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NCI/PDQ^® Health professionals: Adult Hodgkin Lymphoma Treatment (PDQ®)

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National Cancer Institute
Last Modified: August 30, 2012

TABLE OF CONTENTS

• General Information About Adult Hodgkin Lymphoma
  • Incidence and Mortality
  • Related Summaries

• Cellular Classification of Adult Hodgkin Lymphoma
  • Nodular LymphocytePredominant HL

• Stage Information for Adult Hodgkin Lymphoma

• Treatment Option Overview
  • Radiation Therapy
  • Second Malignancies
  • Adverse Effects of Therapy

• Early Favorable Hodgkin Lymphoma
  • Current Clinical Trials

• Early Unfavorable Hodgkin Lymphoma
  • Current Clinical Trials

• Advanced Favorable Hodgkin Lymphoma
  • Current Clinical Trials

• Advanced Unfavorable Hodgkin Lymphoma
  • Current Clinical Trials

• Recurrent Adult Hodgkin Lymphoma
  • Current Clinical Trials

• Hodgkin Lymphoma During Pregnancy
  • Introduction
  • Stage Information
  • Treatment Option Overview

• Changes to This Summary (08/30/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Adult Hodgkin Lymphoma

Incidence and Mortality

Estimated new cases and deaths from Hodgkin lymphoma in the United States in 2012: 1

• New cases: 9,060.
• Deaths: 1,190.

More than 75% of all newly diagnosed patients with adult Hodgkin lymphoma (HL) can be cured with combination chemotherapy and/or radiation therapy. 2 National mortality has fallen more rapidly for adult HL than for any other malignancy over the last 5 decades. 2

Prognosis for a given patient depends on several factors. The most important factors are the presence or absence of systemic symptoms, the stage of disease, presence of large masses, and the quality and suitability of the treatment administered. Other important factors are age (therapy for very young children requires special attention), sex, erythrocyte sedimentation rate, extent of abdominal involvement, hematocrit, and absolute number of nodal sites of involvement. 3 4

HL is the main cause of death over the first 15 years after treatment. By 15 to 20 years after therapy, the cumulative mortality from a second malignancy will exceed the cumulative mortality from HL. 5 6 7

Related Summaries

Other PDQ® summaries containing information related to Hodgkin lymphoma include the following:

• AIDS-Related Lymphoma Treatment
• Childhood Hodgkin Lymphoma Treatment

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. Brenner H, Gondos A, Pulte D: Ongoing improvement in long-term survival of patients with Hodgkin disease at all ages and recent catch-up of older patients. Blood 111 (6): 2977-83, 2008. [PUBMED Abstract]
3. American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. [PUBMED Abstract]
4. Cosset JM, Henry-Amar M, Meerwaldt JH, et al.: The EORTC trials for limited stage Hodgkin's disease. The EORTC Lymphoma Cooperative Group. Eur J Cancer 28A (11): 1847-50, 1992. [PUBMED Abstract]
5. Mauch PM, Kalish LA, Marcus KC, et al.: Long-Term Survival in Hodgkin's Disease Cancer J Sci Am 1 (1): 33-42, 1995. [PUBMED Abstract]
6. Aisenberg AC: Problems in Hodgkin's disease management. Blood 93 (3): 761-79, 1999. [PUBMED Abstract]
7. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al.: Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 21 (18): 3431-9, 2003. [PUBMED Abstract]

Cellular Classification of Adult Hodgkin Lymphoma

Pathologists currently use the World Health Organization (WHO) modification of the Revised European-American Lymphoma (REAL) classification for the histologic classification for adult Hodgkin lymphoma (HL). 1 2

WHO/REAL classification

• Classical HL.
  • Nodular sclerosis HL.
  • Mixed-cellularity HL.
  • Lymphocyte depletion HL.
  • Lymphocyte-rich classical HL.

• Nodular lymphocytepredominant HL.

