The treatment of patients with Hodgkin lymphoma is one of the major success stories in medical oncology. Depending on clinical stage, clinical risk factors, and the treatment given, 60% to 90% of all patients can be cured of their malignancy long-term. Hodgkin lymphoma survivors represent one of the largest groups of cancer survivors in Western countries. This is in part due to the young age of most patients and the excellent outlook after treatment. However, Hodgkin survivors are at high risk of treatment-related side effects including secondary cancers, organ damage, infertility, fatigue, and psychosocial problems. Since these sequelae can occur up to 30 years after treatment, finding the right balance between toxicity and cure is the main goal in Hodgkin lymphoma.
Ongoing Controversies
The scientific discussion among those caring for Hodgkin patients has been highly controversial at times. The questions most often addressed by opinion leaders, cooperative groups, and patient advocates have been: Is combined-modality treatment the optimal compromise between toxicity and efficacy? Is chemotherapy-only an alternative? Should we abandon radiotherapy altogether in this patient population? Should we strive for the best tumor control with first-line treatment and use BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], and prednisone) instead of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or do we have a second shot that is effective enough?
Even after more than 30 years of clinical trials and tens of thousands of patients studied, these questions are still not fully answered. One of the most controversial and emotional discussions has been about the role of radiotherapy in Hodgkin lymphoma. We can refer to a vast number of relevant clinical trials of differing quality, registry data, and personal experience, all of which makes it difficult to maintain an unclouded view. From this hodgepodge of information, it is important to stick to the hardest data available, ie, those data generated within high-quality prospective, randomized trials.
HD.6 Trial
A clinical trial recently published by Meyer and coworkers in The New England Journal of Medicine has again sparked the discussion on the role of radiotherapy in early Hodgkin lymphoma.1 In this trial (HD.6) conducted by the National Cancer Institute of Canada Clinical Trials Group, 405 previously untreated stage IA or IIA nonbulky Hodgkin lymphoma patients were randomly assigned to chemotherapy (ABVD) alone or a large-field radiotherapy–containing treatment strategy. In the group that was assigned to radiation, a favorable cohort of 64 patients received subtotal nodal irradiation (STNI) only and the unfavorable cohort of 125 patients was treated with two cycles of ABVD followed by STNI. Those assigned to ABVD who responded to treatment received four cycles of of the chemotherapy, and those with less than a complete remission had a total of six cycles of ABVD.
The HD.6 study was closed prematurely in April 2002, after results emerged from the EORTC H8-F trial reporting excellent outcomes with combined-modality treatment that included involved-field radiation therapy. The trial committee felt that continuing with a protocol that included STNI would be inappropriate. The initial report of this trial at a median follow up of 4.2 years had reported no difference in overall survival. At 12 years, however, overall survival was 94% among those receiving ABVD alone, compared with 87% for those receiving STNI or ABVD plus STNI. In patients treated with ABVD alone, a total of 12 patients had died, compared with 24 of those who had received STNI as part of their initial treatment.
This final report underscores the impact of sufficient follow-up particularly in the group of Hodgkin lymphoma patients with the best prognosis, ie, early favorable disease. Not surprisingly, this trial has also attracted a number of substantial critiques, including objections to the outdated large-field radiotherapy used and the questionable statistics reported.
Long-term Side Effects
What are the long-term side effects of radiotherapy in Hodgkin lymphoma, and who is at risk? Years after realizing that improved radiation techniques could indeed induce long-lasting remissions in early-stage Hodgkin lymphoma, reports began to emerge about severe late effects including secondary malignancies, thyroid abnormalities, and cardiovascular disease.2 Side effects were correlated with radiation dose and field size. For instance, in carefully performed case-control studies, the addition of limited-field radiation therapy to chemotherapy did not significantly increase the risk of leukemia. However, when large-field radiation was combined with chemotherapy, a 2.5-fold increased risk of leukemia was observed in patients receiving combined-modality treatment compared with those treated with chemotherapy only.
In female Hodgkin patients, the risk of breast cancer was significantly increased only after radiation doses of 38.5 Gy or higher and was not observed at lower doses. In other studies, the significant dose-response relationship between the radiation dose and the risk of breast cancer was limited to women who received radiation therapy alone and was not observed among women who received both chemotherapy and radiation therapy. This is very likely due to the effect of chemotherapy on ovarian function.
