Adult Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

General Information About Adult Hodgkin Lymphoma (HL)

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] Over the last five decades, U.S. national mortality has fallen more rapidly for adult HL than for any other malignancy.[2]

Anatomy

ENLARGELymph system; drawing shows the lymph vessels and lymph organs including the lymph nodes, tonsils, thymus, spleen, and bone marrow.  One inset shows the inside structure of a lymph node and the attached lymph vessels with arrows showing how the lymph (clear fluid) moves into and out of the lymph node. Another inset shows a close up of bone marrow with blood cells.
Anatomy of the lymph system.

HL most frequently presents in lymph node groups above the diaphragm and/or in mediastinal lymph nodes. Involvement of Waldeyer’s ring or tonsillar lymph glands is rarely seen.

Risk Factors

Risk factors for adult HL include the following:

  • Being in early adulthood (aged 20–39 years) (most often) or late adulthood (aged 65 years and older) (a smaller increase).
  • Being male.
  • Having a previous infection with the Epstein-Barr virus in the teenage years or early childhood.
  • Having a first-degree relative with HL.

Clinical Features

These and other signs and symptoms may be caused by adult HL or by other conditions:

  • Painless, swollen lymph nodes in the neck, axilla, or inguinal area.
  • Fever defined as 38ºC or higher.
  • Drenching and recurrent night sweats.
  • Weight loss of 10% or more of baseline weight in the previous 6 months.
  • Pruritus, especially after bathing or after ingesting alcohol.
  • Fatigue.

Treatment of HL should relieve these symptoms within days. (Refer to the PDQ summaries on Hot Flashes and Night Sweats, Pruritus, and Fatigue for more information about managing these symptoms.)

Diagnostic Evaluation

Diagnostic evaluation of patients with lymphoma may include the following:

  1. Biopsy (preferably excisional), with interpretation by a qualified pathologist.
  2. History, with special attention given to the presence and duration of fever, night sweats, and unexplained weight loss of 10% or more of body weight in the previous 6 months.
  3. Physical examination.
  4. Laboratory tests.
    • Complete blood cell count and platelet count.
    • Erythrocyte sedimentation rate.
    • Chemistry panel (electrolytes, blood urea nitrogen, creatinine, calcium, aspartate transaminase, alanine aminotransferase, bilirubin, and alkaline phosphatase) plus lactate dehydrogenase, uric acid, and phosphorus.
  5. Radiographic examination
    • Computed tomography (CT) of the neck, chest, abdomen, and pelvis; or metabolic imaging (fluorine F 18-fludeoxyglucose positron emission tomography [PET]) with PET-CT.
  6. HIV testing.
  7. Hepatitis B and C serology.

All stages of adult HL can be subclassified into A and B categories: B for those with defined general symptoms (described below) and A for those without B symptoms. The B designation is given to patients with any of the following symptoms:

  • Unexplained weight loss (more than 10% of body weight in the 6 months before diagnosis).
  • Unexplained fever with temperatures above 38°C.
  • Drenching and recurrent night sweats.

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 classification system.

Prognostic Factors

The prognosis for a given patient depends on several factors. The most important factors are the following:[3-5]

  • Presence or absence of systemic B symptoms.
  • Stage of disease.
  • Presence of large masses.
  • Quality and suitability of the treatment administered.

Other important factors are:[3-5]

  • Age.
  • Sex.
  • Erythrocyte sedimentation rate.
  • Hematocrit.
  • Extent of abdominal involvement.
  • Absolute number of nodal sites of involvement.

Follow-up

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 PET-CT scans at the end of therapy.[6-9] For patients at high risk of relapse, conventional CT scans are employed for screening to avoid the increased false-positive test results and increased radiation exposure of serial PET-CT scans.[10]

For patients with negative findings from a PET-CT scan at the end of therapy, routine scans are not advised because of the very-low risk of recurrence.[11] Opportunistic scanning is applied when patients present with suspicious symptoms, physical findings, or laboratory test results.

