximately 86% overall. Concordance rates were significantly lower for the spleen, lung nodules, bone/bone marrow, and pleural and pericardial effusions.[13] A meta-analysis of nine clinical studies showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma, with focal involvement highly predictive of bone marrow involvement.[14,15]
• Integration of data acquired from PET scans can lead to changes in staging.[4,16]
• Staging criteria using PET and CT scan information is protocol dependent, but generally areas of PET positivity that do not correspond to an anatomic lesion by clinical examination or CT scan size criteria should be disregarded in staging, with the possible exception of focally PET-positive bone marrow findings.
• A suspected anatomic lesion that is PET negative should not be considered involved unless proven by biopsy.

18F-FDG PET has limitations in the pediatric setting. Tracer avidity may be seen in a variety of nonmalignant conditions including thymic rebound commonly observed after completion of lymphoma therapy. 18F-FDG avidity in normal tissues, such as brown fat in the neck, may confound interpretation of the presence of nodal involvement by lymphoma.[7]

Visual PET criteria are scored according to uptake involved by lymphoma from the Deauville 5-point scale, from 1 to 5, as described in Table 2. The COG and EuroNet definitions of PET response of lymph nodes or nodal masses are described in Table 3.

Table 2. Deauville Score Criteria

Deauville Score (Visual Score)	Criteria
1	No uptake.
2	Uptake ≤ mediastinal blood pool.
3	Uptake > mediastinal blood pool and ≤ normal liver.
4	Moderately increased uptake > normal liver.
5	Markedly increased uptake > normal liver.

Table 3. Children's Oncology Group and EuroNet Definition of PET Response of Lymph Node or Nodal Masses

Timing of 18F-FDG PET	18F-FDG PET Avidity
18F-FDG = fluorine F 18-fludeoxyglucose; PET = positron emission tomography.
Baseline PET (PET 0) response visual threshold utilizes mediastinal blood pool as the reference activity:	18F-FDG PET positive is defined as visual score 3, 4, 5.
	18F-FDG PET negative is defined as visual score 1, 2.
Interim postcycle 2 PET (PET 2) response visual threshold uses normal liver as the reference activity:	18F-FDG PET positive is defined as visual score 4, 5.
	18F-FDG PET negative is defined as visual score 1, 2, 3.
End of chemotherapy PET (PET 4 or 5) response visual threshold also utilizes mediastinal blood pool as the reference activity:	18F-FDG PET positive is defined as visual score 3, 4, 5.
	18F-FDG PET negative is defined as visual score 1, 2.

Establishing the Diagnosis of Hodgkin Lymphoma

After a careful physiologic and radiographic evaluation of the patient, the least invasive procedure should be used to establish the diagnosis of lymphoma. However, this should not be interpreted to mean that a needle biopsy is the optimal methodology. Small fragments of lymphoma tissue are often inadequate for diagnosis, resulting in the need for second procedures that delay the diagnosis.

If possible, the diagnosis should be established by biopsy of one or more peripheral lymph nodes. The likelihood of obtaining sufficient tissue should be carefully considered when selecting a biopsy procedure. Other issues to consider in choosing the diagnostic approach to lymph node biopsy include the following:

• Type of biopsy procedure.
  • Aspiration cytology alone is not recommended because of the lack of stromal tissue, the small number of cells present in the specimen, and the difficulty of classifying Hodgkin lymphoma into one of the subtypes.
  • An image-guided biopsy may be used to obtain diagnostic tissue from intra-thoracic or intra-abdominal lymph nodes. On the basis of the involved sites of disease, alternative procedures that may be considered include thoracoscopy, mediastinoscopy, and laparoscopy. Thoracotomy or laparotomy is rarely needed to access diagnostic tissue.
  • Because bone marrow involvement is relatively rare in pediatric Hodgkin lymphoma patients, bilateral bone marrow biopsy should be performed only in patients with advanced disease (stage III or stage IV) and/or B symptoms.[17]
    In support of this, a meta-analysis of nine clinical studies including both pediatric and adult patients showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma.[14] (Refer to the Stage Information for Adult HLsection in the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) In a consensus statement based on these studies, this group no longer recommends bone marrow biopsy in the initial evaluation of adults with Hodgkin lymphoma, with PET-CT being used instead to identify bone marrow involvement.[4]
• Procedure-related complications.
  • Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[18] After careful planning with anesthesia, peripheral lymph node biopsy or image-guided core-needle biopsy of mediastinal lymph nodes may be feasible using light sedation and local anesthesia before proceeding to more invasive procedures.
  • If airway compromise precludes the performance of a diagnostic operative procedure, preoperative treatment with steroids or low-dose, localized radiation therapy should be considered, although that can be technically difficult if the patient cannot recline. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks associated with general anesthesia or heavy sedation are alleviated.