Nodular LymphocytePredominant HL

Nodular lymphocytepredominant HL is a clinicopathologic entity of B-cell origin that is distinct from classic HL. 3 4 5 The typical immunophenotype for lymphocyte-predominant disease is CD15-, CD20+, CD30-, CD45+, while the profile for classic HL is CD15+, CD20-, CD30+, CD45-. Patients with lymphocyte-predominant disease have earlier-stage disease, longer survival, and fewer treatment failures than those with classic HL. 6 Despite a usually favorable prognosis, there is a tendency for histologic transformation to diffuse large B-cell lymphoma in around 10% of patients by 10 years. 7 Lymphocyte-predominant HL is usually diagnosed in asymptomatic young males with cervical or inguinal lymph nodes but usually without mediastinal involvement. Based on retrospective analyses spanning several decades and because of the rarity of this histology, limited-field radiation therapy is the most common treatment approach for patients with early-stage disease. 8 9 10

The REAL Classification of Lymphoid Neoplasms proposed separating nodular lymphocytepredominant HL (CD15-, CD20+, CD30-) from lymphocyte-rich classical HL (CD15+, CD20-, CD30+), on the basis of these immunophenotypic differences. 2 11 The largest retrospective report of 426 cases showed no significant difference in clinical response or outcome to standard therapies for these two subgroups. 12[Level of evidence: 3iiiA] Of interest, with a median follow-up of 7 to 8 years, more patients died of treatment-related toxic effects (acute and long-term) than from Hodgkin recurrence. Limitation of radiation dose and fields and avoidance of leukemogenic chemotherapeutic agents, along with watchful waiting policies, should be investigated for these subgroups. 13 14 For patients with advanced-stage nodular lymphocytepredominant HL, chemotherapy regimens designed for non-HLs may be preferred, based on a retrospective review. 15[Level of evidence: 3iiiDii]

References:

1. Lukes RJ, Craver LF, Hall TC, et al.: Report of the Nomenclature Committee. Cancer Res 26 (1): 1311, 1966. [PUBMED Abstract]
2. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999. [PUBMED Abstract]
3. von Wasielewski R, Mengel M, Fischer R, et al.: Classical Hodgkin's disease. Clinical impact of the immunophenotype. Am J Pathol 151 (4): 1123-30, 1997. [PUBMED Abstract]
4. Bodis S, Kraus MD, Pinkus G, et al.: Clinical presentation and outcome in lymphocyte-predominant Hodgkin's disease. J Clin Oncol 15 (9): 3060-6, 1997. [PUBMED Abstract]
5. Orlandi E, Lazzarino M, Brusamolino E, et al.: Nodular lymphocyte predominance Hodgkin's disease: long-term observation reveals a continuous pattern of recurrence. Leuk Lymphoma 26 (3-4): 359-68, 1997. [PUBMED Abstract]
6. Nogová L, Reineke T, Brillant C, et al.: Lymphocyte-predominant and classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 26 (3): 434-9, 2008. [PUBMED Abstract]
7. Al-Mansour M, Connors JM, Gascoyne RD, et al.: Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin's lymphoma. J Clin Oncol 28 (5): 793-9, 2010. [PUBMED Abstract]
8. Chen RC, Chin MS, Ng AK, et al.: Early-stage, lymphocyte-predominant Hodgkin's lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28 (1): 136-41, 2010. [PUBMED Abstract]
9. Nogová L, Reineke T, Eich HT, et al.: Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG). Ann Oncol 16 (10): 1683-7, 2005. [PUBMED Abstract]
10. Wilder RB, Schlembach PJ, Jones D, et al.: European Organization for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte very favorable and favorable, lymphocyte-predominant Hodgkin disease. Cancer 94 (6): 1731-8, 2002. [PUBMED Abstract]
11. Shimabukuro-Vornhagen A, Haverkamp H, Engert A, et al.: Lymphocyte-rich classical Hodgkin's lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin's Study Group trials. J Clin Oncol 23 (24): 5739-45, 2005. [PUBMED Abstract]
12. Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 17 (3): 776-83, 1999. [PUBMED Abstract]
13. Aster JC: Lymphocyte-predominant Hodgkin's disease: how little therapy is enough? J Clin Oncol 17 (3): 744-6, 1999. [PUBMED Abstract]
14. Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al.: Lymphocyte-predominant Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node resection--a Study of the French Society of Pediatric Oncology. J Clin Oncol 21 (15): 2948-52, 2003. [PUBMED Abstract]
15. Canellos GP, Mauch P: What is the appropriate systemic chemotherapy for lymphocyte-predominant Hodgkin's lymphoma? J Clin Oncol 28 (1): e8, 2010. [PUBMED Abstract]

