Adult Hodgkin Lymphoma Treatment – Health Professional Version

Incidence and Mortality

Estimated new cases and deaths from HL in the United States in 2018:[1]

• New cases: 8,500.
• Deaths: 1,050.

More than 75% of all newly diagnosed patients with adult 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 and Survival Factors

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, sex, erythrocyte sedimentation rate, extent of abdominal involvement, hematocrit, and absolute number of nodal sites of involvement.[3–5]

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.[6–8]

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 2018. Atlanta, Ga: American Cancer Society, 2018. Available onlineExit Disclaimer. Last accessed January 5, 2018.
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.Exit Disclaimer Last accessed June 22, 2016.
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. Evens AM, Helenowski I, Ramsdale E, et al.: A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood 119 (3): 692-5, 2012. [PUBMED Abstract]
6. 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]
7. Aisenberg AC: Problems in Hodgkin’s disease management. Blood 93 (3): 761-79, 1999. [PUBMED Abstract]
8. 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]

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 lymphocyte–predominant HL.

Among 10,019 patients who underwent central expert pathology review for the German Hodgkin Study Group, 84 patients (<1%) were identified as having lymphocyte-depleted classical HL.[3] These patients present with more advanced-stage HL and usually with B symptoms.

Nodular Lymphocyte–Predominant HL

Nodular lymphocyte–predominant HL (NLPHL) is a clinicopathologic entity of B-cell origin that is distinct from classic HL.[4–6] 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.[7,8] Despite a usually favorable prognosis, there is a tendency for histologic transformation to diffuse large B-cell lymphoma or T-cell–rich large B-cell lymphoma in approximately 10% of patients by 10 years.[9–11] This propensity of NLPHL to transform to aggressive B-cell lymphoma underscores the importance of long-term follow-up and re-biopsy at relapse.[10] 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.[8,12–14]

The REAL Classification of Lymphoid Neoplasms proposed separating NLPHL (CD15-, CD20+, CD30-) from lymphocyte-rich classical HL (CD15+, CD20-, CD30+), on the basis of these immunophenotypic differences.[2,15] The largest retrospective report of 426 cases showed no significant difference in clinical response or outcome to standard therapies for these two subgroups.[16][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.[8,17,18] For patients with advanced-stage NLPHL, chemotherapy regimens designed for patients with non-HLs may be preferred, based on two retrospective reviews and a phase II study.[19–21][Level of evidence: 3iiiDii]

Rituximab had a 100% response rate in a phase II trial of 39 previously untreated and relapsed NLPHL patients. With a median follow-up of 9.8 years, the median PFS was 3.0 years for patients who received rituximab induction only and 5.6 years for patients who received rituximab induction plus rituximab maintenance.[10][Level of evidence: 3iiiDiii] With induction only, 9 of 23 patients relapsed with an aggressive B-cell lymphoma.

References

1. Lukes RJ, Craver LF, Hall TC, et al.: Report of the Nomenclature Committee. Cancer Res 26 (1): 1311, 1966.
2. Harris NL: Hodgkin’s lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999. [PUBMED Abstract]
3. Klimm B, Franklin J, Stein H, et al.: Lymphocyte-depleted classical Hodgkin’s lymphoma: a comprehensive analysis from the German Hodgkin study group. J Clin Oncol 29 (29): 3914-20, 2011. [PUBMED Abstract]
4. 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]
5. 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]
6. 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]
7. 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]
8. Eichenauer DA, Plütschow A, Fuchs M, et al.: Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group. J Clin Oncol 33 (26): 2857-62, 2015. [PUBMED Abstract]
9. 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]
10. Advani RH, Horning SJ, Hoppe RT, et al.: Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol 32 (9): 912-8, 2014. [PUBMED Abstract]
11. Kenderian SS, Habermann TM, Macon WR, et al.: Large B-cell transformation in nodular lymphocyte-predominant Hodgkin lymphoma: 40-year experience from a single institution. Blood 127 (16): 1960-6, 2016. [PUBMED Abstract]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. Aster JC: Lymphocyte-predominant Hodgkin’s disease: how little therapy is enough? J Clin Oncol 17 (3): 744-6, 1999. [PUBMED Abstract]
18. 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]
19. 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]
20. Xing KH, Connors JM, Lai A, et al.: Advanced-stage nodular lymphocyte predominant Hodgkin lymphoma compared with classical Hodgkin lymphoma: a matched pair outcome analysis. Blood 123 (23): 3567-73, 2014. [PUBMED Abstract]
21. Fanale MA, Lai CM, McLaughlin P, et al.: Outcomes of nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL) patients treated with R-CHOP. [Abstract] Blood 116 (21): A-2812, 2010.

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 with or without positron emission tomography (PET).[1,2]

PET scans combined with CT scans have become the standard imaging for clinical staging.[2] A prospective, multinational study of 260 newly diagnosed patients with advanced-stage HL obtained PET scans at baseline and after two cycles (four doses) of doxorubicin plus bleomycin plus vinblastine plus dacarbazine (ABVD); with a median follow-up of 2.2 years, the 2-year progression-free survival (PFS) was 12.8% with a positive PET scan after two cycles and 95% with a negative PET scan after two cycles (P < .0001).[3] In a prospective trial of BEACOPP-based therapy—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.[4] 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 that compare a PET response–adapted strategy versus standard therapy without alteration can assess whether improved outcomes can be achieved by altering the therapeutic strategy based on PET scan results.[5,6] In two prospective randomized trials encompassing 1,739 patients with clinical stage I or II HL, acute relapse rates were lower with combined modality therapy, even for patients with a negative interim PET scan.[7,8] These trials do not support using interim PET scans to determine the value of radiation therapy for early-stage disease. Both studies showed that patients with early-stage disease and a negative PET scan after two or three cycles of ABVD had a very good prognosis (PFS exceeding 90% at 3 years in one of the studies) with or without consolidation radiation therapy. Neither of these studies has been followed long enough (>10 years) to assess long-term toxicities or treatment-related mortality.[9]

Bone marrow involvement occurs in 5% of patients; biopsy may be indicated in the presence of constitutional B symptoms or anemia, leukopenia, or thrombocytopenia. In a retrospective review and meta-analysis of 955 patients in nine studies, fewer than 2% of patients with a positive bone marrow biopsy had only stage I or II disease on PET-CT scans; omission of the bone marrow biopsy for PET-CT–designated early-stage patients did not change treatment selection.[10] Staging laparotomy is no longer recommended and should be considered only when the results will allow substantial reduction in treatment. Staging laparotomy 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.[11–14] The staging classification that is currently used for HL was adopted in 1971 at the Ann Arbor Conference [15] 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 38°C.
• Drenching night sweats. (Refer to the PDQ summary on Hot Flashes and Night Sweats 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 Pruritus 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.

N = nodes	H = liver	L = lung	M = bone marrow
S = spleen	P = pleura	O = bone	D = skin

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.[16]

Stage	Prognostic Groups
aReprinted with permission from AJCC: 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.
I	Involvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I).
	Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma).
II	Involvement of ≥2 lymph node regions on the same side of the diaphragm (II).
	Localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE).
	The number of regions involved may be indicated by an arabic numeral, as in, for example, II3.
III	Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, S).
	Splenic involvement is designated by the letter S.
IV	Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.
	Isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s).
	Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.

