1. health and fitness
2. disease
3. cancer

27
Late Complications after
Treatment of Hodgkin’s Disease
HARRY QUON, MD
PAUL GLIEDMAN, MD
The treatment of Hodgkin’s disease (HD) has
improved significantly over the past 30 years. What
was once a near-fatal disease now is curable in 70 to
90 percent of cases.1 Success has been achieved
through clinical trials defining the optimal therapy
as well as through collaborative international
efforts2,3 identifying treatment prognostic factors
and risk factors for late complications. This refinement has permitted the more precise application of
risk-appropriate therapy as a strategy to combat the
increased risk of late complications while maintaining therapeutic efficacy. It is now apparent that the
treatment strategies of the past have contributed to
the majority of the late sequelae and the need for
therapeutic modifications.4 This review highlights
the risk factors contributing to the spectrum of late
complications (Tables 27–1 and 27–2, Figure 27–1)
faced by survivors of HD and the subsequent rationale underlying therapeutic modifications attempting to reduce these risks.
SECOND MALIGNANCIES
The major causes of late mortality, other than HDspecific mortality, are second malignancies and cardiac complications.4,5 Several institutional series4,6–10
and the International Database on Hodgkin’s Disease
(IDHD)11 provide data with sufficient follow-up
duration and statistical power to permit delineation
of the natural history and risk factors associated with
various competing causes of late mortality. With
follow-up longer than 15 to 19 years, the risk of mor442
tality from other causes, particularly second malignancies, begins to exceed that from HD (Figures
27–2 and 27–3).4,6,11 Hence, the study of late complications is particularly relevant. These efforts also
have demonstrated the significant latency in the
manifestation of many of these complications. As
such, recent therapeutic modifications will likely
require further long-term follow-up and evaluation to
accurately delineate their success and associated
risks for late complications.
Second malignancies may include leukemias,
non-Hodgkin’s lymphoma, and various solid
tumors.12–22 Second malignancies account for
approximately 20 percent of intercurrent deaths (see
Table 27–2).4,7 Of the solid malignancies, carcinomas of the lung and breast represent the majority of
the secondary malignancies. Therefore, screening
and appropriate therapeutic modifications have the
potential to alter significantly the cumulative risks
of late malignancies in survivors of HD.
Overall, the cumulative risk of secondary
leukemia in HD survivors is low, ranging from 1.4 to
4.1 percent,12,18 reflecting the rarity of this condition
despite relative risks ranging from 10.3 to 78.8.17,21
The most common form of leukemia is acute nonlymphocytic leukemia. Most cases develop within
the first 5 to 10 years following therapy. The occurrence of leukemia reaches a plateau at 10 to 15 years
post therapy and is associated with a poor prognosis.
Despite reported 5-year survival rates of less than 5
percent, secondary leukemias contribute to less than
5 percent of all mortality in patients treated for HD.12
Table 27–1. LATE COMPLICATIONS AFTER TREATMENT OF HODGKIN’S DISEASE
Second
Cancers
Pulmonary
Thyroid
Gonadal
Gastrointestinal
Immune
Musculoskeletal
Other
Leukemia*
Chronic
constrictive
pericarditis
Pneumonitis
Radiation
Bleomycin
Hypothyroidism
Infertility
Gastric/duodenal
ulcer or disease
Lymphopenia†
Soft tissue atrophy
and skeletal
deformity
Xerostomia
Myelodysplastic
syndromes
Pericardial
effusion
Pulmonary
fibrosis
Hyperthyroidism
Graves’ disease
Thyroiditis
Azoospermia
Gastritis
Infectious
complications‡
Avascular
necrosis
Bladder fibrosis/
hemorrhagic
cystitis
Non-Hodgkin’s
lymphoma
Pericardial
tamponade
Thyrotoxicosis
Small bowel
obstructions/
perforations
Bacterial sepsis
Slipped femoral
capital
epiphysis
Renal
dysfunction
Solid cancers
Lung
Breast
Thyroid
Soft tissue
Bone
Cervix
Melanoma
Esophagus
Stomach
Pancreas
Colon
Rectum
Salivary gland
Skin
Bladder
Arrhythmias
Myocarditis
Cardiomyopathy
Coronary artery
disease
Valvular defects
Benign nodules
Herpes zoster
Osteoporosis
Pneumonia
Skin infections
Myelosuppression
Radiation
myelopathy
Peripheral
neuropathies
Fatigue
Prevalence
Severity
Longer duration
Depression
Problems in
psychosocial
adaptation§
*Most commonly, acute nonlymphocytic leukemia.
