Introduction

Pediatric Hodgkins lymphoma (HL) is a highly curable malignancy. The emphasis of treatment in pediatric Hodgkins lymphoma has shifted towards risk stratified approach, so that long term side-effects of chemotherapy and radiotherapy can be reduced. The age standardised rates (ASR) of Hodgkins lymphoma in India is 0.4/100000 population, whereas the global ASR varies between 0.3/100000 in less developed countries and 0.6/100000 in developed countries [1]. Hodgkins lymphoma is more common in boys than in girls with the gender gap being wider in developing countries than developed countries [2]. Children with Hodgkins lymphoma in India present at a younger age when compared to Western patients [2]. Long term outcomes reported from various centres in India are comparable to outcomes reported from western centres. The current manuscript is written with the objective of developing a consensus guideline for practitioners at a National level.

Material and Methods

This document on consensus guidelines for management of Hodgkins lymphoma was arrived at after an initial round of meetings with National experts in the field of Pediatric Hematology Oncology. Thereafter an exhaustive review of literature of National and International data was undertaken and the manuscript was drafted. This was then presented in a second round meeting with the experts till a final consensus was obtained after mutiple rounds of discussion. The final consensus document was once again sent to all the authors for proofing and then submitted.

Treatment Philosophy for Pediatric Hodgkins Lymphoma [3]

There is no one standard treatment regimen for pediatric Hodgkins lymphoma. The treatment of an individual patient is based on various parameters like 1. Risk stratification, 2. Response to initial chemotherapy, 3. Age and Gender, 4. Associated co-morbidities like cardiac and pulmonary diseases, and 5. Stage of disease. The goal is to minimise treatment related short term and long term toxicity without compromising cure.

Chemotherapy is indicated in all patients with Hodgkins lymphoma as use of radiotherapy alone does not lead to complete cure in majority of the patients and is associated with significant long-term toxicities. Combination chemotherapy is preferred over single agent drugs. It is important to remember that alkylating agents like procarbazine and cyclophosphamide can cause sterility especially in males and therefore should be omitted or used with caution. Anthracyclines like doxorubicin in higher cumulative doses can cause cardiac dysfunction and when combined with mediastinal radiotherapy can contribute to long-term cardiac toxicities like ischemic heart disease. Etoposide can cause secondary leukemia which is dependent on the cumulative dose used, whereas bleomycin induced pulmonary toxicity is idiosyncratic. Therefore it is essential to limit the cumulative doses of the above drugs in chemotherapy regimens used for treating pediatric Hodgkins lymphoma. Emphasis is shifting from Involved Field radiotherapy (IFRT) to Involved Nodal RT (INRT) in pediatric Hodgkins lymphoma due to long-term concerns of second malignancies, growth retardation, endocrine dysfunction, sterility if gonads are irradiated and cardiovascular disease when mediastinum is irradiated. The radiation field in IFRT will depend on the location of the nodes. Radiotherapy dose used varies from 20 to 36 Gy depending upon the response to chemotherapy. The pre-treatment nodal size needs to be irradiated.

Risk Stratification [4]

Risk stratification is used in all the protocols for treating Hodgkins lymphoma to tailor the treatment. The risk stratification has also evolved over the last few decades. The goal of risk stratification is to minimise treatment in patients with favourable disease thereby reducing long-term toxicity and escalate treatment in patients with high-risk disease so as to not to compromise on survival. There is considerable variation in risk stratification among various trials and treatment groups and therefore, it becomes difficult to compare trials in pediatric Hodgkins lymphoma. The general risk stratification followed by various groups are given below

  • Favourable: Stage I or II without adverse prognostic factors

  • Intermediate: Stage I or II with adverse prognostic factors (presence of “B” symptoms, bulky lymphadenopathy, extranodal extension to contiguous structures, involvement of three or more nodal areas)

  • Advanced: Stage II BE, II BX, IIIAE, IIIAX, IIIB-IV

Review of Literature

Management of pediatric Hodgkins lymphoma has evolved over the last 5–6 decades. Multiple prospective randomised controlled trials in pediatric Hodgkins lymphoma have been conducted in North America and Europe. Majority of the data on Hodgkins lymphoma management from India has been retrospective in nature. The current guidelines therefore will be based mainly on the results of prospective randomised controlled trials (RCT) data from the western countries.

The optimum treatment of Hodgkins lymphoma in children is not clearly defined. There is wide variation among the treatment protocols used in various centres in India and abroad. Although protocols using ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen are standard for treating adults, their use in children is limited due to the cumulative toxicity of the regimen.