Stage Information for Adult Hodgkin Lymphoma

Clinical staging for patients with Hodgkin lymphoma (HL) includes a history, physical examination, laboratory studies (including sedimentation rate), and thoracic and abdominal/pelvic computerized tomographic (CT) scans. 1

Positron emission tomography (PET) scans, sometimes combined with CT scans, have replaced gallium scans and lymphangiography for clinical staging. 2 3 4 The use of PET scans to assess response and define the use or avoidance of further treatment is under clinical evaluation. 5 6 7 8 9 10 A prospective, multinational study of 260 newly diagnosed patients with HL obtained PET scans at baseline and after two cycles (four doses) of ABVD (doxorubicin plus bleomycin plus vinblastine plus dacarbazine); with a median follow-up of 2.2 years, the 2-year progression-free survival was 12.8% with a positive PET scan after two cycles and 95% with a negative PET scan after two cycles (P < .0001). 8 In a prospective trial of BEACOPP-based therapywhich includes the drugs bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine, and prednisone for previously untreated patients with advanced-stage HL, patients with residual abnormalities measuring 2.5 cm or more received a PET scan at the end of therapy. 11 A negative PET scan predicted no progression or relapse within 1 year for 94% of patients (confidence interval, 91%97%). Whether consolidation with radiation therapy can be omitted for PET-negative patients must await overall survival data at 5 years. Only further prospective studies can assess whether improved outcomes can be achieved by altering the therapeutic strategy based on PET scan results. 10

Bone marrow involvement occurs in 5% of patients; biopsy is indicated in the presence of constitutional B symptoms or anemia, leukopenia, or thrombocytopenia. Staging laparotomy is no longer recommended; it should be considered only when the results will allow substantial reduction in treatment. It should not be done in patients who require chemotherapy. If the laparotomy is required for treatment decisions, the risks of potential morbidity should be considered. 12 13 14 15 The staging classification that is currently used for HL was adopted in 1971 at the Ann Arbor Conference 16 with some modifications 18 years later from the Cotswolds meeting. 1

Subclassification of stage

Stages I, II, III, and IV adult HL can be subclassified into A and B categories: B for those with defined general symptoms and A for those without B symptoms. The B designation is given to patients with any of the following symptoms:

• Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.
• Unexplained fever with temperatures above 38C.
• Drenching night sweats. (Refer to the PDQ® summary on Fever, Sweats, and Hot Flashes for more information.)

[Note: The most significant B symptoms are fevers and weight loss. Night sweats alone do not confer an adverse prognosis. Pruritus as a systemic symptom remains controversial and is not considered a B symptom in the Ann Arbor staging system. (Refer to the PDQ® summary on Pruritis for more information.) This symptom is hard to define quantitatively and uniformly, but when it is recurrent, generalized, and otherwise unexplained, and when it ebbs and flows parallel to disease activity, it may be the equivalent of a B symptom.]

The designation E is used when well-localized extranodal lymphoid malignancies arise in or extend to tissues beyond, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Current practice is to assign a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings of invasive procedures.

For example, a patient who has disease in the chest and neck, systemic symptoms, and a negative lymphangiogram might be found at laparotomy to have involvement of the spleen, liver, and bone marrow. Thus, the precise stage of such a patient would be CS IIB, PS IVB (S+)(H+)(M+).