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.[17] Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter.[18]

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:[19]

• 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: 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 the following seven adverse factors:[20]
  • 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. Barrington SF, Kirkwood AA, Franceschetto A, et al.: PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study. Blood 127 (12): 1531-8, 2016. [PUBMED Abstract]
3. 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]
4. 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]
5. Gallamini A, Kostakoglu L: Interim FDG-PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? Blood 120 (25): 4913-20, 2012. [PUBMED Abstract]
6. Evens AM, Kostakoglu L: The role of FDG-PET in defining prognosis of Hodgkin lymphoma for early-stage disease. Blood 124 (23): 3356-64, 2014. [PUBMED Abstract]
7. Raemaekers JM, André MP, Federico M, et al.: Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 32 (12): 1188-94, 2014. [PUBMED Abstract]
8. Radford J, Illidge T, Counsell N, et al.: Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372 (17): 1598-607, 2015. [PUBMED Abstract]
9. Longo DL, Armitage JO: Controversies in the treatment of early-stage Hodgkin’s lymphoma. N Engl J Med 372 (17): 1667-9, 2015. [PUBMED Abstract]
10. Adams HJ, Kwee TC, de Keizer B, et al.: Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol 25 (5): 921-7, 2014. [PUBMED Abstract]
11. Urba WJ, Longo DL: Hodgkin’s disease. N Engl J Med 326 (10): 678-87, 1992. [PUBMED Abstract]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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.
17. 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]
18. 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]
19. 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]
20. 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]

Drug combinations described in this section include the following:

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.[3–6] 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.

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 after 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%.[9] 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.[7,11–18] 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 (cumulative incidence of a second cancer) is approximately 13%;[7,12] at a 20-year follow-up, the risk is approximately 17%;[19] at a 25-year follow-up, the risk is approximately 22%;[11,20] and at a 40-year follow-up, the risk is approximately 48%.[21] 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.[19]

Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer is increased with cigarette smoking.[22–25] 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.[26] Breast cancer is seen with increased frequency after radiation therapy or combined modality therapy.[11,13,15,27–30] The risk appears greatest for women treated with radiation before age 30 years and especially close to menarche, and the incidence increases substantially after 15 years of follow-up.[11,14,31–34] 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.[35,36] 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.[37] These cohort studies show a continued increase in cumulative excess risk of breast cancer beyond 20 years of follow-up.[35,36]

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.[28,38] 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.[38] Reduction of radiation volume also decreased the risk of breast cancer after HL.[38] 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.[39–41] 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.[42]

Adverse Effects of Therapy

A toxic effect that is primarily related to chemotherapy is infertility, usually after MOPP-containing or BEACOPP-containing regimens;[12,43–45] 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.[46] ABVD appears to spare long-term testicular and ovarian function.[44,47,48]

Late complications primarily related to radiation therapy include hypothyroidism and cardiac disease, which may persist through to 25 years after first treatment.[49–55] 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).[50–52,54,55] 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.[51] 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.[54] 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.[56]

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.[57] Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years).[58] Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.[59]

Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL;[60] 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.[61] Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter.[62]

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 with age-matched controls.[63] Quality-of-life questionnaires given to 5,306 patients on German Hodgkin Study Group trials showed that 20% of patients complained of severe fatigue 5 years after therapy, and those patients had significantly increased problems with employment and financial stability.[64]

Recommendations for screening for secondary malignancies or follow-up of long-term survivors are consensus based rather than derived from randomized trials.[65]

Patients older than 60 years with HL may experience more treatment-related morbidity and mortality; maintaining dose intensity of standard chemotherapy may be difficult.[66,67] Alternative therapies have been proposed for elderly patients, but no randomized trials have been conducted with these regimens.[68] A series of 27 previously untreated patients older than 60 years, judged by the investigator to be in too poor a condition to undergo chemotherapy, received brentuximab. A 92% overall response rate and 73% complete remission rate were reported.[69][Level of evidence: 3iiiDiv]

Recommendations for posttreatment follow-up are not evidence based, but a variety of opinions have been published for high-risk patients who present with advanced-stage disease or for patients who achieve less-than-complete remission by positron emission tomography–computed tomography scans at the end of therapy.[70–73]

References

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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]
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5. 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]
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. 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]
8. 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]
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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]
16. 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]
17. Chowdhry AK, McHugh C, Fung C, et al.: Second primary head and neck cancer after Hodgkin lymphoma: a population-based study of 44,879 survivors of Hodgkin lymphoma. Cancer 121 (9): 1436-45, 2015. [PUBMED Abstract]
18. Dores GM, Curtis RE, van Leeuwen FE, et al.: Pancreatic cancer risk after treatment of Hodgkin lymphoma. Ann Oncol 25 (10): 2073-9, 2014. [PUBMED Abstract]
19. 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]
20. 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]
21. Schaapveld M, Aleman BM, van Eggermond AM, et al.: Second Cancer Risk Up to 40 Years after Treatment for Hodgkin’s Lymphoma. N Engl J Med 373 (26): 2499-511, 2015. [PUBMED Abstract]
22. 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]
23. 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]
24. 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]
25. 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]
26. 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]
27. 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]
28. 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]
29. 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]
30. 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]
31. 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]
32. 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]
33. 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]
34. Cooke R, Jones ME, Cunningham D, et al.: Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors. Br J Cancer 108 (11): 2399-406, 2013. [PUBMED Abstract]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. 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]
41. Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin’s disease. N Engl J Med 322 (1): 7-13, 1990. [PUBMED Abstract]
42. 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]
43. 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]
44. 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]
45. 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]
46. 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]
47. 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.
48. 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]
49. 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]
50. 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]
51. 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]
52. 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]
53. 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]
54. 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]
55. van Nimwegen FA, Schaapveld M, Cutter DJ, et al.: Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma. J Clin Oncol 34 (3): 235-43, 2016. [PUBMED Abstract]
56. 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]
57. 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]
58. 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]
59. 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]
60. 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]
61. 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]
62. 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]
63. 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]
64. Behringer K, Goergen H, Müller H, et al.: Cancer-Related Fatigue in Patients With and Survivors of Hodgkin Lymphoma: The Impact on Treatment Outcome and Social Reintegration. J Clin Oncol 34 (36): 4329-4337, 2016. [PUBMED Abstract]
65. Ng AK: Current survivorship recommendations for patients with Hodgkin lymphoma: focus on late effects. Blood 124 (23): 3373-9, 2014. [PUBMED Abstract]
66. 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]
67. Evens AM, Hong F: How can outcomes be improved for older patients with Hodgkin lymphoma? J Clin Oncol 31 (12): 1502-5, 2013. [PUBMED Abstract]
68. Kolstad A, Nome O, Delabie J, et al.: Standard CHOP-21 as first line therapy for elderly patients with Hodgkin’s lymphoma. Leuk Lymphoma 48 (3): 570-6, 2007. [PUBMED Abstract]
69. Forero-Torres A, Holkova B, Goldschmidt J, et al.: Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood 126 (26): 2798-804, 2015. [PUBMED Abstract]
70. Hoppe RT, Advani RH, Ai WZ, et al.: Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines. J Natl Compr Canc Netw 10 (5): 589-97, 2012. [PUBMED Abstract]
71. Ng A, Constine LS, Advani R, et al.: ACR Appropriateness Criteria: follow-up of Hodgkin’s lymphoma. Curr Probl Cancer 34 (3): 211-27, 2010 May-Jun. [PUBMED Abstract]
72. Armitage JO: Who benefits from surveillance imaging? J Clin Oncol 30 (21): 2579-80, 2012. [PUBMED Abstract]
73. Picardi M, Pugliese N, Cirillo M, et al.: Advanced-stage Hodgkin lymphoma: US/chest radiography for detection of relapse in patients in first complete remission–a randomized trial of routine surveillance imaging procedures. Radiology 272 (1): 262-74, 2014. [PUBMED Abstract]