Summary of Important Trials

The pediatric oncology group response based risk adapted therapy showed that in patients with favourable risk (stage IA, IB, IIA, IIIA), 2 cycles ABVE (Doxorubicin, bleomycin, vincristine, etoposide) with IFRT (25.5 Gy) was equivalent to 4 cycles of ABVE with IFRT (25.5 Gy) in patients who achieved complete response (CR) after 2 cycles [5]. In patients with unfavourable advanced disease, patients who achieved rapid response after 3 cycles of dose dense ABVE-PC (Doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) had outcomes comparable to patients who achieved rapid response and received 5 cycles of dose dense ABVE-PC [6]. All patients received 21 Gy IFRT [6]. The Children’s Cancer Group (CCG) trial compared COPP/ABV (Cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine) hybrid chemotherapy followed by randomisation to IFRT or no IFRT in patients achieving CR. In this trial, Event Free Survival (EFS) was inferior in patients in whom IFRT was omitted [7]. In another CCG trial, response adapted de-escalation treatment was planned in patients with stage IIB, IIIB and stage IV disease. Patients with rapid early response after four cycles of dose intensive BEACOPP (Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine) could be de-escalated to 4 cycles of COPP/ABV without IFRT in girls and 2 cycles of ABVD followed by IFRT in boys [8]. IFRT was avoided in girls to reduce the long-term risk of breast cancer. The Stanford, St Jude and Boston Consortium trials showed that patients with favourable Hodgkins lymphoma who achieved early CR with 4 cycles, VAMP (Vinblastine, doxorubicin, methotrexate, prednisone) chemotherapy had outcomes similar to patients who received 4 cycles VAMP with 25.5 Gy IFRT [9].

The HD-95 trial done in Germany has shown that omission of radiotherapy in intermediate or high risk patients who achieve CR leads to inferior outcome. However, omission of radiotherapy in favourable risk group patients did not result in inferior outcome. All patients received OEPA (Vincristine, etoposide, prednisone, doxorubicin) or OPPA (Vincristine, procarbazine, prednisone, doxorubicin) /COPP (Cyclophosphamide, vincristine, procarbazine, prednisone) chemotherapy in this trial [10]. The interim analysis of Euronet Trial which is an ongoing multi-centre trial in Europe has revealed that COPP and COPDac (Cyclophosphamide, vincristine, prednisone, dacarbazine) are similarly efficacious and therefore, procarbazine (COPP) can be eliminated in boys thereby decreasing risk of sterility. EFS of all patients did not differ whether they received radiotherapy [11]. Tables 1 and 2 summarise the results of prospective trials in low risk (favourable) and Intermediate and Advanced Hodgkins lymphoma from the Western world.

Table 1 Results of recent trials for pediatric low-risk Hodgkins lymphoma
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Table 2 Results of recent trials for pediatric intermediate and high-risk HL
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Indian Experience

A meta-analysis of all published data on Hodgkins lymphoma from India reported the outcomes in 958 children [16]. The median age at presentation was 7–9 y in majority of the studies and the median male to female ratio was 4.4:1. Majority (median 64%, range 33–92%) had stage IIB/III Hodgkins lymphoma at presentation. Mixed cellularity was the most common histology (median 50%, range 27–86%). Positive Emission Tomography (PET) combined with computed tomography (CT) was not used in any centre. Treatment consisted of chemotherapy and radiotherapy, but there was considerable variation among centres. Several chemotherapy regimens were used, most commonly ABVD. Table 3 provides the details of studies on Hodgkins lymphoma published from India.

Table 3 Studies on pediatric Hodgkins lymphoma from India
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Review of literature from India suggests that multi-agent chemotherapy without radiotherapy may be sufficient to treat majority of Hodgkins lymphoma patients. Radiotherapy can be reserved for patients with bulky disease not responding to chemotherapy alone. A survey of main pediatric cancer centres in India has shown that 75% of them use ABVD protocol for treating pediatric Hodgkins lymphoma. In India, the management of Hodgkins lymphoma will be influenced by the availability of PET/CT imaging and radiotherapy facilities. PET/CT and radiotherapy add significant costs to the treatment of Hodgkins lymphoma and are not available in various parts of the country. Therefore, the practice of PET/CT based response tailored treatment may not be feasible (though desirable), in various centres across India.

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

Assessment of response to treatment after completing 2–3 cycles of chemotherapy has been found to be useful in de-escalating treatment in patients with good response or escalating treatment in patients with poor response. The interim assessment can be performed using CT scans or PET/CT scan. There is no standard definition of a good response or poor response and various protocols have used their own definitions to define response. Clinical findings and laboratory investigations have also been incorporated along with radiological findings to define response. The Lugano classification is the most widely accepted classification for response assessment [25].

