Treatment for Hodgkin lymphoma (HL) is tailored to each individual and may include surgery, radiation therapy, chemotherapy, precision cancer medicines and or stem cell transplant in selected situations. The specific treatment depends on the stage of the cancer and its genomic profile.1,2,3,4,5,6,7,8,9,10
Individuals with obvious stage III or IV disease, those with a single large defined mass, mediastinal disease, or the presence of “B” symptoms, are treated with a combination of chemotherapy and precision cancer medicines with or without additional radiation therapy.4,5
Individuals with non-bulky stage IA or IIA disease are candidates for chemotherapy, combined chemo-radiation therapy, or radiation therapy alone.1,2
Individuals with recurrent disease are treated with additional chemotherapy and precision cancer medicines, stem cell transplantation, CAR-T cell therapy or on a clinical trial evaluating emerging precision cancer medicines that target Hodgkin lymphoma or a combination of these treatment approaches.3,4,5,6,7,8,9,10
Surgery. The role of surgery in the management of Hodgkin lymphoma is primarily to secure a biopsy specimen for evaluation.
Radiation therapy. Radiation therapy uses high-powered energy beams, such as X-rays or protons, to kill cancer cells. The objective of radiation therapy is to kill cancer cells for a maximum probability of cure with a minimum of side effects. Radiation is usually given in the form of high-energy beams that deposit the radiation dose into the body where cancer cells are located. Radiation therapy, unlike chemotherapy, is considered a local treatment. Cancer cells can only be killed where the actual radiation is delivered to the body. If cancer exists outside the radiation field, the cancer cells are not destroyed by the radiation.
Radiation therapy is an important treatment modality for patients with Hodgkin lymphoma. However, radiation therapy is usually not the sole treatment for Hodgkin lymphoma except in selected circumstances. Chemotherapy alone or combined modality treatment with chemotherapy and radiation therapy is typically utilized even for early stage lymphoma. Therefore, it is essential for patients with Hodgkin lymphoma to be treated at medical centers where medical oncologists, radiation oncologists and surgeons work together.
Systemic Therapy: Precision Cancer Medicines, Chemotherapy, and Immunotherapy
Systemic therapy is any treatment directed at destroying cancer cells throughout the body and may include chemotherapy, immunotherapy or newer precision cancer medicines. Treatment of patients with stage II, III, IV or recurrent Hodgkin lymphoma typically consists of systemic therapy.4,5
Chemotherapy
Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, administered through a vein, or delivered orally in the form of a pill. Most chemotherapy drugs cannot tell the difference between a cancer cell and a healthy cell. Therefore, chemotherapy often affects the body’s normal tissues and organs, which can result in complications or side effects. In order to more specifically target the cancer and avoid unwanted side effects researchers are increasingly developing precision cancer medicines.
Precision Cancer Medicines
Through genomic-biomarker testing performed on cells from the biopsy or collected in blood doctors are increasingly able to define the genomic alterations in a cancers DNA that are driving the growth of the cancer. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Individuals can undergo genomic testing to determine whether newer precision cancer medicines are a treatment option. These medicines are currently used mainly in the treatment of advanced disease alone or in combination with other therapies.
- Adcetris (brentuximab vedotin): Adcetris is a precision cancer medicine that targets the CD30 protein present on HL cells.5
Immuno-oncology
Precision immunotherapy treatment of cancer has also progressed considerably over the past few decades and has now become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.
Researchers are mainly focused on two promising types of immunotherapy. One type creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer, and then infusing them back into the bloodstream the other uses precision medications to enhance the immune systems response to the cancer.
- Checkpoint Inhibitors: Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the cancer cells. A diagnostic test to measure the level of PD-L1 is available.7,8
- Keytruda (pembrolizumab) is a “checkpoint inhibitor” and has anti-cancer activity in Hodgkin lymphoma. There are several other PD-1 and PD-L1 checkpoint inhibitors being developed.9
High Dose Chemotherapy & Autologous Stem Cell Transplant
High-dose chemotherapy (HDC) is a standard treatment for the majority of patients with relapsed HL. The basic strategy uses higher doses of chemotherapy and radiation therapy, which kill more cancer cells than lower doses. Unfortunately, the higher doses of therapy used to destroy cancer cells also damages normal cells. The body’s normal cells that are most sensitive to destruction by high-dose therapy are the blood-producing stem cells in the bone marrow. To “rescue” the bone marrow and hasten blood cell production and immune system recovery, high-dose therapy is followed by an infusion of autologous stem cells collected from the patient prior to administering the HDC.10
Treatment of Hodgkin Lymphoma by Stage
Stage I: Cancer is found only in a single lymph node, in the area immediately surrounding that node or in a single organ.