In other case studies, a radiation dose > 4 Gy to the breast was associated with a 3.2-fold higher breast cancer risk compared to women who received lower doses of radiotherapy and had no alkylating agent–based chemotherapy. The risk increased to 8-fold for women who received > 40 Gy to the breast.
Other Adverse Effects
As far as treatment-related cardiovascular disease is concerned, there is a clear correlation with mediastinal radiotherapy in Hodgkin lymphoma survivors. Cardiac mortality in dose-related fashion was reported in patients who had received more than 30 Gy to the mediastinum. More recent studies show that with longer follow-up, the relative risk of cardiac mortality was significantly elevated at 12.1. Of note, patients who received ABVD chemotherapy without mediastinal irradiation also had a significantly elevated relative risk of cardiac mortality at a factor of 7.8.
Importantly, the peak incidence of cardiac mortality in this study was 15 to 19 years after treatment and remained significant up to at least 25 years. There is a clear need to carefully monitor particularly young Hodgkin lymphoma patients who have received higher doses of anthracyclines.
Major side effects of radiotherapy such as secondary cancers or cardiovascular disease are mainly confined to the original radiation field. Thus, major reductions in field size and dose over the past 20 years represent an important step toward reducing the overall risk of radiation-related side effects. While subtotal-nodal or extended-field techniques were used historically, this has changed to the more frequent use of involved-field technology, which reduces the nonspecific irradiation of healthy tissue by up to 10-fold.
Sufficiently powered prospective randomized trials from cooperative groups have clearly shown that subtotal-nodal and extended fields are not needed when combined-modality therapy is used. As few as two cycles of ABVD combined with 20 Gy of involved-field radiotherapy can cure more than 90% of Hodgkin patients in early favorable stages.3 In addition, field size of radiotherapy in Hodgkin lymphoma has been further reduced more recently to the so-called involved-node radiation field, in which only a rather small margin around the initially involved lymph node is addressed.
Clinical Trials
The major problem in the controversy of combined-modality or chemotherapy-only strategies in early-stage Hodgkin lymphoma is the lack of randomized trials. Few trials have used identical numbers of chemotherapy cycles that would allow for a proof of principle of chemotherapy-alone concepts. When chemotherapy was compared with combined-modality treatment, meta-analyses found significant differences in terms of tumor control and overall survival favoring combined modalities in early-stage Hodgkin lymphoma patients.
In addition, more recent randomized trials clearly send a note of caution to those who believe in chemotherapy-only approaches. In the EORTC-GELA H9 trial for early favorable Hodgkin lymphoma, the failure-free survival at 5 years was significantly reduced in patients who did not receive additional radiotherapy after six cycles of chemotherapy (EBVP [epirubicin, bleomycin, vinblastine, prednisone]).
Very recent reports from the EORTC-GELA-IIL H10 study in patients with early favorable and unfavorable disease provided additional relevant data. In this PET-guided trial, the chemotherapy-only arms in patients who were PET-negative after two cycles of ABVD had to be closed due to significantly more events, in both early favorable and early unfavorable disease. These data ague against the uncritical use of chemotherapy only in early-stage Hodgkin lymphoma outside of clinical trials.
Conclusions
We should be cautious not to overinterpret studies such as the recent Canadian HD.6 investigation, given the rather small subgroups of patients included, the outdated radiotherapy used, and the problematic statistics. What we would really need to change the current standard approach of combined-modality treatment in early-stage Hodgkin lymphoma are sufficiently powered prospectively randomized trials of high quality.
There are simply too many well performed studies today demonstrating that the combination of small-field radiotherapy and a few cycles of chemotherapy currently is the best available choice of treatment for patients in these risk groups. In addition, emerging data show that the actuarial risk associated with ABVD—both acute and long-term—might have been underestimated. ■
Disclosure: Dr. Engert reported no potential conflicts of interest.
Dr. Engert is Professor of Internal Medicine, Hematology and Oncology, Department of Internal Medicine I, Cologne University Hospital, Cologne, Germany.
References
1. Meyer RM, Gospodarowicz MK, Connors JM: ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 366:399-408, 2012.
2. Ng A, Travis L: Acute and long-term complications of radiotherapy for Hodgkin Lymphoma, in Specht L, Yahalom J (eds): Radiotherapy for Hodgkin Lymphoma. New York, Springer, 2011, pp 183-196.
3. Engert A, Plütschow A, Eich HT, et al: Reduced treatment intensity in patients with early stage Hodgkin lymphoma. N Engl J Med 363:640-652, 2010.