Drug combinations described in this section include the following:

Patients are designated as having early favorable Hodgkin lymphoma (HL) if they have clinical stage I or stage II disease and no adverse risk factors. Adverse risk factors include the following:

Historically, radiation therapy alone had been the primary treatment for patients with early favorable HL, often after confirmatory negative staging laparotomy. A randomized, prospective trial involving 542 patients with early favorable HL compared MOPP-ABV for three cycles plus involved-field radiation therapy (IF-XRT) with subtotal nodal radiation; with a median follow-up of 7.7 years, combined modality was favored in terms of 5-year event-free survival (98% vs. 74%, P < .001) and 10-year overall survival (OS) (97% vs. 92%, P = .001).[1][Level of evidence: 1iiA] The late mortality from solid tumors, especially in the lung, breast, gastrointestinal tract, and connective tissue, and from cardiovascular disease makes radiation therapy a less attractive option for the best-risk patients, who have the highest probability of cure and long-term survival.[2–6] Recent clinical trials have focused on regimens with chemotherapy and IF-XRT or with chemotherapy alone.[7]

A randomized, prospective trial from the National Cancer Institute of Canada involving 123 patients with early favorable HL compared ABVD for four to six cycles with subtotal nodal radiation; with a median follow-up of 11.3 years, no difference was observed in event-free survival (89% vs. 86%; P = .64) or in OS (98% vs. 98%; P = 0.95).[8][Level of evidence: 1iiA]

In a randomized study from the Milan Cancer Institute of patients with clinical early-stage HL, 4 months of ABVD followed by either IF-XRT or extended-field radiation therapy (EF-XRT) showed similar OS and freedom-from-progression with a 10-year median follow-up, but the study had inadequate statistical power to determine noninferiority of IF-XRT versus EF-XRT.[9][Level of evidence: 1iiDii]

The German Hodgkin Lymphoma Study Group (GHSG) randomly assigned 1,190 patients with early favorable HL to the following:

With a 7.6-year median follow-up, no differences were observed in freedom-from-progression (97%) or OS (98%) for all four groups.[10][Level of evidence: 1iiA]

The GHSG study (HD 13) compared reduced chemotherapy schedules while maintaining IF-XRT at 30 Gy: two cycles of ABVD, two cycles of ABV, two cycles of AVD, or two cycles of AV among 1,502 patients. After 5 years, freedom from treatment failure was significantly worse when dacarbazine, bleomycin, or both were omitted. This trial suggests that ABVD remains the standard therapy when given in four doses with radiation therapy for early-stage favorable disease.[11].

A specialized approach to therapy can be taken when patients with nonbulky lymphocyte–predominant disease presenting in unilateral high neck (above the thyroid notch) or epitrochlear locations require only IF-XRT after clinical staging.[12] A retrospective report of 426 cases of lymphocyte-predominant HL (including the so-called nodular lymphocyte–predominant and lymphocyte-rich classical subtypes) showed that more patients died of treatment-related toxicity (both acute and long term) than from recurrence of HL.[13][Level of evidence: 3iiiA] Limitation of radiation dose and radiation fields and avoidance of leukemogenic chemotherapeutic agents, along with watchful waiting policies, should be investigated for these subgroups.[14] Patients with nonbulky nodular sclerosing disease presenting in the anterior mediastinum only after clinical staging also do well with mantle radiation alone.[15]

Treatment options include the following:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Fermé C, Eghbali H, Meerwaldt JH, et al.: Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 357 (19): 1916-27, 2007. [PUBMED Abstract]
2. 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]
3. 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]
4. Longo DL: Radiation therapy in Hodgkin disease: why risk a Pyrrhic victory? J Natl Cancer Inst 97 (19): 1394-5, 2005. [PUBMED Abstract]
5. 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]
6. Engert A, Franklin J, Eich HT, et al.: Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: final results of the GHSG HD7 trial. J Clin Oncol 25 (23): 3495-502, 2007. [PUBMED Abstract]
7. Canellos GP, Abramson JS, Fisher DC, et al.: Treatment of favorable, limited-stage Hodgkin’s lymphoma with chemotherapy without consolidation by radiation therapy. J Clin Oncol 28 (9): 1611-5, 2010. [PUBMED Abstract]
8. Meyer RM, Gospodarowicz MK, Connors JM, et al.: ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 366 (5): 399-408, 2012. [PUBMED Abstract]
9. Bonadonna G, Bonfante V, Viviani S, et al.: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol 22 (14): 2835-41, 2004. [PUBMED Abstract]
10. Engert A, Plütschow A, Eich HT, et al.: Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363 (7): 640-52, 2010. [PUBMED Abstract]
11. Behringer K, Goergen H, Hitz F, et al.: Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet 385 (9976): 1418-27, 2015. [PUBMED Abstract]
12. Russell KJ, Hoppe RT, Colby TV, et al.: Lymphocyte predominant Hodgkin’s disease: clinical presentation and results of treatment. Radiother Oncol 1 (3): 197-205, 1984. [PUBMED Abstract]
13. 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]
14. Aster JC: Lymphocyte-predominant Hodgkin’s disease: how little therapy is enough? J Clin Oncol 17 (3): 744-6, 1999. [PUBMED Abstract]
15. Backstrand KH, Ng AK, Takvorian RW, et al.: Results of a prospective trial of mantle irradiation alone for selected patients with early-stage Hodgkin’s disease. J Clin Oncol 19 (3): 736-41, 2001. [PUBMED Abstract]
16. Landgren O, Axdorph U, Fears TR, et al.: A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients. Ann Oncol 17 (8): 1290-5, 2006. [PUBMED Abstract]

Drug combinations described in this section include the following:

Patients are designated as having early unfavorable Hodgkin lymphoma (HL) if they have clinical stage I or stage II disease and one or more of the following risk factors:

Patients with early unfavorable HL showed relapse rates greater than 30% at 5 years with radiation therapy alone, prompting evaluation of chemotherapy plus involved-field radiation therapy (IF-XRT) versus chemotherapy alone.[1] The late mortality from solid tumors, especially in the lung, breast, gastrointestinal tract, and connective tissue, and from cardiovascular disease makes radiation therapy a less attractive option unless therapeutic benefits exceed the long-term complications.[2–6]

A randomized, prospective trial from the National Cancer Institute of Canada (NCIC) involving 276 patients with early unfavorable HL compared ABVD for four to six cycles with ABVD for two cycles plus extended-field radiation therapy (EF-XRT); with a median follow-up of 11.3 years, the freedom-from-progression favored combined modality therapy (86% vs. 94%; P = .006), but the overall survival (OS) was better for ABVD alone (92% vs. 81%; P = .04).[7][Level of evidence: 1iiA] The trend toward a worse survival for the combined modality arm was attributed to excess secondary malignancies and cardiovascular deaths. In this trial, the extended-field radiation used higher doses and significantly larger exposure to body sites than are employed in current practice.