Ann Arbor Staging Classification for Hodgkin Lymphoma

Stage is determined by anatomic evidence of disease using CT or MRI scanning in conjunction with functional imaging. The staging classification used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971 [19] and revised in 1989 (refer to Table 4).[20] Staging is independent of the imaging modality used.

Table 4. Ann Arbor Staging Classification for Hodgkin Lymphomaa

Stage	Description
aReprinted with permission from AJCC: Hodgkin and non-Hodgkin lymphomas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607-11.[21]
I	Involvement of a single lymphatic site (i.e., nodal region, Waldeyer's ring, thymus, or spleen) (I); or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE).
II	Involvement of two or more lymph node regions on the same side of the diaphragm (II); or localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE).
III	Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE,S).
IV	Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.
Designations applicable to any stage
A	No symptoms.
B	Fever (temperature >38.0ºC), drenching night sweats, unexplained loss of >10% of body weight within the preceding 6 months.
E	Involvement of a single extranodal site that is contiguous or proximal to the known nodal site.
S	Splenic involvement.

Extralymphatic disease resulting from direct extension of an involved lymph node region is designated E. Extralymphatic disease can cause confusion in staging. For example, the designation E is not appropriate for cases of widespread disease or diffuse extralymphatic disease (e.g., large pleural effusion that is cytologically positive for Hodgkin lymphoma), which should be considered stage IV. If pathologic proof of noncontiguous involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Current practice is to assign a clinical stage on the basis of findings of the clinical evaluation; however, pathologic confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.

Risk Stratification

After the diagnostic and staging evaluation data are acquired, patients are further classified into risk groups for the purposes of treatment planning. The classification of patients into low-, intermediate-, or high-risk categories varies considerably among the different pediatric research groups, and often even between different studies conducted by the same group, as summarized in Figure 1.[22]

ENLARGE

Figure 1. Variation in risk stratification across pediatric Hodgkin study groups and protocols. E, extranodal extension; X, bulky disease (peripheral >6 cm and mediastinal bulk); mX, mediastinal bulk (≥0.33 mediastinal to thoracic ratio); ns, nodal site; TG, treatment group; TL, treatment level; RF, risk factors: erythrocyte sedimentation rate (ESR) ≥30 mm/hour and/or bulk ≥200 mL. (*) EuroNet-PHL-C1 was amended in 2012: Low-risk (TG1) patients with ESR ≥30 mm/hour and/or bulk ≥200 mL were treated in TG2 (intermediate risk). Christine Mauz-Körholz, Monika L. Metzger, Kara M. Kelly, Cindy L. Schwartz, Mauricio E. Castellanos, Karin Dieckmann, Regine Kluge, and Dieter Körholz, Pediatric Hodgkin Lymphoma, Journal of Clinical Oncology, volume 33, issue 27, pages 2975–2985. Reprinted with permission. © (2015) American Society of Clinical Oncology. All rights reserved.

Although all major research groups classify patients according to clinical criteria, such as stage and presence of B symptoms, extranodal involvement, or bulky disease, comparison of outcomes across trials is further complicated because of differences in how these individual criteria are defined.[3]

Response Assessment

Further refinement of risk classification may be performed through assessment of response after initial cycles of chemotherapy or at the completion of chemotherapy.

Interim response assessment

The interim response to initial therapy, which may be assessed on the basis of volume reduction of disease, functional imaging status, or both, is an important prognostic variable in both early- and advanced-stage pediatric Hodgkin lymphoma.[23-26]

Definitions for interim response are variable and protocol specific but can range from 2-dimensional reductions in size of greater than 50% to the achievement of a complete response with 2-dimensional reductions in size of greater than 75% or 80% or a volume reduction of greater than 95% by anatomic imaging or resolution of 18F-FDG PET avidity.[5,27,28]

The rapidity of response to early therapy has been used in risk stratification to tailor therapy in an effort to augment therapy in higher-risk patients or to reduce the late effects while maintaining efficacy.[25,26,28,29]

Results of selected trials using interim response to titrate therapy

Several studies have evaluated the use of interim response to titrate additional therapy:

