Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 2/2019
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.
Most recently clinical trials have demonstrated that Adcetris (brentuximab vedotin) in combination with chemotherapy in adult patients with previously untreated Stage III or IV classical Hodgkin lymphjoma appear to have a cure rate in excess of 75% and this is superior to the historical standard of ABVD.
The clinical trial that compared Adcetris plus AVD (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) chemotherapy was performed because Adcetris AVD reduces the risk of relapse, improves survival and avoids bleomycin lung toxicity.
In this pivotal clinical study, 1,334 patients with previously untreated advanced HL were treated with either the historical standard therapy of ABVD or Adcetris plus doxorubicin, vinblastine, and dacarbazine (A + AVD). When directly compared 82.1% of HL patients treated with A+AVD survived 2 years without cancer recurrence compared to only 77.2% of those treated with ABVD. The experimental combination of 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.
Advanced stage Hodgkin’s lymphoma has long 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 Hodgkin’s lymphoma. In the 1970’s, a new 4-drug chemotherapy regimen ABVD (doxorubicin, bleomycin, Velban®, dacarbazine) was found to be superior to MOPP and had fewer long-term side effects. Several variations of MOPP and ABVD chemotherapy drug combinations have been compared in clinical trials and none have been shown to be superior to ABVD.
Radiation therapy also may play a role in the treatment of advanced stage Hodgkin’s lymphoma; however this role is not well defined. The rationale for using radiation therapy in Hodgkin’s lymphoma is that it is very active in killing cancer cells and many patients whose cancer progresses after treatment experience a relapse in a site of previous Hodgkin’s lymphoma. Radiation is a local treatment capable of killing cancer cells within a defined radiation field. Delivery of the radiation beam to areas with a large amount of cancer or “bulky” disease may effectively prevent local cancer recurrences. However, radiation therapy is associated with additional side effects.
One clinical trial has been performed that directly compared modern combination chemotherapy to combination chemotherapy plus radiation treatment. The number of patients alive without cancer recurrence 5 years from treatment was not improved in patients who received radiation in addition to chemotherapy. Currently, the standard treatment of advanced Hodgkin’s lymphoma is combination chemotherapy typically with ABVD with or without radiation therapy to sites of bulky disease.
Improved Methods to Detect Residual Lymphoma: The appearance of a residual mass after initial treatment of lymphoma can create problems for management because the mass may represent active cancer or merely be scar or dead tissue from chemotherapy damage. The usual method of evaluating a residual mass is with repeated CT scans or surgical biopsy. CT scans have not been very effective at recognizing cancer versus scar or dead tissue since they only recognize an abnormal mass. Often, a surgical biopsy is necessary to determine whether cancer remains. PET (positron emission tomography) scanning may help doctors more accurately determine the presence of residual cancer following treatment.
A PET scan is similar to a CT scan; however, PET scans can detect live cancer tissue. Prior to a PET scan, the patient receives an injection of a substance that contains a type of sugar attached to a radioactive isotope. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons). The positrons react with electrons in the cancer cells, which creates the production of gamma rays. The gamma rays are then detected by the PET machine, which transforms the information into a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.
Doctors in Belgium recently reported that PET scans were more effective in detecting residual cancer than CT scans. In patients with Hodgkin’s disease, relapse occurred in 100% of patients with a residual mass detected on a PET scan, compared to only 26% of patients with a residual mass on a CT scan. In the future, PET scans should help identify patients who need further treatment after initial treatment.
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
The progress that has been made in the treatment of advanced stage Hodgkin’s lymphoma has resulted from the development of multi-drug combination chemotherapy regimens and the performance of clinical trials. Future progress will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of advanced Hodgkin’s lymphoma.
Continued evaluation of the role of radiation therapy in the management of patients at risk of treatment failure: Over 70% of patients with advanced Hodgkin’s disease achieve a complete remission following initial treatment of combination chemotherapy with or without radiation therapy. However, 20-30% of patients who achieve a complete remission ultimately experience cancer recurrence. The ultimate cure rate for patients with advanced Hodgkin’s disease ranges from 40-70%. The role of radiation therapy in achieving optimal control of advanced Hodgkin’s lymphoma has been controversial and there have been attempts to treat such patients with chemotherapy alone.