Among 6,840 patients enrolled in German Hodgkin Study Group (GHSG) 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. Treatment-related adverse effects and late relapses may occur beyond 20 years of follow-up.[12]

Adverse Long-term Effects of Therapy

Patients who complete therapy for HL are at risk of developing long-term side effects, ranging from direct damage to organ function or the immune system to second malignancies. For the first 15 years after treatment, HL is the main cause of death. By 15 to 20 years after therapy, the cumulative mortality from a second malignancy, cardiovascular disease, or pulmonary fibrosis will exceed the cumulative mortality from HL.[13-16] This risk of developing a second malignancy is even higher for individuals with a family history of cancer.[17]

Second malignancies

Recommendations for screening for secondary malignancies or follow-up of long-term survivors are consensus based and not derived from randomized trials.[18]

Hematologic cancers:

  • Acute myelogenous leukemia (AML): Acute nonlymphocytic leukemia may occur in patients treated with combined-modality therapy or with combination chemotherapy alone, especially with increased exposure to alkylating agents.[19,20]
    • At 10 years after therapy with regimens containing MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), the risk of AML is approximately 3%, with the peak incidence occurring 5 to 9 years after therapy.[19,20] The risk of acute leukemia at 10 years after therapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) appears to be less than 1%.[21]
    • A population-based study of more than 35,000 survivors during a 30-year time span identified 217 patients who developed AML. The absolute excess risk (AER) was significantly higher for older patients (i.e., >35 years at diagnosis) than for younger survivors (AER, 9.9 vs. 4.2 per 10,000 patient years, P < .001).[22]
  • Non-Hodgkin lymphoma (NHL): The risk of NHL is also increased, but this risk is not clearly related to the type or extent of treatment.[23]
Solid tumors

An increase in second solid tumors has also been observed, especially mesothelioma and cancers of the lung, breast, thyroid, bone/soft tissue, stomach, esophagus, colon and rectum, uterine cervix, and head and neck.[19,23-30] These tumors occur primarily after radiation therapy or with combined-modality treatment, and approximately 75% occur within radiation ports. The risk of developing a second solid tumor (cumulative incidence of a second cancer) increases with time after treatment.

  • At 15-year follow-up, the risk is approximately 13%.[19,23]
  • At 20-year follow-up, the risk is approximately 17%.[31]
  • At 25-year follow-up, the risk is approximately 22%.[24,32]
  • At 40-year follow-up, the risk is approximately 48%.[33]

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 cancers for 10 to 25 years before the ages when routine screening would be recommended in the general population.[28] Even with involved-field doses of 15 Gy to 25 Gy, sarcomas, breast cancers, and thyroid cancers occurred with similar incidence in young patients compared with those receiving higher-dose radiation.[31]

Lung cancer and breast cancer are among the most-common second solid tumors that develop after therapy for HL.

  • Lung cancer: Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer increases with cigarette smoking.[34-37] 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.[38]
  • Breast cancer: Breast cancer is seen with increased frequency after radiation therapy or combined-modality therapy.[24,25,27,39-42] The risk appears greatest for females treated with radiation before age 30 years, especially for girls close to menarche. The incidence of breast cancer increases substantially after 15 years of posttherapy follow-up.[24,26,43-46]

    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.[47,48] 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 age at diagnosis. These cohort studies show a continued increase in cumulative excess risk of breast cancer beyond 20 years of follow-up.[47,48]

    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 did those treated with radiation therapy alone.[40,49] Reaching early menopause with fewer than 10 years of intact ovarian function appeared to account for the reduction in risk among patients who received combined-modality therapy.[49] Reduction of radiation volume also decreased the risk of breast cancer after HL.[49]

Several studies suggest that splenic-field radiation therapy and splenectomy increase the risk of a treatment-related second cancer.[50-52]

Late effects of autologous stem cell transplantation for failure of induction chemotherapy include second malignancies, hypothyroidism, hypogonadism, herpes zoster, depression, and cardiac disease.[53]

Other adverse long-term effects

Treatment for HL also affects the endocrine, cardiac, pulmonary, skeletal, and immune systems. Chronic fatigue can be a debilitating symptom for some long-term survivors.

Infertility: A toxic effect that is primarily related to chemotherapy is infertility, usually after regimens containing MOPP or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).[23,54-56] After six to eight cycles of BEACOPP, most men had testosterone levels within normal range; however, 82% of women younger than 30 years recovered menses (mostly within 12 months), but only 45% of women older than 30 years recovered menses.[57] ABVD appears to spare long-term testicular and ovarian function.[55,58,59]

Hypothyroidism: Hypothyroidism is a late complication primarily related to radiation therapy.[60-62] Long-term survivors who receive radiation therapy to the neck are followed up with annual thyroid-stimulating hormone testing.

