Hodgkin lymphoma is a B-cell lymphoproliferative malignancy that effects approximately 8,500 patients per year in the United States and has a worldwide incidence of approximately 60,000 cases annually.1 Patients with this disease typically can have a good outcome and approximately 80% of patients are cured with current therapies. Patients present with this disease in a bimodal age distribution. A peak incidence is seen in patients in their early 20s and also in patients who are elderly. The goal of optimizing therapy is to improve the overall cure rate in this disease while recognizing that patients will live with the consequences of therapy, potentially for a very long time. The goal of treatment therefore is to obtain the best clinical results with the fewest long-term side effects.
A 26-year-old female patient presents with a new lymph node palpable in the left supraclavicular area. The patient has been in good health with no other significant findings. She has no fevers, night sweats, weight loss, or pruritus and she has no other palpable sites of lymphadenopathy. Laboratory testing shows a normal hemoglobin, white cell count, and platelet count. The patient’s serum albumin is within the normal range but she does have a slightly elevated sedimentation rate of 32 mm/hour. Imaging, including a chest x-ray and a CT/PET scan, is done and the chest x-ray does show a fullness in the upper mediastinum. The CT/PET scan confirms FDG avid lymphadenopathy in the left supraclavicular area and also shows an upper mediastinal mass measuring 4 x 4.5 cm in size. A biopsy obtained from the supraclavicular lymph node confirms classical Hodgkin lymphoma, nodular sclerosis subtype. A review of the CT/PET scan shows no lymphadenopathy at any other site. A bone marrow aspirate and biopsy is negative for involvement by lymphoma. The patient’s cardiovascular and pulmonary functions are normal.
Clinical Risk Factors and Treatment Selection
In a new patient with a low burden of disease clinically, it is important to confirm the stage of disease radiologically and thereafter determine if unfavorable clinical risk factors are present.
Identifying unfavorable risk factors - In this patient, the staging evaluation shows the patient to have Stage IIA disease and the patient has no unfavorable risk factors based on the German Hodgkin Lymphoma Study Group (GHSG)2 as well as the European Organization for Research and Treatment of Cancer (EORTC) risk factor analysis.3 Risk factors defined by the GHSG and associated with unfavorable outcome include a large mediastinal mass greater than one-third of the maximum diameter of the thorax and involvement of extranodal sites, which would include localized involvement of extra lymphatic tissue by continuous growth or disease at sites outside of a lymph node. Additional unfavorable clinical risk factors include involvement of three or more nodal sites or an elevated sedimentation rate greater than 50 mm/hour for patients with early stage disease. The EORTC criteria are very similar but also include involvement of the spleen by Hodgkin lymphoma as an unfavorable factor.
Selecting treatment with the least toxicity while maintaining efficacy - In this patient’s case, the patient has no unfavorable characteristics. The patient’s mediastinal mass is small and the sedimentation rate is normal. The patient is young and has no evidence for extra nodal sites and has less than three areas of nodal involvement. The standard therapeutic approach for patients with early stage favorable disease is to utilize combination chemotherapy followed by involved field radiation therapy. A number of studies have explored the optimal approach and optimal numbers of cycles for treatment, as well as radiation dose in these patients. The GHSG HD10 trial assessed whether patients would benefit from 2 or 4 cycles of ABVD chemotherapy followed by 20 or 30 Gy involved field radiation therapy.4
Overall, patients with favorable characteristics and a low burden of disease (such as this patient) can be treated with 2 cycles of ABVD chemotherapy followed by 20 Gy of radiation treatment. This results in a similar excellent long-term outcome as more intensive therapy, and decreases the likelihood of long-term toxicity. In this study, the complete response rate, as well as the progression free survival and overall survival at both 5 years and 8 years, was no different between any of the groups. This suggests that less therapy maintains the efficacy of this approach and could be considered in a patient such as this.
Strategies to further avoid long-term risks
Patients treated with combination chemotherapy with involved field radiation therapy are at long-term risk of injury to normal tissue. This includes cardiovascular injury including coronary artery disease, as well as increased stroke risk. Furthermore, these patients have an increased risk of second malignancies and a longer term of risk of bone marrow and pulmonary injury. While the planned doses of chemotherapy and radiation therapy are low, these side effects continue to persist, particularly with long-term follow-up. There is particular concern regarding the long-term complication of radiation therapy, specifically in female patients, where radiation therapy will potentially involve breast tissue, as well as radiation therapy to the heart and cardiac vessels. Novel imaging used with radiation therapy has certainly decreased these risks, but toxicity remains a concern long-term. Strategies are therefore being evaluated to replace or omit radiation therapy and to optimize the chemotherapy treatment used.