In 1989, researchers in France began a clinical trial to compare chemotherapy alone with chemotherapy plus radiation therapy for treatment of patients with advanced Hodgkin’s lymphoma. They randomly allocated 559 patients with advanced Hodgkin’s lymphoma to receive chemotherapy plus total nodal irradiation (radiation therapy to lymph nodes in the chest, neck and abdomen) or chemotherapy alone. The 5-year survival without recurrence was 74% for patients receiving chemotherapy alone and 79% for those receiving chemotherapy plus radiation. Overall survival at 5 years was 94% for patients receiving chemotherapy alone and 78% for patients receiving chemotherapy and radiation therapy. These results showed that chemotherapy plus radiation was not superior to chemotherapy alone. These researchers advised that patients with advanced Hodgkin’s lymphoma receive a total of 8 cycles of combination chemotherapy when a complete remission was achieved with 6 cycles of treatment.
Development of multi-modality strategies: Treatment for Hodgkin’s disease usually consists of some combination of chemotherapy with or without radiation therapy. Commonly used chemotherapy drugs include nitrogen mustard, Oncovin®, procarbazine, and prednisone combined with doxorubicin, bleomycin, Velban®, and dacarbazine. A new regimen, often referred to as the Stanford V, involves the use of such drugs over a shorter period of time (12 weeks), effectively reducing the total doses of doxorubicin, bleomycin and nitrogen mustard administered.
Researchers at several medical centers treated 47 individuals with either bulky stage I to II Hodgkin’s disease of the mediastinum (the space between the breast bone and the lungs) or advanced stage III or IV Hodgkin’s disease with the Stanford V chemotherapy regimen. Following chemotherapy, radiation therapy was directed at any areas of bulky disease. Approximately five years following treatment, 45 patients were alive (96%) and only 7 had suffered a recurrence (return) of the cancer. Six of the seven patients who had a recurrence then received high-dose chemotherapy with an autologous stem cell transplant. After three years, five of these patients remain alive and free of disease. There were two deaths in the study, one from Hodgkin’s disease and one from acute leukemia.
These results indicate that an overall treatment program utilizing initial chemotherapy with the Stanford V regimen, followed by radiation therapy to any bulky disease and high-dose chemotherapy with a transplant for patients with recurrent cancer is extremely effective for the treatment of individuals with bulky or advanced Hodgkin’s disease.
Development of Less Toxic Regimens for Children: Hodgkin’s disease in children is a relatively rare cancer with a high cure rate. Because of the high cure rate with chemotherapy and radiation, a major focus of researchers over the past decade has been to attempt to reduce the long-term side effects of therapy while maintaining the high cure rate. Long-term side effects of chemotherapy and radiation may include sterility, cataracts and the development of new cancers.
Physicians from Germany and Austria performed a multi-center clinical trial to evaluate changes in the standard combination chemotherapy regimen, with the goal of decreasing long-term side effects. This clinical trial involved 319 boys and 259 girls with Hodgkin’s disease treated between 1990 and 1995. Based on staging, the cancer was categorized as early, intermediate or advanced. The treatment program consisted of Oncovin®, prednisone, procarbazine, and doxorubicin or cyclophosphamide, Oncovin®, prednisone, and procarbazine chemotherapy with or without radiation. In the boys, a commonly used chemotherapy agent called etoposide was substituted for procarbazine in order to prevent damage to the testes. In addition, both the size of the radiation fields and the dose of radiation were decreased. These changes were expected to reduce side effects without affecting the cure rate.
Five years from initiation of treatment, 91% of children survived without evidence of cancer recurrence and 98% of children were alive. Importantly, the doctors found that etoposide could be substituted for procarbazine in the treatment regimen without increasing the rate of cancer relapses and that radiotherapy could be confined to sites involved with cancer when combined with chemotherapy. With these changes, boys were less likely to experience side effects to the testes.
These physicians concluded that this regimen provided adequate treatment for all stages of Hodgkin’s disease in children, resulting in excellent disease control and a reduction in long-term side effects. Additional studies are ongoing in early stage Hodgkin’s disease in order to further refine treatment and determine whether radiation therapy can be completely omitted without compromising long-term cure rates.
- 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.
- Straus DJ, Collins GP, Walewski JA, et al. Improving outcomes with brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma [ASCO abstract 7534]. J Clin Oncol. 2018;36(15 suppl).