†
Both B cell and T cell.
‡
Gram-positive encapsulated organisms most common: Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis.
§
For example, distress, poorer body image, continued conditioned nausea and vomiting, decreased sexual interest and activity, job discrimination, denial of life and health insurance, a perceived negative socioeconomic effect.
Late Complications after Treatment of Hodgkin’s Disease
Cardiovascular
443
444
MALIGNANT LYMPHOMAS
Table 27–2. STANFORD SERIES DEMONSTRATING
THE CAUSES OF LATE MORTALITY AMONG 2,498 PATIENTS
AFTER TREATMENT OF HODGKIN’S DISEASE*
Causes
Number
Percentage
Hodgkin’s disease
Other cancers
Cardiovascular
Pulmonary
Infection
Accidental
Hematologic
Gastrointestinal
Other, multiple
Unknown
333
160
117
50
31
14
9
4
14
22
44
21
16
7
4
2
1
1
2
3
Total
754
*Duration of follow-up not specified.
Reprinted with permission from Hoppe RT. Hodgkin’s disease: complications
of therapy and excess mortality. Ann Oncol 1997;8 Suppl 1:115–8.
By far, exposure to alkylating-agent chemotherapy—such as mechlorethamine (nitrogen mustard), a
component of the MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) regimen—is
the most established risk factor for secondary
leukemia.23–25 Cumulative doses of mechlorethamine
have been associated with the risk of secondary
leukemia, further strengthening this causative association.24 The introduction of the alternating MOPP/
ABVD (doxorubicin, bleomycin, vinblastine, and
dacarbazine) regimen or the ABVD regimen alone
exposes patients to lower doses of alkylating chemotherapy agents with an expected lower leukemogenic
risk. To date, available data have confirmed a lower
risk.18 Hence, MOPP chemotherapy alone should no
longer be advocated, both because of its toxicity
(leukemia, sterility) and its inferior relapse-free survival as compared with ABVD. Although characterization of the risk associated with other agents is confounded by several factors, including the concurrent
use of alkylating agents, concern exists regarding the
potential interaction between anthracyclines and alkylating agents, as in current hybrid regimens. Ongoing
trials to define the optimal dose intensity with existing
regimens, and studies of new regimens such as Stanford V(doxorubicin, vinblastine, mechlorethamine,
vincristine, bleomycin, etoposide, and prednisone),26
offer the promise of further minimizing the exposure
of patients to alkylating agents.
Other leukemogenic risk factors identified include
radiation therapy, splenectomy, advanced stage, and
age greater than 50 years. In general, a modest association between radiation exposure and secondary
leukemia has been suggested, with variably significant relative risks reported. This risk has been suggested to be increased with larger radiotherapy fields,
such as with subtotal nodal irradiation,27 and with
doses greater than 20 Gy.23 The current doses and volumes of limited radiation portals have been associated
with a negligible risk of leukemia. The addition of
radiation therapy to patients treated with chemotherapy has been inconsistently reported to be associated
with an additional leukemogenic risk and remains
controversial. Confounding this association is the difficulty controlling for the type and dose of leukemogenic chemotherapy agents. In a large case-control
study that was able to control for these factors, the
addition of radiation therapy did not increase the risk
of secondary leukemia.23 However, the IDHD metaanalysis did demonstrate a strong increase in risk
when MOPP was combined with radiotherapy. Current chemotherapy regimens (eg, ABVD) do not
appear to be associated with a synergistic risk for secondary leukemia when combined with radiotherapy.
