Treatment Option Overview
Drug combinations described in this section include the following:
- ABVD: doxorubicin, bleomycin, vinblastine, and dacarbazine.
- BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone.
- MOPP: mechlorethamine, vincristine, procarbazine, and prednisone.
After initial clinical staging for Hodgkin lymphoma (HL), patients with obvious stage III or IV disease, bulky disease (defined as a 10 cm mass or mediastinal disease with a transverse diameter exceeding 33% of the transthoracic diameter), or the presence of B symptoms will require combination chemotherapy with or without additional radiation therapy.
Patients with nonbulky stage IA or IIA disease are considered to have clinical early-stage disease. These patients are candidates for chemotherapy, combined modality therapy, or radiation therapy alone. Staging laparotomy is no longer recommended because it may not alter management and does not enhance ultimate outcome. When chemotherapy alone or combined modality therapy is applied, laparotomy is not required.Radiation Therapy
In adult HL, the appropriate dose of radiation alone is 25 Gy to 30 Gy to clinically uninvolved sites and 35 Gy to 44 Gy to regions of initial nodal involvement.[3-6] These recommendations are often modified in pediatric or advanced-staged adult patients who also receive chemotherapy. Treatment is usually delivered to the neck, chest, and axilla (mantle field) and then to an abdominal field to treat para-aortic nodes and the spleen (splenic pedicle). In some patients, pelvic nodes are treated with a third field. The three fields constitute total nodal radiation therapy. In some cases, the pelvic and para-aortic nodes are treated in a single field called an inverted Y. In patients with a favorable prognosis, treatment of the pelvic lymph nodes is frequently omitted, since fertility can be preserved without affecting relapse-free survival. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on fertility.)Second Malignancies
Acute nonlymphocytic leukemia may occur in patients treated with combined modality therapy or with combination chemotherapy alone, especially with increasing exposure to alkylating agents.[7,8] At 10 years following therapy with regimens containing MOPP, the risk of acute myelogenous leukemia (AML) is approximately 3%, with the peak incidence occurring 5 to 9 years after therapy. The risk of acute leukemia at 10 years following therapy with ABVD appears to be less than 1%. A population-based study of more than 35,000 survivors during a 30-year time span identified 217 patients who developed AML; the excess absolute risk is significantly higher (9.9 vs. 4.2 after 1984, P < .001) for older patients (i.e., >35 years at diagnosis) versus younger survivors.
An increase in second solid tumors has also been observed, especially cancers of the lung, breast, thyroid, bone/soft tissue, stomach, esophagus, colon and rectum, uterine cervix, head and neck, and mesothelioma.[7,11-16] These tumors occur primarily after radiation therapy or with combined modality treatment, and approximately 75% occur within radiation ports. At a 15-year follow-up, the risk of second solid tumors is approximately 13%;[7,12] at a 20-year follow-up, the risk is approximately 17%; and at a 25-year follow-up, the risk is approximately 22%.[11,18] In a cohort of 18,862 5-year survivors from 13 population-based registries, the younger patients had elevated risks for breast, colon, and rectal cancer for 10 to 25 years before the age when routine screening would be recommended in the general population. Even with involved-field doses of 15 Gy to 25 Gy, sarcomas, breast cancers, and thyroid cancers occurred with similar incidence in young patients receiving higher-dose radiation.
Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer is increased with cigarette smoking.[19-22] In a retrospective Surveillance, Epidemiology, and End Results (SEER) analysis, stage-specific survival was decreased by 30% to 60% in HL survivors compared with patients with de novo non-small cell lung cancer. Breast cancer is seen with increased frequency after radiation therapy or combined modality therapy.[11,13,15,24-27] The risk appears greatest for women treated with radiation before age 30 years, and the incidence increases substantially after 15 years of follow-up.[11,14,28-30] In two case control studies of 479 patients who developed breast cancer after therapy for HL, cumulative absolute risks for developing breast cancer were calculated as a function of radiation therapy dose and the use of chemotherapy.[31,32] With a 30-year to 40-year follow-up, cumulative absolute risks of breast cancer with exposure to radiation range from 8.5% to 39.6%, depending on the age at diagnosis. A family history of breast cancer or ovarian cancer does not confer a greater increased risk than that of radiation therapy for one of these cohorts. These cohort studies show a continued increase in cumulative excess risk of breast cancer beyond 20 years of follow-up.[31,32]
In a nested case control study and subsequent cohort study, patients who received both chemotherapy and radiation therapy had a statistically significant lower risk of developing breast cancer than those treated with radiation therapy alone.[25,34] Reaching early menopause with less than 10 years of intact ovarian function appeared to account for the reduction in risk among patients who received combined modality therapy. Reduction of radiation volume also decreased the risk of breast cancer after HL. The risk of non-HL is also increased, but this risk is not clearly related to type or extent of treatment.