Guidelines for Histopathology

Lymph node biopsy is mandatory for confirming the diagnosis [26]. Wherever possible, excisional lymph node biopsy is strongly recommended over core-needle biopsy. However, in inaccessible sites like retroperitoneum and mediastinum, core-needle biopsy will be acceptable. Fine needle aspiration is usually not sufficient for diagnosis of lymphoma in children and is not recommended. For histological diagnosis and subtyping, immunohistochemistry is recommended, where feasible. Immunostaining for CD15, CD30, CD3, CD20, and CD45 is ideal for classical HL (cHL) but a limited profile with CD15 and CD30 may be adequate if histopathology is classical. For nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), CD20 is recommended.

Pathological diagnosis should be made according to the World Health Organization (WHO) classification from a sufficiently large surgical specimen or excisional lymph node biopsy to provide enough material for fresh frozen and formalin-fixed samples. In cHL, the presence of Hodgkin and Reed–Sternberg (HRS) cells is disease-defining while the detection of lymphocyte predominant (LP) cells is required for the diagnosis of NLPHL. The immunophenotype of the malignant cells in cHL and NLPHL differs significantly. In contrast to HRS cells that stain consistently positive for CD30 and CD15, occasionally positive for CD20 and negative for CD45, LP cells are characterised by the expression of CD20 and CD45 but they lack CD15 and CD30.

2008 WHO Classification of Lymphoid Neoplasms

  • Nodular Lymphocyte Predominant

  • Classical Hodgkins Lymphoma

    • ○ Nodular Sclerosing Classical Hodgkins Lymphoma

    • ○ Lymphocyte-Rich Classical Hodgkins Lymphoma

    • ○ Mixed Cellularity Classical Hodgkins Lymphoma

    • ○ Lymphocyte- Depleted Classical Hodgkins Lymphoma

Staging

It is essential that every patient undergoes staging investigations prior to starting disease directed therapy. Stage is determined by anatomic evidence of disease using CT scanning in conjunction with functional imaging (wherever possible) and bone marrow biopsy. The staging classification used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971 and revised in 1989 [27].

Ann Arbor Staging Classification of Hodgkin Lymphoma

Stage 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).

Stage 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).

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE,S).

Stage 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.

Annotations of Stage

HL will be sub-classified into A and B categories. Patients with any of the following specific symptoms will be classified as B:

  • Unexplained loss of more than 10% of body weight in the 6 mo before diagnosis.

  • Unexplained fever with temperatures above 38 °C for more than 3 d.

  • Drenching night sweats.

Definition of Bulky Disease

Bulky mediastinal disease is defined as a mediastinal mass with horizontal tumor diameter > 1/3rd the thoracic diameter (measured transversely at the level of the dome of the diaphragm on a 6 ft upright posterior-anterior chest x-ray). In the presence of hilar nodal disease, the maximal mediastinal tumor measurement may be taken at the level of the hilum. This should be measured as the maximum mediastinal width (at a level containing tumor and any normal mediastinal structures at the level) over the maximum thoracic ratio.

Bulky disease outside the mediastinum is defined as a single node or continuous aggregate of nodal tissue that measures >6 cm in the longest diameter in any nodal area.

Diagnostic Work-Up

  1. 1.

    Clinical evaluation: The workup should include a thorough history and physical examination including B symptoms (unexplained fever, more than 10% weight loss and/or drenching night sweats).

  2. 2.

    Physical examination should be careful and complete:

    1. a.

      Common lymph node areas to be palpated.

    2. b.

      Number of sites / lymph node regions is to be noted.

    3. c.

      Measurement of largest mass (bulky disease).

    4. d.

      The size of liver / spleen in cm below costal margin.

    5. e.

      Baseline pubertal status.

  1. 3.

    Essential laboratory investigations:

    1. a.

      Complete blood counts (CBC) & differential leukocyte counts (DLC) and erythrocyte sedimentation rate (ESR).

    2. b.

      Lactate dehydrogenase (LDH), liver function tests (LFT) and serum creatinine.

    3. c.

      Contrast enhanced CT neck, chest and whole abdomen are mandatory (unless PET scan is done).

    4. d.

      Adequate bilateral bone marrow (BM) biopsy should be performed on patients who have stage III or IV disease or B symptoms. BM biopsy can be omitted in patients who undergo PET/CT for staging.

    5. e.

      Pleural cytology, if there is pleural effusion.

Other Investigations

  1. 1.

    Hepatitis B, Hepatitis C and Human Immunodeficiency (HIV) screening

  2. 2.

    Baseline Echocardiography and Pulmonary function test.

  3. 3.

    PET/CT scan should be done wherever feasible.

  4. 4.

    Bone scan: indicated in case of bone pain, elevated alkaline phosphatase; it is not needed if PET/CT scan has been done.

  5. 5.

    Reproductive counseling (in younger patients) and semen preservation for older male patients and serum pregnancy test (in female patients).