The American Joint Committee on Cancer (AJCC) has designated staging using the Ann Arbor classification system to define adult Hodgkin lymphoma. 17

Massive mediastinal disease has been defined by the Cotswolds meeting as a thoracic ratio of maximum transverse mass diameter of 33% or more of the internal transverse thoracic diameter measured at the T5/6 intervertebral disc level on chest radiography. 1 Some investigators have designated a lymph node mass measuring 10 cm or more in greatest dimension as massive disease. 18 Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter. 19

Many investigators and many new clinical trials employ a clinical staging system that divides patients into four major groups that are also useful for the practicing physician: 20

• Early favorable: Clinical stage I or II without any risk factors.
• Early unfavorable: Clinical stage I or II with one or more of the following risk factors:
  • Large mediastinal mass (>33% of the thoracic width on the chest x-ray, 10 cm on CT scan).
  • Extranodal involvement.
  • Elevated erythrocyte sedimentation rate (>30 mm/h for B stage, >50 mm/h for A stage).
  • Three or more lymph node areas' involvement.
  • B symptoms.

• Advanced favorable: Clinical stage III or IV with zero to three adverse risk factors listed below. Patients with advanced favorable disease have a 60% to 80% freedom-from-progression at 5 years from treatment with first-line chemotherapy. 21[Level of evidence: 3iiiDiii]
• Advanced unfavorable: Clinical stage III or IV with four or more adverse risk factors listed below. 21 Patients with advanced unfavorable disease showed a 42% to 51% freedom-from-progression at 5 years from treatment with first-line chemotherapy. 21[Level of evidence: 3iiiDiii]. For patients with advanced-stage HL, the International Prognostic Factors Project has developed an International Prognostic Index with a prognostic score that is based on seven adverse factors: 21
  • Albumin level of <4.0 g/dL.
  • Hemoglobin level of <10.5 g/dL.
  • Male sex.
  • Age of 45 years.
  • Stage IV disease.
  • White blood cell (WBC) count of 15,000/mm³.
  • Absolute lymphocytic count of <600/mm³ or a lymphocyte count that was <8% of the total WBC count.

References:

1. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989. [PUBMED Abstract]
2. Jerusalem G, Beguin Y, Fassotte MF, et al.: Whole-body positron emission tomography using 18F-fluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin's disease. Haematologica 86 (3): 266-73, 2001. [PUBMED Abstract]
3. Naumann R, Beuthien-Baumann B, Reiss A, et al.: Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin's lymphoma. Br J Cancer 90 (3): 620-5, 2004. [PUBMED Abstract]
4. Munker R, Glass J, Griffeth LK, et al.: Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease. Ann Oncol 15 (11): 1699-704, 2004. [PUBMED Abstract]
5. Weihrauch MR, Re D, Scheidhauer K, et al.: Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease. Blood 98 (10): 2930-4, 2001. [PUBMED Abstract]
6. Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006. [PUBMED Abstract]
7. Dann EJ, Bar-Shalom R, Tamir A, et al.: Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 109 (3): 905-9, 2007. [PUBMED Abstract]
8. Gallamini A, Hutchings M, Rigacci L, et al.: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25 (24): 3746-52, 2007. [PUBMED Abstract]
9. Advani R, Maeda L, Lavori P, et al.: Impact of positive positron emission tomography on prediction of freedom from progression after Stanford V chemotherapy in Hodgkin's disease. J Clin Oncol 25 (25): 3902-7, 2007. [PUBMED Abstract]
10. Terasawa T, Lau J, Bardet S, et al.: Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27 (11): 1906-14, 2009. [PUBMED Abstract]
11. Kobe C, Dietlein M, Franklin J, et al.: Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma. Blood 112 (10): 3989-94, 2008. [PUBMED Abstract]
12. Urba WJ, Longo DL: Hodgkin's disease. N Engl J Med 326 (10): 678-87, 1992. [PUBMED Abstract]
13. Sombeck MD, Mendenhall NP, Kaude JV, et al.: Correlation of lymphangiography, computed tomography, and laparotomy in the staging of Hodgkin's disease. Int J Radiat Oncol Biol Phys 25 (3): 425-9, 1993. [PUBMED Abstract]
14. Mauch P, Larson D, Osteen R, et al.: Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 8 (2): 257-65, 1990. [PUBMED Abstract]
15. 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]
16. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971. [PUBMED Abstract]
17. Hodgkin and non-Hodgkin lymphomas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607-11. [PUBMED Abstract]
18. Bradley AJ, Carrington BM, Lawrance JA, et al.: Assessment and significance of mediastinal bulk in Hodgkin's disease: comparison between computed tomography and chest radiography. J Clin Oncol 17 (8): 2493-8, 1999. [PUBMED Abstract]
19. Mauch P, Goodman R, Hellman S: The significance of mediastinal involvement in early stage Hodgkin's disease. Cancer 42 (3): 1039-45, 1978. [PUBMED Abstract]
20. Jost LM, Stahel RA; ESMO Guidelines Task Force.: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Hodgkin's disease. Ann Oncol 16 (Suppl 1): i54-5, 2005. [PUBMED Abstract]
21. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339 (21): 1506-14, 1998. [PUBMED Abstract]