A randomized study from the Southwest Oncology Group of clinically staged patients (no laparotomy) compared subtotal lymphoid radiation with 3 months of AV followed by subtotal lymphoid radiation therapy; the combined modality arm showed superior failure-free survival (94% vs. 81%; P < .001) but not OS at 3.3 years’ median follow-up.[8][Level of evidence: 1iiDiii]

In a randomized study from the Milan Cancer Institute of patients with clinical early-stage HL, 4 months of ABVD followed by either IF-XRT or EF-XRT showed similar OS and freedom-from-progression with 10 years’ median follow-up, but the study had inadequate statistical power to determine noninferiority of IF-XRT versus EF-XRT.[9][Level of evidence: 1iiDii] Similarly, in a randomized study from the German Hodgkin Lymphoma Study Group (GHSG) of more than 1,000 patients with early unfavorable HL, 4 months of COPP plus ABVD followed by IF-XRT versus EF-XRT showed equivalent OS and freedom-from-treatment failure (FFTF) with 5 years’ median follow-up.[10][Level of evidence: 1iiA] Another randomized study of 996 patients with early unfavorable HL also showed no difference in OS and event-free survival at 10 years, comparing four to six cycles of MOPP-ABV plus IF-XRT versus the same chemotherapy plus subtotal nodal radiation therapy.[11][Level of evidence: 1iiA]

In the HD11 trial, the GHSG randomly assigned 1,395 patients with early unfavorable HL to the following:

With a 6.8 year median follow-up no differences were observed in OS (93%–96%) for all four groups.[12,13][Level of evidence: 1iiA] In the arms of the study with 30 Gy of IF-XRT, there was no difference in FFTF between BEACOPP and ABVD (P = .65), but a significant difference in favor of BEACOPP was seen for FFTF when 20 Gy of IF-XRT was used (P = .02).[13][Level of evidence: 1iiD]

In the HD14 trial, the GHSG randomly assigned 1,528 patients with early unfavorable HL to either four cycles of ABVD plus 30 Gy of IF-XRT or two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy of IF-XRT. With a median follow-up of 43 months, no difference was observed in OS.[14][Level of evidence: 1iiA]

A prospective, randomized trial from the European Organization for Research and Treatment of Cancer and Groupe d’Etudes de Lymphomes de L’Adulte of 808 patients with early unfavorable HL compared the following:

With a 64-month median follow-up, in a preliminary report in abstract form, no differences were observed in event-free survival (89%–92%; P = .38) or OS (91%–96%; P = .98).[15][Level of evidence: 1iiA]

In summary, these randomized trials support the use of ABVD for four cycles with 20 Gy to 30 Gy IF-XRT. Could the radiation therapy be omitted to minimize late morbidity and mortality from secondary solid tumors and from cardiovascular disease?[16] The NCIC study is the only trial to address this question in patients with early unfavorable HL; although four to six cycles of ABVD alone has improved OS compared with a combined modality approach, the use of EF-XRT in the combined modality arm is excessive by current standards, and late effects will be magnified with these larger fields.[7] In addition, chemotherapy alone was 8% worse in freedom-from-progression compared with the combined modality approach.

How can we balance an improvement in freedom-from-progression using radiation therapy with chemotherapy against late morbidity and mortality from late effects?[16,17] Randomized studies with or without IF-XRT would be required, but no such studies are currently under way.[16] An indirect comparison for using ABVD alone is that the 94% OS seen for early unfavorable patients in the NCIC study [7] at 11 years is equivalent to the survival seen in the GHSG’s HD6 [NCT00002561], ™HD10 [NCT01399931], and HD11 trials using combined modality therapy at 11 years.[18] A Cochrane meta-analysis of 1,245 patients in five randomized, clinical trials suggested improved survival for combined modality therapy versus chemotherapy alone (HR, 0.40; 95% CI, 0.27–0.61).[19] However, the NCIC study does demonstrate a 92% OS for ABVD alone at a median follow-up of 11.3 years. This would support the use of ABVD for patients with early unfavorable disease. Long-term follow-up, which would account for late toxicities and deaths from combined modality therapy, will not be forthcoming from these trials.[19]

Patients with bulky disease (≥10 cm) or massive mediastinal involvement were excluded from most of the aforementioned trials. Based on historical comparisons to chemotherapy or radiation therapy alone, these patients currently receive combined modality therapy.[20–22][Level of evidence: 3iiiDiii]

Treatment options include the following:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Tubiana M, Henry-Amar M, Carde P, et al.: Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin’s disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987. Blood 73 (1): 47-56, 1989. [PUBMED Abstract]
2. 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]
3. 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]
4. Longo DL: Radiation therapy in Hodgkin disease: why risk a Pyrrhic victory? J Natl Cancer Inst 97 (19): 1394-5, 2005. [PUBMED Abstract]
5. 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]
6. Engert A, Franklin J, Eich HT, et al.: Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: final results of the GHSG HD7 trial. J Clin Oncol 25 (23): 3495-502, 2007. [PUBMED Abstract]
7. Meyer RM, Gospodarowicz MK, Connors JM, et al.: ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 366 (5): 399-408, 2012. [PUBMED Abstract]
8. Press OW, LeBlanc M, Lichter AS, et al.: Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin’s disease. J Clin Oncol 19 (22): 4238-44, 2001. [PUBMED Abstract]
9. Bonadonna G, Bonfante V, Viviani S, et al.: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol 22 (14): 2835-41, 2004. [PUBMED Abstract]
10. Engert A, Schiller P, Josting A, et al.: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 21 (19): 3601-8, 2003. [PUBMED Abstract]
11. Fermé C, Eghbali H, Meerwaldt JH, et al.: Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 357 (19): 1916-27, 2007. [PUBMED Abstract]
12. Diehl V, Brillant C, Engert A, et al.: Recent interim analysis of the HD11 trial of the GHSG: intensification of chemotherapy and reduction of radiation dose in early unfavorable stage Hodgkin’s lymphoma. [Abstract] Blood 106 (11): A-816, 2005.
13. Eich HT, Diehl V, Görgen H, et al.: Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 28 (27): 4199-206, 2010. [PUBMED Abstract]
14. von Tresckow B, Plütschow A, Fuchs M, et al.: Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German hodgkin study group HD14 trial. J Clin Oncol 30 (9): 907-13, 2012. [PUBMED Abstract]
15. Noordijk EM, Thomas J, Fermé C, et al.: First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin’s lymphoma (HL) . [Abstract] J Clin Oncol 23 (Suppl 16): A-6505, 561s, 2005.
16. Canellos GP, Abramson JS, Fisher DC, et al.: Treatment of favorable, limited-stage Hodgkin’s lymphoma with chemotherapy without consolidation by radiation therapy. J Clin Oncol 28 (9): 1611-5, 2010. [PUBMED Abstract]
17. Bar Ad V, Paltiel O, Glatstein E: Radiotherapy for early-stage Hodgkin’s lymphoma: a 21st century perspective and review of multiple randomized clinical trials. Int J Radiat Oncol Biol Phys 72 (5): 1472-9, 2008. [PUBMED Abstract]
18. Meyer RM, Hoppe RT: Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy. Blood 120 (23): 4488-95, 2012. [PUBMED Abstract]
19. Herbst C, Rehan FA, Skoetz N, et al.: Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma. Cochrane Database Syst Rev (2): CD007110, 2011. [PUBMED Abstract]
20. Longo DL, Glatstein E, Duffey PL, et al.: Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin’s disease. J Clin Oncol 15 (11): 3338-46, 1997. [PUBMED Abstract]
21. Horning SJ, Hoppe RT, Breslin S, et al.: Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 20 (3): 630-7, 2002. [PUBMED Abstract]
22. Advani RH, Hong F, Fisher RI, et al.: Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial. J Clin Oncol 33 (17): 1936-42, 2015. [PUBMED Abstract]