Splenectomy, performed as part of a staging
laparotomy, has been associated with a risk of secondary leukemia.24 However, this association may
potentially reflect a confounding effect between
splenectomy and other unidentified risk factors
inherent in patients with HD, such as an altered
underlying immune system. A recent large metaanalysis has confirmed this finding.12 For this reason, as well as its failure to improve outcome, staging laparotomy is rarely used in the contemporary
management of patients with HD.
As with secondary leukemia, the cumulative risk
of developing non-Hodgkin’s lymphoma is low, at 1.2
to 2.1 percent 15 years post therapy, despite reported
relative risks ranging from 3.0 to 35.6.12,17 Several
series, including data from the IDHD, have demonstrated an increasing relative risk with increasing follow-up. A gender difference may exist, with the risk
reaching a peak for women between 5 and 9 years
post therapy.12 Overall, the 5-year survival rates range
from 30 to 40 percent, contributing to less than 5 percent of the mortality observed for treated HD patients.
The vast majority of secondary non-Hodgkin’s lymphomas are of intermediate- to high-grade histology
Late Complications after Treatment of Hodgkin’s Disease
and appear to have a comparable natural history to
primary non-Hodgkin’s lymphomas.28
Somewhat discordant results have been demonstrated when treatment-based factors were examined
as potential risk factors for secondary nonHodgkin’s lymphoma. Of these, only the IDHD,
with the largest sample size, was able to demonstrate
that combined modality therapy and therapy at
relapse were associated with an increased risk.12
Current first-line effective therapy for Hodgkin’s
disease may help reduce this risk.
Other risk factors reported for the development of
non-Hodgkin’s lymphoma have included a higher
risk associated with advancing age12 and a lymphocyte-predominant histology that has been interpreted
to reflect either an initial diagnostic misclassification, an initial composite lymphoma, or a transformation as part of the natural history of lymphocyte
predominance HD.12,29 It also has been postulated
that the risk of non-Hodgkin’s lymphoma may reflect
underlying immunosuppression, as is observed in
transplanted patients. Possibly, the increased risk
associated with more intensive therapy and advancing age may reflect this immunosuppression risk.
Solid Malignancies
Lung Malignancies
The increased risk of secondary lung cancer has
been demonstrated in several institutional cohort
studies with a latent period of approximately 5 years
and a continued relative risk to at least 20
years.13–15,18 The relative risk may be greater in
patients treated at a younger age, underscoring the
importance of this late complication.15,29
The most consistent risk factor for secondary lung
cancers has been the exposure of patients to radiotherapy. This risk is further supported by evidence of
a dose-response relationship with threshold and ceiling responses appearing at 9 Gy and 15 Gy, respectively.30 The relative risk was 9.6 for a dose of 9 Gy or
greater when compared with a dose of < 1 Gy. In fact,
the risk appeared to decrease after 15 Gy, suggesting
that the greatest risk for lung cancer may lie within
the radiotherapy field margins with current mantle
field doses. Hence, current dose reduction efforts
445
may not achieve any significant risk modification
unless a sufficiently significant dose reduction is
achieved; this may compromise tumor control.
The risk of secondary lung cancers resulting
from chemotherapy exposure alone in the treatment
of HD remains controversial, with conflicting results
from different studies.30–32 When combined with
radiotherapy, no convincing evidence exists to support an increase in the relative risk of secondary
lung cancers as compared with radiotherapy
alone.14–16,18,31–33 Two studies have examined the
influence of smoking on the risk of secondary lung
cancers among HD patients.30,31 Both demonstrated
an elevated risk; one study noted a relative risk of 13
when comparing ever-smokers with never-smokers;
the other study demonstrated a significant relationship between the amount smoked after the diagnosis
of HD compared with never-smokers.31 There was
evidence of a synergistic interaction between smoking after the diagnosis and exposure to radiotherapy.
Interestingly, no such relationship was demonstrated
for the group that smoked prior to the diagnosis.
