Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 11/2019
Patients classified as having stage III or IV disease with “A” or “B” symptoms, stage II disease and “B” symptoms, or bulky disease (site of disease greater than 10 centimeters) are all considered to have advanced stage Hodgkin’s lymphoma (HL).
Chemotherapy treatment with ABVD (doxorubicin, bleomycin, Velban, and dacarbazine) for 6 cycles consistently cures a majority of patients with stage IB to IV HL and has been the standard of care for many years. (1-4)
In 2019 the U.S. Food and Drug Administration (FDA) approved Adcetris (brentuximab vedotin) in combination with chemotherapy in adult patients with previously untreated stage III or IV classical HL based on the successful outcome of the ECHELON-1 clinical trial that compared Adcetris plus AVD (Adriamycin, vinblastine and dacarbazine) to standard ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) chemotherapy. Adcetris + AVD reduces the risk of relapse, improve survival and avoids bleomycin lung toxicity. (5,6)
Adcetris is a precision cancer medicine that targets a protein known as CD30, which is present on HL cells. Adcetris attaches to and enters CD30-positive cells where it releases the potent chemotherapy drug monomethyl auristatin E.
In order to reduce the risk of HL recurrence and avoid bleomycin lung toxicity researchers initially conducted a small phase I clinical study that evaluated Adcetris as an addition to ABVD or as a substitute for bleomycin. (2) The results of this trial suggested that HL outcomes could be improved so a larger comparative trial was initiated to confirm these results.
The ECHELON-1 clinical trial enrolled 1,334 individuals with previously untreated advanced HL to receive treatment with either the historical standard therapy of ABVD or with Adcetris + doxorubicin, vinblastine, and dacarbazine (A + AVD). When directly compared 82% of HL patients treated with A+AVD survived 2 years without cancer recurrence compared to only 77% of those treated with ABVD. Adcetris + AVD did cause more nerve damage, episodes of fever, and neutropenia than ABVD. The doctors reported that the nerve damage largely reversed during follow-up and that the prophylactic use of a white blood cell growth factor to improve bone marrow function and recovery helps prevent fever and neutropenia. (5,6)
Impact of Prophylactic G-CSF
Granulocyte colony stimulating factor (G-CSF) enhances the recovery of infection fighting white blood cells that are reduced with chemotherapy treatment. A low white blood count (neutropenia) increases the risk of infection and prevents doctors from administering the full dose of chemotherapy necessary to achieve cure.
The ECHELON-1 clinical trial evaluated the use G-CSF following the observation that there were increased rates of fever and neutropenia observed with Acetris + AVD and this led to the recommendation to use G-CSF prophylaxis. (6) In the trial some patients received primary G-CSF prophylaxis, and they were compared to others who did not. The rate of neutropenia decreased from 73% to 35%, and severe neutropenia dropped from 70% to 29% with the use of G-CSF prophylaxis. Fever and neutropenia decreased from 21% to 11%.
In addition, patients who received G-CSF had far fewer dose delays of Adcetris plus AVD compared with patients without prophylaxis (35% vs 49%). The researchers have theorized that this could explain the improvement in survival without cancer progression seen with primary G-CSF prophylaxis. At 2 years survival was 84.6% for those receiving primary G-CSF prophylaxis compared to 81.7% for those without. Patients who received primary G-CSF prophylaxis had fewer dose delays and experienced less toxicity, and therefore they could tolerate more treatment administered on time, possibly leading to better outcomes. (6)
Advanced stage HL has always been a curable cancer because it is very susceptible to treatment with chemotherapy and radiation therapy. In the 1960’s, doctors at the National Cancer Institute developed the MOPP (methotrexate, nitrogen mustard, procarbazine and prednisone) combination chemotherapy regimen, which was able to cure approximately half of all patients with advanced stage HL. In the 1970’s the current 4-drug chemotherapy regimen ABVD was found to be superior to MOPP and had fewer long-term side effects. Now A + AVD appears to produce superior outcomes for the initial treatment of advanced HL and may represent a new standard of care. Several variations of MOPP and ABVD chemotherapy drug combinations have been compared in clinical trials and A + AVD is the first to improve upon the results attained with ABVD. (1-4)
Researchers have evaluated the delivery of radiation in addition to ABVD to areas with a large amount of HL in several clinical trials with mixed results. (7-12) Most trials have not demonstrated that the addition of radiation to systemic therapy improves outcomes and it is not routinely used because it is associated with additional long-term side effects.
Complications of Treatment for Hodgkin’s Lymphoma
One of the major side effects of treatment of Hodgkin’s lymphoma is the development of a second cancer. These second cancers are caused by the radiation, chemotherapy or the combination of radiation and chemotherapy used to treat Hodgkin’s lymphoma. In one clinical study evaluating the risk of second cancers in over 5,500 patients treated for Hodgkin’s lymphoma, there were 322 second cancers. Thus 6% pf all treated patients developed a second cancer. In another study of 420 patients, the risk of developing a second cancer 15 years following treatment was 11.7%. These included cancers of the gastrointestinal tract, lung, breast, bone, soft tissue and leukemia.
Strategies to Improve Treatment
- Canellos GP, Niedzwiecki D: Long-term follow-up of Hodgkin's disease trial. N Engl J Med 346 (18): 1417-8, 2002. [
- Duggan DB, Petroni GR, Johnson JL, et al.: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol 21 (4): 607-14, 2003. [
- Federico M, Luminari S, Iannitto E, et al.: ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 27 (5): 805-11, 2009.
- Viviani S, Zinzani PL, Rambaldi A, et al.: ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med 365 (3): 203-12, 2011.
- Joseph M Conners et al: Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) As Frontline Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients with Previously Untreated Stage III or IV Hodgkin Lymphoma (HL): The Phase 3 Echelon-1 Study
- Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344.
- Fabian CJ, Mansfield CM, Dahlberg S, et al.: Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study. Ann Intern Med 120 (11): 903-12, 1994.
- Aleman BM, Raemaekers JM, Tirelli U, et al.: Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med 348 (24): 2396-406, 2003.
- Fermé C, Mounier N, Casasnovas O, et al.: Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 107 (12): 4636-42, 2006.
- Loeffler M, Brosteanu O, Hasenclever D, et al.: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group. J Clin Oncol 16 (3): 818-29, 1998.
- Brice P, Colin P, Berger F, et al.: Advanced Hodgkin disease with large mediastinal involvement can be treated with eight cycles of chemotherapy alone after a major response to six cycles of chemotherapy: a study of 82 patients from the Groupes d'Etudes des Lymphomes de l'Adulte H89 trial. Cancer 92 (3): 453-9, 2001.