Treatment Option Overview

Drug combinations described in this section:

• ABVD: doxorubicin plus bleomycin plus vinblastine plus dacarbazine.
• BEACOPP: bleomycin plus etoposide plus doxorubicin plus cyclophosphamide plus vincristine plus procarbazine plus prednisone.
• MOPP: mechlorethamine plus vincristine plus procarbazine plus 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. 1 Staging laparotomy is no longer recommended because it may not alter management and does not enhance ultimate outcome. 2 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 4 5 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. 7 8 9 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%. 7 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. 10

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. 8 11 12 13 14 15 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%; 8 12 at a 20-year follow-up, the risk is approximately 17%; 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. 16 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. 17

Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer is increased with cigarette smoking. 19 20 21 22 Breast cancer is seen with increased frequency after radiation therapy or combined modality therapy. 11 13 15 23 24 25 26 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 27 28 29 In a case control study of 106 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. 30 With a 30-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 this cohort. 31 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. 24 32 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. 32 Reduction of radiation volume also decreased the risk of breast cancer after HL. 32 The risk of non-HL is also increased, but this risk is not clearly related to type or extent of treatment. 12

Several studies suggest that splenic-field radiation therapy and splenectomy increase the risk of a treatment-related second cancer. 33 34 35 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. 36

Adverse Effects of Therapy

A toxic effect that is primarily related to chemotherapy is infertility, usually after MOPP-containing or BEACOPP-containing regimens; 12 37 38 39 ABVD appears to spare long-term testicular and ovarian function. 38 40 Late complications primarily related to radiation therapy include hypothyroidism and cardiac disease, which may persist through to 25 years after first treatment. 41 42 43 44 45 46 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). 42 43 44 46 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. 43 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. 46 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. 47 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. 48 Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years). 49 Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy. 50 Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL; 51 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 Haemophilus influenzae type b conjugate, meningococcal, and pneumococcal vaccines at least 1 week before treatment. 52 Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter. 53

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. 54

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. 55 56

References:

1. Armitage JO: Early-stage Hodgkin's lymphoma. N Engl J Med 363 (7): 653-62, 2010. [PUBMED Abstract]
2. Advani RH, Horning SJ: Treatment of early-stage Hodgkin's disease. Semin Hematol 36 (3): 270-81, 1999. [PUBMED Abstract]
3. 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]
4. Ng AK, Mauch PM: Radiation therapy in Hodgkin's lymphoma. Semin Hematol 36 (3): 290-302, 1999. [PUBMED Abstract]
5. Dí¼hmke 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]
6. 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]
7. 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]
8. Hancock SL, Hoppe RT: Long-Term Complications of Treatment and Causes of Mortality After Hodgkin's Disease. Semin Radiat Oncol 6 (3): 225-242, 1996. [PUBMED Abstract]
9. van Leeuwen FE, Chorus AM, van den Belt-Dusebout AW, et al.: Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. J Clin Oncol 12 (5): 1063-73, 1994. [PUBMED Abstract]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
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