To date, risk modification with patient counseling appears to be of paramount importance in minimizing the risk of secondary lung cancers in patients
treated for HD. It remains to be demonstrated
whether this risk may be affected by reductions in
radiotherapy. The role of screening in the detection
of secondary lung cancers remains to be evaluated.
Breast Malignancies
The most significant observation that has emerged
from studies of secondary breast cancers in patients
treated for HD is the consistent demonstration of an
increased relative risk observed with decreasing age at
initial treatment.19,21,22,32,34 The risk appears to increase
dramatically for patients less than 25 years, reflecting
a period of increased organ radiosensitivity. By the
age of 30 years, the risk of secondary breast cancer
no longer appears significantly elevated. The relative
risk for patients under the age of 16 years has ranged
from 17 to 458.34,35 The latency period is typically 15
years or greater. The relative risk of secondary breast
cancer appears to increase to at least 20 years.
The most convincing risk factor for secondary
breast cancer is the exposure to radiotherapy in the
446
MALIGNANT LYMPHOMAS
management of HD.34 Consistent with the use of
mantle field radiotherapy portals, an increased incidence of bilateral and medial half malignancies of
the breasts has been observed compared with that in
primary breast cancers.36 The vast majority of breast
cancers identified in HD survivors have been correlated to occur within or at the margins of the mantle
field. As well, several studies have strengthened this
relationship by demonstrating a dose-response relationship, particularly in children.21,34 A dose of 40 Gy
has been demonstrated to be associated with an
increased risk compared with lower doses. Other
less convincing risk factors for secondary breast
cancer include the addition of MOPP chemotherapy34,35 and splenectomy or splenic radiation.21,37
B
A = Mantle Field
B = Para-aortic Splenic Field
B + C = Spade Field
A + B = Subtotal Nodal Irradiation Field (STNI)
A + B + C + D = Total Nodal Irradiation Field
(TNI)
A
Secondary breast cancer is a serious concern
regarding mantle field radiotherapy in young
women and must be considered in the treatment
decision-making process and during radiotherapy
planning. Recent efforts to develop treatment planning techniques that minimize the amount of breast
tissue within the radiotherapy portal likely will be
beneficial.38 The magnitude of any incremental risk
reduction will again depend on the nature of the
dose-response relationship. In the pediatric population, low doses of radiation combined with chemotherapy have had no association with secondary
breast cancers in the Stanford series.4 Radiation
dosimetry studies correlating dose to the location
and risk of secondary breast cancers are needed.
C
Figure 27–1. Radiation portals commonly employed in the treatment of Hodgkin’s disease
(HD) demonstrating the major lymph node regions and the underlying normal organs irradiated. Panels A and B demonstrate the various combinations of radiotherapy portals that may
be employed to treat the major lymph node regions including total nodal irradiation (TNI),
subtotal nodal irradiation (STNI), or a mantle field. The para-aortic splenic field may be modified inferiorly to include the common iliac lymph nodes (the classic spade field). In women,
the inferior extent is limited to the superior level of the sacroiliac joints to minimize the irradiation to the ovaries if no oophoropexy has been performed (broken line). Normal organs that
may be irradiated include cardiac (C) and respiratory organs (D), breast and genitourinary
organs (E), endocrine organs (F), gastrointestinal organs (G), and the musculoskeletal organs
(H). A heart block may be used for doses greater than 3000 cGy (C).
Late Complications after Treatment of Hodgkin’s Disease
Understanding the nature of the dose-response relationship will provide a rational basis for further riskmodification strategies.
Thyroid Malignancies
As with the risk of secondary breast cancer, the relative risk of secondary thyroid cancer appears to
D
increase with decreasing age at initial treatment; the
risk appears to decrease, remaining independent of
age after the age of 20 years at initial treatment. The
relative risk is as high as 790 observed in children
under 4 years of age22 and may be elevated with
increasing follow-up:17,21 one study suggested a constant risk and another demonstrated increasing risk
with follow-up.