Several studies suggest that splenic-field radiation therapy and splenectomy increase the risk of a treatment-related second cancer.[35-37] Late effects after autologous stem cell transplantation that is given for failure of induction chemotherapy include second malignancies, hypothyroidism, hypogonadism, herpes zoster, depression, and cardiac disease.Adverse Effects of Therapy
A toxic effect that is primarily related to chemotherapy is infertility, usually after MOPP-containing or BEACOPP-containing regimens;[12,39-41] After six to eight cycles of BEACOPP, most men had testosterone levels within normal range; however, among women younger than 30 years, 82% recovered menses (mostly within 12 months), but only 45% of women older than 30 years recovered menses. ABVD appears to spare long-term testicular and ovarian function.[40,43,44]
Late complications primarily related to radiation therapy include hypothyroidism and cardiac disease, which may persist through to 25 years after first treatment.[45-50] The absolute excess risk of fatal cardiovascular disease ranges from 11.9 to 48.9 per 10,000 patient years and is mostly attributable to fatal myocardial infarction (MI).[46-48,50] The use of subcarinal blocking did not reduce the incidence of fatal MI in a retrospective review, perhaps because of the exposure of the proximal coronary arteries to radiation. In a cohort of 7,033 HL patients, MI mortality risk persisted through to 25 years after first treatment with supradiaphragmatic radiation therapy (dependent on the details of treatment planning), doxorubicin, or vincristine. HL patients treated with mediastinal radiation compared with a normal-matched population have been reported to be at increased risk with the use of cardiac procedures.
Impairment of pulmonary function may occur as a result of mantle-field radiation therapy; this impairment is not usually clinically evident, and recovery in pulmonary testing often occurs after 2 to 3 years. Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years). Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.
Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL; it is much more frequent in children than in adults. The Advisory Committee on Immunization Practices recommends that all patients with HL, whether or not they have had a splenectomy, should be immunized with Haemophilusinfluenzae type b conjugate, meningococcal, and pneumococcal vaccines at least 1 week before treatment. Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter.
Fatigue is a commonly reported symptom of patients who have completed chemotherapy. In a case-control study design, a majority of HL survivors reported significant fatigue lasting for more than 6 months after therapy compared to age-matched controls.
Patients older than 60 years with HL experience more treatment-related morbidity and mortality and typically receive a lower dose intensity of chemotherapy because of poorer tolerance of treatment than comparably staged younger patients.[59-61]References
- Armitage JO: Early-stage Hodgkin's lymphoma. N Engl J Med 363 (7): 653-62, 2010. [PUBMED Abstract]
- Advani RH, Horning SJ: Treatment of early-stage Hodgkin's disease. Semin Hematol 36 (3): 270-81, 1999. [PUBMED Abstract]
- Sears JD, Greven KM, Ferree CR, et al.: Definitive irradiation in the treatment of Hodgkin's disease. Analysis of outcome, prognostic factors, and long-term complications. Cancer 79 (1): 145-51, 1997. [PUBMED Abstract]
- Ng AK, Mauch PM: Radiation therapy in Hodgkin's lymphoma. Semin Hematol 36 (3): 290-302, 1999. [PUBMED Abstract]
- Dühmke E, Franklin J, Pfreundschuh M, et al.: Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 19 (11): 2905-14, 2001. [PUBMED Abstract]
- Mendenhall NP, Rodrigue LL, Moore-Higgs GJ, et al.: The optimal dose of radiation in Hodgkin's disease: an analysis of clinical and treatment factors affecting in-field disease control. Int J Radiat Oncol Biol Phys 44 (3): 551-61, 1999. [PUBMED Abstract]
- Swerdlow AJ, Higgins CD, Smith P, et al.: Second cancer risk after chemotherapy for Hodgkin's lymphoma: a collaborative British cohort study. J Clin Oncol 29 (31): 4096-104, 2011. [PUBMED Abstract]
- Koontz MZ, Horning SJ, Balise R, et al.: Risk of therapy-related secondary leukemia in Hodgkin lymphoma: the Stanford University experience over three generations of clinical trials. J Clin Oncol 31 (5): 592-8, 2013. [PUBMED Abstract]