1. The Pediatric Oncology Group used a response-based therapy approach consisting of dose-dense ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) for intermediate-stage and advanced-stage patients, in combination with 21 Gy involved-field radiation therapy (IFRT).[28]
   • The dose-dense approach permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response on CT imaging after three ABVE-PC cycles.
   • Five-year event-free survival (EFS) was comparable for rapid early responders (86%; treated with three cycles of ABVE-PC) and slow early responders (83%; treated with five cycles of ABVE-PC). All patients received 21 Gy of regional radiation therapy.
2. The Children's Cancer Group (CCG) (CCG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[29]
   1. For rapid early responding girls, an additional four courses of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine) (without IFRT) was given in an effort to reduce breast cancer risk.
   2. Rapid early responding boys received two cycles of ABVD followed by IFRT.
   3. Slow early responders received four additional courses of BEACOPP and IFRT.
      • Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four BEACOPP cycles and 5-year EFS among the cohort was 94% (median follow-up, 6.3 years).
3. The COG AHOD0031 (NCT00025259), AHOD0831 (NCT01026220), and AHOD0431 (NCT00302003) trials also used interim response to titrate therapy. (Refer to the North American cooperative and consortium trial results section of this summary for more information.) The AHOD0031 trial was designed to evaluate this paradigm of care by randomly assigning patients to receive either standard or response-based therapy.

End of chemotherapy response assessment

Restaging is carried out upon the completion of all planned initial chemotherapy and may be used to determine the need for consolidative radiation therapy. Key concepts to consider include the following:

• Defining complete response. The definition of complete response may vary by cooperative group or protocol.
  • The International Working Group (IWG) defined complete response for adults with Hodgkin lymphoma in terms of complete metabolic response as assessed by 18F-FDG PET, even when a persistent mass is present.[30] These criteria were endorsed in the Lugano Classification, with the recommendation for using a 5-point scale in assessing response.[4,31] COG protocols have adopted this approach for defining complete response.
  • Previous studies have varied in the use of findings from clinical exam, anatomic imaging, and functional imaging to assess response. Although complete response can be defined as absence of disease by clinical examination and/or imaging studies, complete response in Hodgkin lymphoma trials is often defined by a greater than 80% reduction of disease and a change from initial positivity to negativity on functional imaging.[32] This definition is necessary in Hodgkin lymphoma because fibrotic residual disease is common, particularly in the mediastinum. In some studies, such patients are designated as having an unconfirmed complete response.
  • The EuroNet Hodgkin lymphoma trials use a similar early response assessment definition of PET positivity, which is a Deauville score of greater than 3 after two cycles of OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]).[33]
  • GPOH studies use very stringent criteria for treatment group 1 (TG1) patients that includes at least 95% reduction in tumor volume or less than 2 mL residual volume on CT, as patients achieving these metrics will have radiation therapy omitted. Treatment group 2 (TG2) and treatment group 3 (TG3) patients received radiation therapy despite their potential morphologic complete response (refer to Figure 1).[5]
  • The COG AHOD1331 (NCT02166463) high-risk Hodgkin lymphoma initial therapeutics clinical trial uses 18F-FDG PET assessment graded by a 5-point visual scale or Deauville criteria after two chemotherapy cycles to define a rapid early-responding lesion for which radiation will be omitted. A mass of any size is permitted for a complete response designation if the PET is negative. The results of using the latter criteria are not yet available; therefore, it may not be considered standard of care.
• Timing of PET scanning after completing therapy. Timing of PET scanning after completing therapy is an important issue.
  • For patients treated with chemotherapy alone, PET scanning is ideally performed a minimum of 3 weeks after the completion of therapy, while patients whose last treatment modality was radiation therapy should not undergo PET scanning until 8 to 12 weeks postradiation.[30]
• Screening frequency and overscreening.
  • A COG study evaluated surveillance CT and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma. Most relapses occurred within the first year after therapy and were detected based on symptoms, laboratory, or physical findings. The method of detection of late relapse, whether by imaging or clinical change, did not affect overall survival. Routine use of CT at the intervals used in this study did not improve outcome.[34] The concept of reduced frequency of imaging has been supported by other investigations.[35-37]
  • Caution should be used in making the diagnosis of relapsed or refractory disease based solely on anatomic and functional imaging because false-positive results are not uncommon.[38-40] Consequently, pathologic confirmation of refractory or recurrent disease is recommended before modification of therapeutic plans.

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