Stage II: Cancer involves more than one lymph node on one side of the diaphragm (the breathing muscle separating the abdomen from the chest).
Stage III: The cancer involves lymph node regions above and below the diaphragm. For example, there may be swollen lymph nodes under the arm and in the abdomen.
Stage IV: Cancer involves one or more organs outside the lymph system or a single organ and a distant lymph node site.
Patients with Hodgkin lymphoma may also experience general symptoms from their lymphoma. Patients with fever, night sweats or significant weight loss are said to have “B” symptoms. Patients who do not experience these specific symptoms are classified as “A”.
Relapsed/Refractory: The cancer has persisted or returned (recurred/relapsed) following treatment.
Radiation Therapy for Hodgkin Lymphoma
Radiation therapy can be an important treatment for some patients with HL, however the current trend is to use less radiation in order to avoid longer term side effects. Radiation therapy is usually not the sole treatment and is typically combined with chemotherapy treatment for early stage disease. It is essential for patients with HL to be treated at medical centers where medical oncologists, radiation oncologists and surgeons work together.
The objective of radiation therapy is to kill cancer cells for a maximum probability of cure with a minimum of side effects. Radiation is usually given in the form of high-energy beams that deposit the radiation dose into the body where cancer cells are located. Radiation therapy, unlike chemotherapy, is considered a local treatment. Cancer cells can only be killed where the actual radiation is delivered to the body. If cancer exists outside the radiation field, the cancer cells are not destroyed by the radiation. It is also important to realize that the treatment of HL with radiation therapy and chemotherapy is still evolving, with a trend towards the use of less radiation therapy and more chemotherapy in order to decrease the long-term side effects of radiation.
Delivery of Radiation Therapy for Hodgkin’s Lymphoma
Modern radiation therapy for HL is given via machines called linear accelerators, which produce high-energy external radiation beams that penetrate the tissues and deliver the radiation dose deep into the areas where the cancer resides. These modern machines and other state-of-the-art techniques have enabled radiation oncologists to significantly reduce side effects, while improving the ability to deliver radiation to areas of HL.
Simulation
After an initial consultation with a radiation oncologist, the next session is usually a planning session, which is called a “simulation”. During this session, the radiation treatment fields and most of the treatment planning are determined. Of all of the visits to the radiation oncology facility, the simulation session may actually take the most time. During simulation, patients lie on a table somewhat similar to that used for a CT scan. The table can be raised and lowered and rotated around a central axis. The “simulator” machine is a machine whose dimensions and movements closely match that of an actual linear accelerator. Rather than delivering radiation treatment, the simulator lets the radiation oncologist and technologists see the area to be treated. The simulation is usually guided by fluoroscopy, so that a patient’s internal anatomy can be observed (mainly the skeleton, but if contrast material is given, the kidneys, bowels, bladder or esophagus can be visualized as well). The room is periodically darkened while the treatment fields are being set and temporary marks may be made on the patient’s skin with magic markers. The radiation oncologist is aided by one or more radiation technologists and often a dosimetrist, who performs calculations necessary in the treatment planning.
The simulation may last anywhere from 15 minutes to an hour or more, depending on the complexity of what is being planned. Once the aspects of the treatment fields are satisfactorily set, x-rays representing the treatment fields are taken. In most centers, the patient is given multiple “tattoos” which mark the treatment fields and replace the marks previously made with magic markers. These tattoos are not elaborate and consist of no more than pinpricks followed by ink, appearing like a small freckle. Tattoos enable the radiation technologists to set up the treatment fields each day with precision, while allowing the patient to wash and bathe without worrying about obscuring the treatment fields.
Radiation treatment is usually given in another room separate from the simulation room. The treatment plans and treatment fields resulting from the simulation session are transferred over to the treatment room, which contains a linear accelerator focused on a patient table similar to the one in the simulation room. The treatment plan is verified and treatment started only after the radiation oncologist and technologists have rechecked the treatment field and calculations, and are thoroughly satisfied with the “setup.”
Radiation “Fields” Used to Treat Hodgkin’s Lymphoma
Involved Field Radiation: Patients with Hodgkin’s disease treated with radiation always receive treatment to the area where the lymphoma is located including adjacent lymph nodes. Sometimes a “boost” or extra dose of radiation is given to the area where the primary lymphoma was located.