Using PET scan results to potentially omit radiation therapy - One strategy to diminish toxicity is to utilize PET scanning to direct therapy in early stage Hodgkin lymphoma, with the goal of discontinuing treatment if the PET scan is negative, assuming that in a high percentage of patients this will be sufficient therapy to prevent disease relapse. Two trials have tested this assessment. The RAPID trial, conducted in the United Kingdom, was recently reported.5 This study included newly diagnosed patients with Stage IA and Stage IIA Hodgkin lymphoma. All patients received three cycles of ABVD chemotherapy and then underwent a PET scan. Patients with a negative PET scan were then randomly assigned to receive involved field radiation therapy or to discontinue treatment. The analysis of this study showed that patients receiving radiation therapy had a slightly higher likelihood of remaining in remission. The 3-year progression free survival was 95% in the radiation group and 91% in the patients who discontinued treatment. The absolute risk difference was 4 percentage points. While radiation therapy clearly added benefit, there has been some discussion as to whether the small additional benefit from radiation therapy is worth the long-term consequences. Similar results were seen with an EORTC/LYSA trial.6 This H10 study also evaluated omitting radiation therapy in early PET negative Stage I and II Hodgkin lymphoma patients and found that omission of radiation therapy was associated with an increased risk of relapse. The recommendation from this trial remained that combination chemotherapy with radiation therapy resulted in fewer early progressions and therefore remained the standard of care. It was noted, however, that the outcome in both arms of this trial was excellent. Data such as these have led to a decrease in the use of radiation therapy in recent years, but it should be noted that the addition of radiation therapy has been reported to improve survival when large datasets were analyzed.7 Overall, the treating physician, in discussion with the patient, needs to weigh the risks and benefits of the combination approach. The PET-negative population has an excellent outcome and therefore radiation therapy could possibly be omitted in selected patients. However, the addition of involved field radiation therapy to chemotherapy in the management of early stage Hodgkin lymphoma remains the standard of care.
Incorporating novel agents into early stage treatment - An additional approach to minimizing long-term toxicity is to avoid radiation therapy by adding novel agents to the treatment approach.
To date, a number of trials have evaluated the use of brentuximab vedotin, either in combination with chemotherapy or alternatively after chemotherapy, as a consolidation. In initial studies utilizing brentuximab vedotin after chemotherapy instead of radiation therapy, the outcomes have appeared excellent.8 There is, however, concern that the addition of brentuximab vedotin contributes other side effects. These complications, such as long-term neuropathy resulting from brentuximab vedotin treatment, may contribute to an undesirable outcome and therefore, additional studies are clearly necessary to determine whether new agents result in similar excellent outcomes but do not contribute their own long-term complications. More data and longer follow up of patients treated with novel agents are needed, and patients such as the one highlighted in this article should be encouraged to participate in clinical trials that are addressing this issue.9
Overall, the outcome for patients with early stage Hodgkin lymphoma, particularly those with no unfavorable clinical characteristics, is excellent. The patients can be treated with very modest amounts of chemotherapy and radiation therapy with very gratifying long-term outcomes. It is imperative to balance the success of therapy with long-term consequences of treatment, and therefore, utilizing PET-directed approaches as well as low doses of chemotherapy and radiation therapy is desirable. Longer follow up is needed to clearly define whether PET-directed approaches using chemotherapy-only treatment are feasible and effective. Furthermore, additional new agents will be incorporated into frontline approaches and this may further decrease long-term side effects while maintaining durable benefit for Hodgkin lymphoma patients. Based on the data available today, however, the standard approach remains the use of combination chemotherapy and involved field radiation therapy. The current goal for the treating physician is to use abbreviated courses of chemotherapy and lower doses of radiation therapy based on prognostic factors. The hope for the future is to further improve outcomes and minimize toxicity by further decreasing therapy. Patients should be encouraged to participate in clinical trials that are testing new strategies.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.
- Diehl V, Stein H, Hummel M, et al. Hodgkin's lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease. Hematology Am Soc Hematol Educ Program. 2003:225-247.
- Tubiana M, Henry-Amar M, Carde P, et al. Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987. Blood. 1989;73(1):47-56.
- Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med. 2010;363(7):640-652.
- Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015;372(17):1598-1607.
- Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32(12):1188-1194.
- Parikh RR, Grossbard ML, Harrison LB, et al. Early-Stage Classic Hodgkin Lymphoma: The Utilization of Radiation Therapy and Its Impact on Overall Survival. Int J Radiat Oncol Biol Phys. 2015;93(3):684-693.
- Abramson JS, Arnason JE, LaCasce AS, et al. Brentuximab vedotin plus AVD for non-bulky limited stage Hodgkin lymphoma: A phase II trial. J Clin Oncol. 2015;33:(supple; abstr 8505).
- Clinicaltrials.gov. Brentuximab Vedotin Plus AD in Non-bulky Limited Stage Hodgkin Lymphoma. ClinicalTrials.gov Identifier: NCT02505269.