- Valagussa P, Santoro A, Fossati-Bellani F, et al.: Second acute leukemia and other malignancies following treatment for Hodgkin's disease. J Clin Oncol 4 (6): 830-7, 1986. [PUBMED Abstract]
- Schonfeld SJ, Gilbert ES, Dores GM, et al.: Acute myeloid leukemia following Hodgkin lymphoma: a population-based study of 35,511 patients. J Natl Cancer Inst 98 (3): 215-8, 2006. [PUBMED Abstract]
- Dores GM, Metayer C, Curtis RE, et al.: Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol 20 (16): 3484-94, 2002. [PUBMED Abstract]
- Swerdlow AJ, Douglas AJ, Hudson GV, et al.: Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304 (6835): 1137-43, 1992. [PUBMED Abstract]
- Yahalom J, Petrek JA, Biddinger PW, et al.: Breast cancer in patients irradiated for Hodgkin's disease: a clinical and pathologic analysis of 45 events in 37 patients. J Clin Oncol 10 (11): 1674-81, 1992. [PUBMED Abstract]
- Mauch PM, Kalish LA, Marcus KC, et al.: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome. Blood 87 (9): 3625-32, 1996. [PUBMED Abstract]
- Franklin J, Pluetschow A, Paus M, et al.: Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials. Ann Oncol 17 (12): 1749-60, 2006. [PUBMED Abstract]
- Hodgson DC, Gilbert ES, Dores GM, et al.: Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma. J Clin Oncol 25 (12): 1489-97, 2007. [PUBMED Abstract]
- O'Brien MM, Donaldson SS, Balise RR, et al.: Second malignant neoplasms in survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy. J Clin Oncol 28 (7): 1232-9, 2010. [PUBMED Abstract]
- Bonadonna G, Viviani S, Bonfante V, et al.: Survival in Hodgkin's disease patients--report of 25 years of experience at the Milan Cancer Institute. Eur J Cancer 41 (7): 998-1006, 2005. [PUBMED Abstract]
- van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 87 (20): 1530-7, 1995. [PUBMED Abstract]
- Swerdlow AJ, Schoemaker MJ, Allerton R, et al.: Lung cancer after Hodgkin's disease: a nested case-control study of the relation to treatment. J Clin Oncol 19 (6): 1610-8, 2001. [PUBMED Abstract]
- Travis LB, Gospodarowicz M, Curtis RE, et al.: Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst 94 (3): 182-92, 2002. [PUBMED Abstract]
- Lorigan P, Radford J, Howell A, et al.: Lung cancer after treatment for Hodgkin's lymphoma: a systematic review. Lancet Oncol 6 (10): 773-9, 2005. [PUBMED Abstract]
- Milano MT, Li H, Constine LS, et al.: Survival after second primary lung cancer: a population-based study of 187 Hodgkin lymphoma patients. Cancer 117 (24): 5538-47, 2011. [PUBMED Abstract]
- Cutuli B, Dhermain F, Borel C, et al.: Breast cancer in patients treated for Hodgkin's disease: clinical and pathological analysis of 76 cases in 63 patients. Eur J Cancer 33 (14): 2315-20, 1997. [PUBMED Abstract]
- van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 95 (13): 971-80, 2003. [PUBMED Abstract]
- Wahner-Roedler DL, Nelson DF, Croghan IT, et al.: Risk of breast cancer and breast cancer characteristics in women treated with supradiaphragmatic radiation for Hodgkin lymphoma: Mayo Clinic experience. Mayo Clin Proc 78 (6): 708-15, 2003. [PUBMED Abstract]
- Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003. [PUBMED Abstract]
- Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst 85 (1): 25-31, 1993. [PUBMED Abstract]
- Sankila R, Garwicz S, Olsen JH, et al.: Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14 (5): 1442-6, 1996. [PUBMED Abstract]
- Alm El-Din MA, Hughes KS, Finkelstein DM, et al.: Breast cancer after treatment of Hodgkin's lymphoma: risk factors that really matter. Int J Radiat Oncol Biol Phys 73 (1): 69-74, 2009. [PUBMED Abstract]
- Travis LB, Hill D, Dores GM, et al.: Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 97 (19): 1428-37, 2005. [PUBMED Abstract]
- Swerdlow AJ, Cooke R, Bates A, et al.: Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study. J Clin Oncol 30 (22): 2745-52, 2012. [PUBMED Abstract]
- Hill DA, Gilbert E, Dores GM, et al.: Breast cancer risk following radiotherapy for Hodgkin lymphoma: modification by other risk factors. Blood 106 (10): 3358-65, 2005. [PUBMED Abstract]
- De Bruin ML, Sparidans J, van't Veer MB, et al.: Breast cancer risk in female survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes. J Clin Oncol 27 (26): 4239-46, 2009. [PUBMED Abstract]
- Dietrich PY, Henry-Amar M, Cosset JM, et al.: Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen? Blood 84 (4): 1209-15, 1994. [PUBMED Abstract]