Cardiac disease: A late complication primarily related to radiation therapy is cardiac disease, the risk of which may persist for 25 years after first treatment.[60,63-68] The AER 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).[63-65,67] In a cohort of 7,033 HL patients, MI mortality risk persisted for 25 years after first treatment with supradiaphragmatic radiation therapy (dependent on the details of treatment planning), doxorubicin, or vincristine.[67,68] The use of subcranial 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.[64] Compared with a normal-matched population, HL patients treated with mediastinal radiation have been reported to be at increased risk of complications, especially during cardiac surgery.[69]

Pulmonary impairment: 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.[70] Pulmonary toxic effects from bleomycin as used in ABVD are seen in patients older than 40 years.[71]

Bone necrosis: Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.[72]

Bacterial sepsis: Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL;[73] it is much more common in children than in adults.

Fatigue: Fatigue is a commonly reported symptom of patients who have completed chemotherapy and radiation therapy. 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. Quality-of-life questionnaires given to 5,306 patients on GHSG 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.[74,75] (Refer to the PDQ summary on Fatigue for more information about managing fatigue.)

Related Summaries

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

References
  1. American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available online. Last accessed August 3, 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. 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. 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]
  7. 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]
  8. Armitage JO: Who benefits from surveillance imaging? J Clin Oncol 30 (21): 2579-80, 2012. [PUBMED Abstract]
  9. 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]
  10. El-Galaly TC, Mylam KJ, Brown P, et al.: Positron emission tomography/computed tomography surveillance in patients with Hodgkin lymphoma in first remission has a low positive predictive value and high costs. Haematologica 97 (6): 931-6, 2012. [PUBMED Abstract]
  11. Hartridge-Lambert SK, Schöder H, Lim RC, et al.: ABVD alone and a PET scan complete remission negates the need for radiologic surveillance in early-stage, nonbulky Hodgkin lymphoma. Cancer 119 (6): 1203-9, 2013. [PUBMED Abstract]
  12. 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]
  13. 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]
  14. Aisenberg AC: Problems in Hodgkin’s disease management. Blood 93 (3): 761-79, 1999. [PUBMED Abstract]
  15. 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]
  16. 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]
  17. Sud A, Thomsen H, Sundquist K, et al.: Risk of Second Cancer in Hodgkin Lymphoma Survivors and Influence of Family History. J Clin Oncol 35 (14): 1584-1590, 2017. [PUBMED Abstract]
  18. Ng AK: Current survivorship recommendations for patients with Hodgkin lymphoma: focus on late effects. Blood 124 (23): 3373-9, 2014. [PUBMED Abstract]
  19. 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]
  20. 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]
  21. Valagussa P, Santoro A, Fossati-Bellani F, et al.: Second acute leukemia and other malignancies following treatment for Hodgkin’s disease. J Clin Oncol 4 (6): 830-7, 1986. [PUBMED Abstract]
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  37. 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]
  38. 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]
  39. 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]
  40. 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]
  41. 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]
  42. 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]
  43. 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]
  44. 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]
  45. 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]
  46. 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]
  47. 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]
  48. 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]
  49. 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]
  50. 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]
  51. 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]
  52. Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin’s disease. N Engl J Med 322 (1): 7-13, 1990. [PUBMED Abstract]
  53. 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]
  54. 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]
  55. 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]
  56. 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]
  57. 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]
  58. 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.
  59. 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]
  60. 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]
  61. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin’s disease. N Engl J Med 325 (9): 599-605, 1991. [PUBMED Abstract]
  62. Cella L, Conson M, Caterino M, et al.: Thyroid V30 predicts radiation-induced hypothyroidism in patients treated with sequential chemo-radiotherapy for Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 82 (5): 1802-8, 2012. [PUBMED Abstract]
  63. 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]
  64. 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]
  65. 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]
  66. 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]
  67. 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]
  68. 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]
  69. 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]
  70. 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]
  71. 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]
  72. 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]
  73. 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]
  74. 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]
  75. 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]