Drug combinations described in this section include the following:

In multiple prospective trials and a meta-analysis, ABVD therapy for 6 to 8 months remains the standard of care for patients with advanced Hodgkin lymphoma (HL), with equivalent overall survival (OS) when compared with other regimens (i.e., BEACOPP, escalated BEACOPP, Stanford V, and MOPP-ABV).[1–8][Level of evidence: 1iiA]

Three prospective, randomized trials did not show a benefit in OS from the addition of consolidative radiation therapy to chemotherapy for patients with advanced-stage disease.[9–11][Level of evidence: 1iiA] In a meta-analysis of 1,740 patients treated on 14 different trials, no improvement was observed in 10-years’ OS for patients with advanced-stage HL who received combined modality therapy versus chemotherapy alone.[12][Level of evidence: 3iiiA] The German Hodgkin Lymphoma Study Group HD15 trial showed that a negative positive–emission tomographic (PET) scan after BEACOPP induction therapy was highly predictive for a good outcome even with omission of consolidative radiation therapy (negative predictive value for PET was 94% [95% confidence interval, 91%–97%]).[13] No survival advantage is known for the use of radiation consolidation for patients with massive mediastinal disease and advanced stage disease, though differences exist in sites of first relapse.[14]

Treatment options include the following:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Canellos GP, Niedzwiecki D: Long-term follow-up of Hodgkin’s disease trial. N Engl J Med 346 (18): 1417-8, 2002. [PUBMED Abstract]
2. 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. [PUBMED Abstract]
3. 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. [PUBMED Abstract]
4. 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. [PUBMED Abstract]
5. Bauer K, Skoetz N, Monsef I, et al.: Comparison of chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for patients with early unfavourable or advanced stage Hodgkin lymphoma. Cochrane Database Syst Rev (8): CD007941, 2011. [PUBMED Abstract]
6. Chisesi T, Bellei M, Luminari S, et al.: Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin’s lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol 29 (32): 4227-33, 2011. [PUBMED Abstract]
7. Carde P, Karrasch M, Fortpied C, et al.: Eight Cycles of ABVD Versus Four Cycles of BEACOPPescalated Plus Four Cycles of BEACOPPbaseline in Stage III to IV, International Prognostic Score ≥ 3, High-Risk Hodgkin Lymphoma: First Results of the Phase III EORTC 20012 Intergroup Trial. J Clin Oncol 34 (17): 2028-36, 2016. [PUBMED Abstract]
8. Mounier N, Brice P, Bologna S, et al.: ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥ 4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol 25 (8): 1622-8, 2014. [PUBMED Abstract]
9. 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. [PUBMED Abstract]
10. 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. [PUBMED Abstract]
11. 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. [PUBMED Abstract]
12. 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. [PUBMED Abstract]
13. 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]
14. 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. [PUBMED Abstract]

Recommendations for posttreatment follow-up are not evidence based, but a variety of opinions have been published for high-risk patients who present with advanced-stage disease or for patients who achieve less-than-complete remission by positron emission tomography–computed tomography (PET-CT) scans at the end of therapy.[1–4] For patients with a negative PET-CT scan at the end of therapy, routine scans are not advised; opportunistic scanning is applied when patients present with suspicious symptoms, physical findings, or laboratory tests.

Among 6,840 patients enrolled in German Hodgkin Study Group trials, with a median follow-up of 10.3 years, 141 patients relapsed after 5 years, compared with 466 patients who relapsed within 5 years.[5] Treatment-related adverse effects and late relapses may occur even beyond 20 years of follow-up.[5]

Patients who experience a relapse after initial wide-field, high-dose radiation therapy have a good prognosis. Combination chemotherapy results in 10-year disease-free survival (DFS) and overall survival (OS) rates of 57% to 81% and 57% to 89%, respectively.[6–9] For patients who experience a relapse after initial combination chemotherapy, prognosis is determined more by the duration of the first remission than by the specific induction or salvage combination chemotherapy regimen. Patients whose initial remission after chemotherapy was longer than 1 year (late relapse) have long-term survival with salvage chemotherapy of 22% to 71%.[9–14] Patients whose initial remission after chemotherapy was shorter than 1 year (early relapse) do much worse and have long-term survival rates of 11% to 46%.[9,13,15]

Because of CD30 expression on malignant Reed-Sternberg cells of Hodgkin Lymphoma (HL), but limited expression on normal cells, CD30 is a target for therapy. Brentuximab vedotin is a chimeric antibody directed against CD30, which is linked to the microtubule-disrupting agent, monomethyl auristatin E.[16–18] For relapsing patients, response rates around 75% are seen with complete remissions around 30% to 50% and median progression-free survival (PFS) of 4 to 8 months.[16–19][Level of evidence: 3iiiDiv] A series of 27 previously untreated patients older than 60 years, judged by the investigator to be in poor condition and unable to undergo chemotherapy, received brentuximab. A 92% overall response rate and 73% complete remission rate were reported.[20][Level of evidence: 3iiiDiv] Successful treatment with brentuximab for relapsed patients has been reported with a response rate of 60%.[21][Level of evidence: 3iiiDiv]

Patients who relapse after initial combination chemotherapy can undergo reinduction with the same or another chemotherapy regimen followed by high-dose chemotherapy and autologous bone marrow or peripheral stem cell or allogeneic bone marrow rescue.[22–26] This therapy has resulted in a 3- to 4-year DFS rate of 27% to 48%. Patients who are responsive to reinduction chemotherapy may have a better prognosis. In a retrospective review of 105 patients, those older than 60 years fared better with a combination of chemotherapy and salvage radiation therapy than with the use of intensified transplant consolidation.[27][Level of evidence: 3iiiDiv]

Two randomized trials have compared aggressive conventional chemotherapy versus high-dose chemotherapy with autologous hematopoietic stem cell transplantation for relapsed chemosensitive HL. Both trials show improvement in freedom from treatment failure at 3 years for the transplantation arm (75% vs. 45% and 55% vs. 34%, respectively); but no difference was observed in OS.[28,29][Level of evidence: 1iiDii] A Cochrane meta-analysis also concluded that autologous stem cell transplantation after reinduction chemotherapy improves relapse-free survival by 20% to 30% over chemotherapy alone but without an OS benefit.[30][Level of evidence: 1iiDii]