Treatment Recommendations

Treatment recommendations for pediatric Hodgkins lymphoma patients is given below. It is important to remember that if one treatment regimen or protocol is selected then the said protocol or regimen should be followed and not mixed and matched with other regimens. The chemotherapy and radiotherapy doses and schedule given in the protocol should be followed. Definition of good response or poor response after 2–3 cycles of chemotherapy will vary according to the treatment protocol used. Patients who have achieved CR on PET/CT or CT after 2–3 cycles of chemotherapy are considered good (rapid) responders and patients who have stable disease are considered poor (slow) responders. Patients with partial response (PR) on PET/CT or CT can be either good or poor responders based on the protocol/study being followed. Patients with progressive disease after 2 cycles of chemotherapy should be considered for escalation to more intense chemotherapy protocols. The protocols recommended below are not in any particular order of preference. Table 4 provides the schedule and doses for commonly used chemotherapy protocols in pediatric Hodgkins lymphoma.

Table 4 Chemotherapy protocols for pediatric Hodgkins lymphoma
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Favourable Risk

  1. 1.

    Stage IA and IIA without risk factors: 4 cycles of chemotherapy regimens like ABVD, ABVE, or VAMP or 2 cycles of OEPA

  2. 2.

    Patients with poor response in interim assessment and those with residual disease after 4 cycles of chemotherapy should be given involved field RT at a dose of 15–30 Gy. Omission of IFRT can be considered in patients achieving CR on PET/CT or CT after 2 cycles of chemotherapy

Intermediate Risk

Good initial response to 2 cycles of chemotherapy

  1. 1.

    4 cycles of ABVD with IFRT (20–26 Gy)

  2. 2.

    4 cycles ABVD +2 cycles COPP

  3. 3.

    4 cycles of ABVE-PC (Doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) +/− IFRT (Involved field radiotherapy) (20–26 Gy)

  4. 4.

    2 cycles O(E/P)PA [Vincristine(etoposide/procarbazine) prednisone, adriamycin] + 2 COP(P/Dac) [Cyclophosphamide, vincristine, prednisone, (procarbazine/ dacarbazine)] + 20–35 Gy IFRT

Poor initial response to 2 cycles of chemotherapy

  1. 1.

    5 cycles of ABVE-PC +/− IFRT (20–26 Gy)

  2. 2.

    2 cycles O(E/P)PA + 4 COP(P/Dac) + 20–35 Gy IFRT

  3. 3.

    6–8 cycles of BEACOPP

Advanced Stage

Good initial response to 2 cycles of chemotherapy

  1. 1.

    2 cycles O(E/P)PA + 4 COP(P/Dac) + 20–35 Gy IFRT

  2. 2.

    5 cycles ABVE-PC + 20–26 Gy IFRT

  3. 3.

    6 cycles ABVD + 20–26 Gy IFRT

  4. 4.

    8 cycles BEACOPP + 20–26 Gy IFRT

Treatment of Relapse/ Refractory Disease

Approximately 10–20% of patients with advanced stage Hodgkins lymphoma relapse after front-line treatment. Most relapses in patients with Hodgkins lymphoma occur within the first three years. Response to salvage therapy is directly related to duration of initial response. Progression during induction therapy or within 12 mo of completion of treatment has a dismal prognosis with 5-y disease-free survival rates of 0% and 20% respectively. Relapses occurring 12 mo or greater have better outcomes with salvage chemotherapy followed by autologous stem cell transplant. Because of the small number of patients that fail primary therapy, no uniform second-line treatment strategy exists for this patient population. Patients with late relapse and good response to initial two cycles of chemotherapy can be salvaged in 40–50% of cases with high dose chemotherapy and autologous stem cell transplant (SCT) [31, 32]. Various relapse regimens have been used, the most popular among them being ifosfamide, carboplatin, etoposide (ICE) [33]. The commonly used conditioning regimen for autologous SCT is BEAM (BCNU, etoposide, cytosine arabinoside, and melphalan) [33]. Allogenic SCT represents an option in a small subset of highest risk patients in whom there are probably no other realistic options for cure at present. However, treatment related toxicity and relapse rates are very high.

Follow-Up of Treated Patients and Late Effects

Patients need clinical evaluation by the physician once in every 3 mo for the first 2 y after completing treatment and then once in every 6 mo till 5 y after completing treatment and following which they can be reviewed annually. No imaging studies or blood investigations to detect relapse are routinely recommended during follow-up if the patient is asymptomatic and clinical examination is normal [34].

Pediatric Hodgkins lymphoma patients are at risk of second malignancies, cardiovascular and pulmonary diseases and infertility secondary to the effects of chemotherapy and/or radiotherapy received by them. Female patients who have received mediastinal radiation should be screened for breast cancer as per guidelines when they become adults. Patients who receive radiation to the neck should be closely followed up for thyroid dysfunction. Patients should be encouraged to lead healthy life style with avoidance of alcohol and tobacco, control of blood pressure and diabetes and regular exercise to reduce pulmonary and cardiovascular morbidities [34].