Mantle Field Radiation: Mantle field radiation is administered to patients with Hodgkin’s lymphoma in the mediastinum (behind the breast bone), lymph nodes in the neck or under the armpits and is designed to encompass the area of the cancer and the common lymph node drainage. The areas irradiated include the mediastinum, some lung tissue and the lymph draining areas of the neck and armpits. Radiation oncologists attempt to avoid, as much as possible, radiation to the lungs and breast which are the most sensitive to damage.
Inverted Y: This describes radiation to the lymph nodes in front of the lower spine (para-aortic) and the groin. Each groin makes up an arm of the inverted Y.
Treatment of the spleen: The spleen is often involved with Hodgkin’s lymphoma. In the past, when radiation therapy was the primary treatment, patients had the spleen removed and radiation treatment to the area where the blood vessels were tied off. In some instances, radiation therapy is given to the spleen without removal. However, most of these types of radiation treatment have been abandoned with the development of effective systemic combination chemotherapy.
Treatment Schedules
A typical course of radiation for Hodgkin’s lymphoma would involve daily radiation treatments, Monday through Friday, for 3 to 5 weeks. The actual treatment with radiation generally last no more than a few minutes, during which time the patient is unlikely to feel any discomfort. Anesthesia is not needed for radiation treatments, and patients generally have few restrictions on activities during radiation therapy. Many patients continue to work during the weeks of treatment. Patients are encouraged, however, to carefully gauge how they feel and not overexert themselves.
Side Effects and Complications of Radiation
The vast majority of patients are able to complete radiation therapy for Hodgkin’s lymphoma without significant difficulty. Side effects and potential complications of radiation therapy are infrequent and when they do occur are typically limited to the areas that are receiving treatment with radiation. The chance of a patient experiencing side effects, however, is highly variable. A dose that causes some discomfort in one patient may cause no side effects in other patients. If side effects occur, the patient should inform the technologists and radiation oncologist, because treatment is almost always available and effective.
Radiation therapy to the abdominal/pelvic area may cause diarrhea, abdominal cramping or increased frequency of bowel movements or urination. These symptoms are usually temporary and resolve once the radiation is completed. Occasionally, abdominal cramping may be accompanied by nausea.
Blood counts can be affected by radiation therapy, but this is not usually the case in patients with Hodgkin’s lymphoma. However, many radiation therapy institutions make it a policy to check the blood counts at least once during the radiation treatments. It is not unusual for some patients to note changes in sleep or rest patterns during the time they are receiving radiation therapy and some patients will describe a sense of tiredness and fatigue.
A significant late complication following radiation treatment for Hodgkin’s disease is lung damage with fibrosis and difficulty breathing. In one study of 36 patients with stage I-IIA Hodgkin’s lymphoma treated with radiation therapy, a decrease in lung function was noted in all patients. However, this decrease in lung function appeared to improve over time and was thought to be reversible.
Hypothyroidism: (abnormally low levels of thyroid hormone) is one of the more frequently encountered late complications of radiation therapy for HL, occurring in approximately one-third of patients receiving radiation therapy alone or combined with chemotherapy. This is not a complication that occurs when chemotherapy alone is used to treat HL. It is important for patients who have received radiation therapy to be tested on a regular basis because signs and symptoms of hypothyroidism occur very late and are subtle. Heart disease is also a late complication of radiation to the mediastinum. In one group of 157 patients receiving primary treatment with radiation to the mediastinum, 8.3% died of heart disease, which was 5 times what would have been expected for this age group. The risk of heart disease is associated with higher radiation doses and larger field sizes.
Secondary Cancers: 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 HL. In one clinical study evaluating the risk of second cancers in over 5,500 patients treated 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.
References
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2 Advani RH, Horning SJ: Treatment of early-stage Hodgkin’s disease. Semin Hematol 36 (3): 270-81, 1999.
3 Nademanee A, O’Donnell MR, Snyder DS, et al.: High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin’s disease: results in 85 patients with analysis of prognostic factors. Blood 85 (5): 1381-90,1995.
4 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
5 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.
6 Moskowitz C, Nadamanee A, Masszi T, et al. The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma. Presented at the 56th Annual Meeting of the American Society of Hematology, December 6-9, 2014. Abstract 673.
7 https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm
8 fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569366.htm
9 Moskowitz C, Ribrag V, Michot J-M, et al. PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study (KEYNOTE-013). Presented at the 56th Annual Meeting of the American Society of Hematology. December 6-9, 2014. Abstract 290.
10 Sirohi B, Cunningham D, Powles R, et al. Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma. Annals of Oncology. 2008;19: 1312-1319.