In two retrospective reviews of patients who underwent autologous bone marrow transplantation (ABMT) for relapsed or refractory disease, a comparison was made of those who received involved-field radiation therapy (IF-XRT) for residual masses after high-dose therapy versus no further treatment.[31,32] Those who received IF-XRT had improved PFS. Normalization of fluorine F 18-fludeoxyglucose PET-CT scans after reinduction therapy predicted a much better outcome after stem cell transplantation, with an event-free survival rate of 80% versus 29% in one phase II trial.[33][Level of evidence: 3iiiDi]

For 329 patients at high risk of residual HL after stem cell transplant, the double-blind AETHERA trial [NCT01100502] evaluated brentuximab vedotin versus placebo; the median PFS of 42.9 months for the brentuximab group was better than the 24.1 months for the control group (hazard ratio, 0.57; 95% confidence interval [CI], 0.40–0.81; P = .0013).[34][Level of evidence: 1iDiii]

The use of human leukocyte antigen-matched sibling marrow (allogeneic transplantation) results in a lower relapse rate, but the benefit may be offset by increased toxic effects.[24,35,36] Reduced-intensity conditioning for allogeneic stem cell transplantation is also under clinical evaluation.[37–41]

The anti-PD1 monoclonal antibody nivolumab, one of the new immune checkpoint inhibitors, has shown an overall response rate of 65% to 87% and a complete response rate of 16% to 28%, with durations usually exceeding 1 year for heavily pretreated, relapsed patients.[42–44][Level of evidence: 3iiiDiv]

A phase II trial reported a response rate higher than 50% for bendamustine in relapsing patients.[45][Level of evidence: 3iiiDiv] For patients with recurrent disease after ABMT, weekly vinblastine therapy has provided palliation with minimal toxic effects.[46][Level of evidence: 3iiiDiv]

For the small subgroup of patients with only limited nodal recurrence following initial chemotherapy, radiation therapy with or without additional chemotherapy may provide long-term survival for about 50% of these highly selected patients.[47,48]