- van der Velden JW, van Putten WL, Guinee VF, et al.: Subsequent development of acute non-lymphocytic leukemia in patients treated for Hodgkin's disease. Int J Cancer 42 (2): 252-5, 1988. [PUBMED Abstract]
- Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin's disease. N Engl J Med 322 (1): 7-13, 1990. [PUBMED Abstract]
- Lavoie JC, Connors JM, Phillips GL, et al.: High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood 106 (4): 1473-8, 2005. [PUBMED Abstract]
- Behringer K, Breuer K, Reineke T, et al.: Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin's Lymphoma Study Group. J Clin Oncol 23 (30): 7555-64, 2005. [PUBMED Abstract]
- van der Kaaij MA, Heutte N, Le Stang N, et al.: Gonadal function in males after chemotherapy for early-stage Hodgkin's lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 25 (19): 2825-32, 2007. [PUBMED Abstract]
- Scholz M, Engert A, Franklin J, et al.: Impact of first- and second-line treatment for Hodgkin's lymphoma on the incidence of AML/MDS and NHL--experience of the German Hodgkin's Lymphoma Study Group analyzed by a parametric model of carcinogenesis. Ann Oncol 22 (3): 681-8, 2011. [PUBMED Abstract]
- Behringer K, Mueller H, Goergen H, et al.: Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol 31 (2): 231-9, 2013. [PUBMED Abstract]
- Viviani S, Santoro A, Ragni G, et al.: Pre- and post-treatment testicular dysfunction in Hodgkin's disease (HD). [Abstract] Proceedings of the American Society of Clinical Oncology 7: A-877, 227, 1988.
- van der Kaaij MA, Heutte N, Meijnders P, et al.: Premature ovarian failure and fertility in long-term survivors of Hodgkin's lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d'Etude des Lymphomes de l'Adulte Cohort Study. J Clin Oncol 30 (3): 291-9, 2012. [PUBMED Abstract]
- Tarbell NJ, Thompson L, Mauch P: Thoracic irradiation in Hodgkin's disease: disease control and long-term complications. Int J Radiat Oncol Biol Phys 18 (2): 275-81, 1990. [PUBMED Abstract]
- Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al.: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol 51 (1): 35-42, 1999. [PUBMED Abstract]
- Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270 (16): 1949-55, 1993. [PUBMED Abstract]
- Heidenreich PA, Schnittger I, Strauss HW, et al.: Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease. J Clin Oncol 25 (1): 43-9, 2007. [PUBMED Abstract]
- Dabaja B, Cox JD, Buchholz TA: Radiation therapy can still be used safely in combined modality approaches in patients with Hodgkin's lymphoma. J Clin Oncol 25 (1): 3-5, 2007. [PUBMED Abstract]
- Swerdlow AJ, Higgins CD, Smith P, et al.: Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst 99 (3): 206-14, 2007. [PUBMED Abstract]
- Galper SL, Yu JB, Mauch PM, et al.: Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 117 (2): 412-8, 2011. [PUBMED Abstract]
- Horning SJ, Adhikari A, Rizk N, et al.: Effect of treatment for Hodgkin's disease on pulmonary function: results of a prospective study. J Clin Oncol 12 (2): 297-305, 1994. [PUBMED Abstract]
- Martin WG, Ristow KM, Habermann TM, et al.: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 23 (30): 7614-20, 2005. [PUBMED Abstract]
- Prosnitz LR, Lawson JP, Friedlaender GE, et al.: Avascular necrosis of bone in Hodgkin's disease patients treated with combined modality therapy. Cancer 47 (12): 2793-7, 1981. [PUBMED Abstract]
- Schimpff SC, O'Connell MJ, Greene WH, et al.: Infections in 92 splenectomized patients with Hodgkin's disease. A clinical review. Am J Med 59 (5): 695-701, 1975. [PUBMED Abstract]
- Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins for persons with altered immunocompetence. MMWR Recomm Rep 42 (RR-4): 1-18, 1993. [PUBMED Abstract]
- Molrine DC, George S, Tarbell N, et al.: Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin disease. Ann Intern Med 123 (11): 828-34, 1995. [PUBMED Abstract]
- Loge JH, Abrahamsen AF, Ekeberg O, et al.: Hodgkin's disease survivors more fatigued than the general population. J Clin Oncol 17 (1): 253-61, 1999. [PUBMED Abstract]
- Ballova V, Rüffer JU, Haverkamp H, et al.: A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol 16 (1): 124-31, 2005. [PUBMED Abstract]
- Engert A, Ballova V, Haverkamp H, et al.: Hodgkin's lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin's Study Group. J Clin Oncol 23 (22): 5052-60, 2005. [PUBMED Abstract]
- Böll B, Görgen H, Fuchs M, et al.: ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials. J Clin Oncol 31 (12): 1522-9, 2013. [PUBMED Abstract]