Patients who do not respond to induction chemotherapy (about 10%–20% of all presenting patients) have less than a 10% survival rate at 8 years.[13] For these patients, high-dose chemotherapy and autologous bone marrow or peripheral stem cell or allogeneic bone marrow rescue are under clinical evaluation.[24,25,49–55] These trials have resulted in a 3- to 5-year DFS rate of 17% to 48%.[22–25,54]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Hoppe RT, Advani RH, Ai WZ, et al.: Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines. J Natl Compr Canc Netw 10 (5): 589-97, 2012. [PUBMED Abstract]
2. Ng A, Constine LS, Advani R, et al.: ACR Appropriateness Criteria: follow-up of Hodgkin’s lymphoma. Curr Probl Cancer 34 (3): 211-27, 2010 May-Jun. [PUBMED Abstract]
3. Armitage JO: Who benefits from surveillance imaging? J Clin Oncol 30 (21): 2579-80, 2012. [PUBMED Abstract]
4. Picardi M, Pugliese N, Cirillo M, et al.: Advanced-stage Hodgkin lymphoma: US/chest radiography for detection of relapse in patients in first complete remission–a randomized trial of routine surveillance imaging procedures. Radiology 272 (1): 262-74, 2014. [PUBMED Abstract]
5. Bröckelmann PJ, Goergen H, Kohnhorst C, et al.: Late Relapse of Classical Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group HD7 to HD12 Trials. J Clin Oncol 35 (13): 1444-1450, 2017. [PUBMED Abstract]
6. Ng AK, Li S, Neuberg D, et al.: Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin’s disease. Ann Oncol 15 (2): 270-5, 2004. [PUBMED Abstract]
7. Specht L, Horwich A, Ashley S: Salvage of relapse of patients with Hodgkin’s disease in clinical stages I or II who were staged with laparotomy and initially treated with radiotherapy alone. A report from the international database on Hodgkin’s disease. Int J Radiat Oncol Biol Phys 30 (4): 805-11, 1994. [PUBMED Abstract]
8. Horwich A, Specht L, Ashley S: Survival analysis of patients with clinical stages I or II Hodgkin’s disease who have relapsed after initial treatment with radiotherapy alone. Eur J Cancer 33 (6): 848-53, 1997. [PUBMED Abstract]
9. Josting A, Franklin J, May M, et al.: New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the German Hodgkin’s lymphoma study group. J Clin Oncol 20 (1): 221-30, 2002. [PUBMED Abstract]
10. Harker WG, Kushlan P, Rosenberg SA: Combination chemotherapy for advanced Hodgkin’s disease after failure of MOPP: ABVD and B-CAVe. Ann Intern Med 101 (4): 440-6, 1984. [PUBMED Abstract]
11. Tourani JM, Levy R, Colonna P, et al.: High-dose salvage chemotherapy without bone marrow transplantation for adult patients with refractory Hodgkin’s disease. J Clin Oncol 10 (7): 1086-94, 1992. [PUBMED Abstract]
12. Canellos GP, Petroni GR, Barcos M, et al.: Etoposide, vinblastine, and doxorubicin: an active regimen for the treatment of Hodgkin’s disease in relapse following MOPP. Cancer and Leukemia Group B. J Clin Oncol 13 (8): 2005-11, 1995. [PUBMED Abstract]
13. Bonfante V, Santoro A, Viviani S, et al.: Outcome of patients with Hodgkin’s disease failing after primary MOPP-ABVD. J Clin Oncol 15 (2): 528-34, 1997. [PUBMED Abstract]
14. Garcia-Carbonero R, Paz-Ares L, Arcediano A, et al.: Favorable prognosis after late relapse of Hodgkin’s disease. Cancer 83 (3): 560-5, 1998. [PUBMED Abstract]
15. Longo DL, Duffey PL, Young RC, et al.: Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. J Clin Oncol 10 (2): 210-8, 1992. [PUBMED Abstract]
16. Gopal AK, Ramchandren R, O’Connor OA, et al.: Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood 120 (3): 560-8, 2012. [PUBMED Abstract]
17. Younes A, Bartlett NL, Leonard JP, et al.: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363 (19): 1812-21, 2010. [PUBMED Abstract]
18. Younes A, Gopal AK, Smith SE, et al.: Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30 (18): 2183-9, 2012. [PUBMED Abstract]
19. Chen R, Palmer JM, Thomas SH, et al.: Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma. Blood 119 (26): 6379-81, 2012. [PUBMED Abstract]
20. Forero-Torres A, Holkova B, Goldschmidt J, et al.: Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood 126 (26): 2798-804, 2015. [PUBMED Abstract]
21. Bartlett NL, Chen R, Fanale MA, et al.: Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol 7: 24, 2014. [PUBMED Abstract]
22. 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. [PUBMED Abstract]
23. Horning SJ, Chao NJ, Negrin RS, et al.: High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indices. Blood 89 (3): 801-13, 1997. [PUBMED Abstract]
24. Akpek G, Ambinder RF, Piantadosi S, et al.: Long-term results of blood and marrow transplantation for Hodgkin’s lymphoma. J Clin Oncol 19 (23): 4314-21, 2001. [PUBMED Abstract]
25. Tarella C, Cuttica A, Vitolo U, et al.: High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence. Cancer 97 (11): 2748-59, 2003. [PUBMED Abstract]
26. Holmberg L, Maloney DG: The role of autologous and allogeneic hematopoietic stem cell transplantation for Hodgkin lymphoma. J Natl Compr Canc Netw 9 (9): 1060-71, 2011. [PUBMED Abstract]
27. Böll B, Goergen H, Arndt N, et al.: Relapsed hodgkin lymphoma in older patients: a comprehensive analysis from the German hodgkin study group. J Clin Oncol 31 (35): 4431-7, 2013. [PUBMED Abstract]
28. Linch DC, Winfield D, Goldstone AH, et al.: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 341 (8852): 1051-4, 1993. [PUBMED Abstract]
29. Schmitz N, Pfistner B, Sextro M, et al.: Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet 359 (9323): 2065-71, 2002. [PUBMED Abstract]
30. Rancea M, Monsef I, von Tresckow B, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev 6: CD009411, 2013. [PUBMED Abstract]
31. Mundt AJ, Sibley G, Williams S, et al.: Patterns of failure following high-dose chemotherapy and autologous bone marrow transplantation with involved field radiotherapy for relapsed/refractory Hodgkin’s disease. Int J Radiat Oncol Biol Phys 33 (2): 261-70, 1995. [PUBMED Abstract]
32. Poen JC, Hoppe RT, Horning SJ: High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin’s disease: the impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys 36 (1): 3-12, 1996. [PUBMED Abstract]
33. Moskowitz CH, Matasar MJ, Zelenetz AD, et al.: Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood 119 (7): 1665-70, 2012. [PUBMED Abstract]
34. Moskowitz CH, Nademanee A, Masszi T, et al.: Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 385 (9980): 1853-62, 2015. [PUBMED Abstract]
35. Milpied N, Fielding AK, Pearce RM, et al.: Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin’s disease. European Group for Blood and Bone Marrow Transplantation. J Clin Oncol 14 (4): 1291-6, 1996. [PUBMED Abstract]
36. Gajewski JL, Phillips GL, Sobocinski KA, et al.: Bone marrow transplants from HLA-identical siblings in advanced Hodgkin’s disease. J Clin Oncol 14 (2): 572-8, 1996. [PUBMED Abstract]
37. Sureda A, Robinson S, Canals C, et al.: Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 26 (3): 455-62, 2008. [PUBMED Abstract]
38. Thomson KJ, Peggs KS, Smith P, et al.: Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin’s lymphoma following autologous stem cell transplantation. Bone Marrow Transplant 41 (9): 765-70, 2008. [PUBMED Abstract]
39. Sarina B, Castagna L, Farina L, et al.: Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood 115 (18): 3671-7, 2010. [PUBMED Abstract]
40. Kuruvilla J, Pintilie M, Stewart D, et al.: Outcomes of reduced-intensity conditioning allo-SCT for Hodgkin’s lymphoma: a national review by the Canadian Blood and Marrow Transplant Group. Bone Marrow Transplant 45 (7): 1253-5, 2010. [PUBMED Abstract]
41. Peggs KS, Kayani I, Edwards N, et al.: Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for Hodgkin’s lymphoma. J Clin Oncol 29 (8): 971-8, 2011. [PUBMED Abstract]
42. Ansell SM, Lesokhin AM, Borrello I, et al.: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372 (4): 311-9, 2015. [PUBMED Abstract]
43. Younes A, Santoro A, Shipp M, et al.: Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17 (9): 1283-94, 2016. [PUBMED Abstract]
44. Armand P, Shipp MA, Ribrag V, et al.: Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol 34 (31): 3733-3739, 2016. [PUBMED Abstract]
45. Moskowitz AJ, Hamlin PA Jr, Perales MA, et al.: Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 31 (4): 456-60, 2013. [PUBMED Abstract]
46. Little R, Wittes RE, Longo DL, et al.: Vinblastine for recurrent Hodgkin’s disease following autologous bone marrow transplant. J Clin Oncol 16 (2): 584-8, 1998. [PUBMED Abstract]
47. Uematsu M, Tarbell NJ, Silver B, et al.: Wide-field radiation therapy with or without chemotherapy for patients with Hodgkin disease in relapse after initial combination chemotherapy. Cancer 72 (1): 207-12, 1993. [PUBMED Abstract]
48. Josting A, Nogová L, Franklin J, et al.: Salvage radiotherapy in patients with relapsed and refractory Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin Lymphoma Study Group. J Clin Oncol 23 (7): 1522-9, 2005. [PUBMED Abstract]
49. Marshall NA, DeVita VT Jr: Hodgkin’s disease and transplantation: a room with a (nontransplanter’s) view. Semin Oncol 26 (1): 67-73, 1999. [PUBMED Abstract]
50. Lazarus HM, Rowlings PA, Zhang MJ, et al.: Autotransplants for Hodgkin’s disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 17 (2): 534-45, 1999. [PUBMED Abstract]
51. Fermé C, Mounier N, Diviné M, et al.: Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the Groupe d’Etudes des Lymphomes de l’Adulte H89 Trial. J Clin Oncol 20 (2): 467-75, 2002. [PUBMED Abstract]
52. Sweetenham JW, Carella AM, Taghipour G, et al.: High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin’s disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation. Lymphoma Working Party. J Clin Oncol 17 (10): 3101-9, 1999. [PUBMED Abstract]
53. Laurence AD, Goldstone AH: High-dose therapy with hematopoietic transplantation for Hodgkin’s lymphoma. Semin Hematol 36 (3): 303-12, 1999. [PUBMED Abstract]
54. Gopal AK, Metcalfe TL, Gooley TA, et al.: High-dose therapy and autologous stem cell transplantation for chemoresistant Hodgkin lymphoma: the Seattle experience. Cancer 113 (6): 1344-50, 2008. [PUBMED Abstract]
55. Morschhauser F, Brice P, Fermé C, et al.: Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin’s lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol 26 (36): 5980-7, 2008. [PUBMED Abstract]

Introduction

Because Hodgkin lymphoma (HL) affects primarily young adults, most oncologists will eventually face the dilemma of how to provide therapy to a pregnant woman while minimizing the risk to the fetus. Treatment choice must be individualized, taking into consideration the mother’s wishes, the severity and pace of the HL, and the length of the remaining pregnancy. Since general guidelines can never substitute for clinical judgment, oncologists should be prepared to alter the initial plans when necessary.

Stage Information for HL During Pregnancy

To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[1] The presenting stage, clinical behavior, prognosis, and histologic subtypes of HL during pregnancy do not differ from those of nonpregnant women during their childbearing years.[2] (Refer to the Stage Information for Adult Hodgkin Lymphoma (HL) section of this summary for more information.)

Treatment Option Overview for HL During Pregnancy

HL that is diagnosed in the first trimester of pregnancy does not constitute an absolute indication for therapeutic abortion. Each patient must be looked at individually to take into account the stage and rapidity of growth of the lymphoma and the patient’s wishes.[3] If the HL presents in early stage above the diaphragm and appears to be growing slowly, patients can be followed carefully with plans to induce delivery early and proceed with definitive therapy.[4] Alternatively, these patients can receive radiation therapy with proper shielding.[5–8] Investigators at MD Anderson Cancer Center reported no congenital abnormalities in 16 babies delivered after the mothers had received supradiaphragmatic radiation while shielding the uterus with five half-value layers of lead.[9] Because of theoretical risks that the fetus might develop future malignancies from even minimal scattered radiation doses outside the radiation field, radiation therapy should be postponed, if possible, until after delivery.[10]

Chemotherapy that is administered in the first trimester has been associated with congenital abnormalities in as many as 33% of infants.[11,12] However, in one series, there were no adverse effects in 14 children of mothers who received a combination of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) during gestation, five of whom began treatment during the first trimester.[13] Consequently, some women may opt to continue the pregnancy and agree to radiation therapy or chemotherapy if immediate treatment is required.

In the second half of pregnancy, most patients can be followed carefully and can postpone therapy until induction of delivery at 32 to 36 weeks.[11,14,15] If chemotherapy is mandatory before delivery, such as for patients with symptomatic advanced stage disease, vinblastine alone (given at 6 mg/m² IV q 2 wk until induction of delivery) may be considered because it has never been associated with fetal abnormalities in the second half of pregnancy.[14,15] Steroids are employed both for their antitumor effect and for hastening fetal pulmonary maturity. As an alternative, a short course of radiation therapy can be used before delivery in cases of respiratory compromise caused by the rapidly enlarging mediastinal mass. Combination chemotherapy with ABVD appears to be safe in the second half of pregnancy.[13] If chemotherapy is required after the first trimester, many clinicians prefer the combination of drugs over single-agent drugs or radiation therapy.

A multicenter retrospective analysis of 40 patients described pregnancy termination in 3 patients, deferral of therapy to postpartum in 13 patients (median 30 wk gestation), and antenatal therapy applied to the remaining 24 patients (median 21 wk gestation, all done after the first trimester).[16] With a median follow-up of 41 months, the 3-year progression-free survival (PFS) was 85%, and the overall survival (OS) was 97%, often using ABVD.[16][Level of evidence: 3iiiDiv]

A retrospective analysis from MD Anderson of 39 patients described pregnancy termination in 3 patients, deferral of therapy to the postpartum period in 12 patients, and antenatal therapy in 24 patients.[17] Two women miscarried after receiving doxorubicin-based chemotherapy in the first trimester. With a median follow-up of 68 months from diagnosis, the 5-year rate of PFS was 75%, and the OS rate was 82%. These rates did not differ between the antenatal and postpartum timing of therapy.[17][Level of evidence: 3iiiDiv]

In one study, the 20-year survival rate of pregnant women with HL did not differ from the 20-year survival rate of nonpregnant women who were matched for similar stage of disease, age at diagnosis, and calendric year of treatment.[18] The long-term effects on progeny after chemotherapy in utero are unknown, though present evidence tends to be reassuring.[12–15,18] There is no evidence that a pregnancy after completion of therapy increases the relapse rate for patients in remission.[19]

References

1. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000. [PUBMED Abstract]
2. Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996. [PUBMED Abstract]
3. Koren G, Weiner L, Lishner M, et al.: Cancer in pregnancy: identification of unanswered questions on maternal and fetal risks. Obstet Gynecol Surv 45 (8): 509-14, 1990. [PUBMED Abstract]
4. Anselmo AP, Cavalieri E, Enrici RM, et al.: Hodgkin’s disease during pregnancy: diagnostic and therapeutic management. Fetal Diagn Ther 14 (2): 102-5, 1999 Mar-Apr. [PUBMED Abstract]
5. Mazonakis M, Varveris H, Fasoulaki M, et al.: Radiotherapy of Hodgkin’s disease in early pregnancy: embryo dose measurements. Radiother Oncol 66 (3): 333-9, 2003. [PUBMED Abstract]
6. Greskovich JF Jr, Macklis RM: Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol 27 (6): 633-45, 2000. [PUBMED Abstract]
7. Fisher PM, Hancock BW: Hodgkin’s disease in the pregnant patient. Br J Hosp Med 56 (10): 529-32, 1996 Nov 20-Dec 10. [PUBMED Abstract]
8. Friedman E, Jones GW: Fetal outcome after maternal radiation treatment of supradiaphragmatic Hodgkin’s disease. CMAJ 149 (9): 1281-3, 1993. [PUBMED Abstract]
9. Woo SY, Fuller LM, Cundiff JH, et al.: Radiotherapy during pregnancy for clinical stages IA-IIA Hodgkin’s disease. Int J Radiat Oncol Biol Phys 23 (2): 407-12, 1992. [PUBMED Abstract]
10. Lishner M: Cancer in pregnancy. Ann Oncol 14 (Suppl 3): iii31-6, 2003. [PUBMED Abstract]
11. Cardonick E, Iacobucci A: Use of chemotherapy during human pregnancy. Lancet Oncol 5 (5): 283-91, 2004. [PUBMED Abstract]
12. Thomas PR, Biochem D, Peckham MJ: The investigation and management of Hodgkin’s disease in the pregnant patient. Cancer 38 (3): 1443-51, 1976. [PUBMED Abstract]
13. Avilés A, Díaz-Maqueo JC, Talavera A, et al.: Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. Am J Hematol 36 (4): 243-8, 1991. [PUBMED Abstract]
14. Jacobs C, Donaldson SS, Rosenberg SA, et al.: Management of the pregnant patient with Hodgkin’s disease. Ann Intern Med 95 (6): 669-75, 1981. [PUBMED Abstract]
15. Nisce LZ, Tome MA, He S, et al.: Management of coexisting Hodgkin’s disease and pregnancy. Am J Clin Oncol 9 (2): 146-51, 1986. [PUBMED Abstract]
16. Evens AM, Advani R, Press OW, et al.: Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 31 (32): 4132-9, 2013. [PUBMED Abstract]
17. Pinnix CC, Osborne EM, Chihara D, et al.: Maternal and Fetal Outcomes After Therapy for Hodgkin or Non-Hodgkin Lymphoma Diagnosed During Pregnancy. JAMA Oncol 2 (8): 1065-9, 2016. [PUBMED Abstract]
18. Lishner M, Zemlickis D, Degendorfer P, et al.: Maternal and foetal outcome following Hodgkin’s disease in pregnancy. Br J Cancer 65 (1): 114-7, 1992. [PUBMED Abstract]
19. Weibull CE, Eloranta S, Smedby KE, et al.: Pregnancy and the Risk of Relapse in Patients Diagnosed With Hodgkin Lymphoma. J Clin Oncol 34 (4): 337-44, 2016. [PUBMED Abstract]

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of adult Hodgkin lymphoma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for adult Hodgkin lymphoma. Listed after each reference are the sections within this summary where the reference is cited.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Adult Hodgkin Lymphoma (HL)

Updated statistics with estimated new cases and deaths for 2018 (cited American Cancer Society as reference 1.)

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® – NCI’s Comprehensive Cancer Database pages.