E
G
447
F
H
448
MALIGNANT LYMPHOMAS
Figure 27–2. Stanford series demonstrating actuarial mortality risk
due to Hodgkin’s disease (HD) (————) and intercurrent diseases
(- - - - - -). (Reproduced with permission from Donaldson SS, Hancock
SL, Hoppe RT. The Janeway lecture. Hodgkin’s disease—finding the
balance between cure and late effects. Cancer J Sci Am 1999;5:
325–33.)
The principal risk factor for secondary thyroid
malignancies appears to be the exposure to radiotherapy.39 The age-dependent risks are consistent
with an understanding that the thyroid organ is a particularly radiosensitive organ in children. A doseresponse relationship also has been suggested based
on data from children with radiation exposures from
other indications.39,40 Risk has been shown to
increase with doses up to 10 Gy, with a subsequent
plateau or reduction in the risk with further
increases in dose.40 If this ceiling is representative,
then significant dose reductions would be required
before any effective risk modification is achieved.
Chemotherapy exposure, particularly with alkylating agents, has been suggested as a risk factor for
secondary thyroid malignancies, with the greatest
risk occurring within the first 5 years of follow-up.20
trend toward a significant risk for treatment with
radiotherapy alone,41
The risk of malignant melanoma has been
reported to be increased in patients treated for HD.
The relative risk has ranged between 2.2 and 8.9
with no variation with the age at initial treatment
and with most cases manifesting within the first 5
years of follow-up.13,16,18,20 It has been suggested
that this risk may be particularly important in
patients with dysplastic nevus syndrome, possibly
reflecting the adverse effects of an impaired underlying immunity in HD patients.
Bone and soft tissue malignancies have been
reported in HD survivors, with significant relative
risks of 6.2 to 31.012,13 and 8.8 to 16.9,15,18 respectively. The risk is increased following exposure to
radiotherapy33 and chemotherapy.20 A dose-response
relationship has been demonstrated for bone and soft
tissue malignancies occurring in patients receiving
radiotherapy for other indications. Hence, dosereduction strategies may reduce the risk of secondary bone and soft tissue malignancies.
NONMALIGNANT COMPLICATIONS
OF THERAPY
Cardiac Complications
Cardiac complications are third in cumulative mortality risk, after disease relapse and second malig-
Other Complications
An increased risk of gastrointestinal malignancies
has been reported.41 Significant relative risks of 4 to
10 have been reported for stomach malignancies,
with an increased risk observed in males compared
with females in studies that have differentiated the
risk.12,13,15 Colon cancers have been observed in HD
survivors, with a relative risk ranging from 1.9 to 3.2
and an increased risk observed in males compared
with females.12,14 One study has demonstrated a significant association between gastrointestinal malignancies and combination chemoradiotherapy and a
Figure 27–3. Joint Center for Radiation Therapy (JCRT) series
demonstrating actuarial mortality risk due to Hodgkin’s disease and
types of intercurrent diseases in 794 patients. (Adapted with permission from Mauch PM, Kalish LA, Marcus KC, et al. Long-term survival in Hodgkin’s disease. Cancer J Sci Am 1995;1(1):33.)
Late Complications after Treatment of Hodgkin’s Disease
nancies, and contribute up to 10 to 16 percent of all
causes of mortality (see Table 27–2).7,9 Long-term
follow-up has demonstrated a significant increasing risk of death for both myocardial infarctions
(which account for over 60 percent of deaths) and
other cardiac causes of mortality. In the Stanford
series, the relative risks of death were 5.6 and 8.8
for myocardial infarctions and other causes,
respectively, with long-term follow-up.42 In other
series, the 10-year cumulative risk of myocardial
infarctions was 2.4 to 4.6 percent.9,43 Other cardiac
complications have included pericarditis, chronic
pericardial effusions and fibrosis, pancarditis, conduction defects, congestive heart failures, and
valvular disease.
Studies to date confirm that mantle field irradiation significantly contributes to this spectrum of
complications. Technical improvements in the delivery of mantle field irradiation, including equally
weighted radiotherapy fields, smaller fraction sizes,
and cardiac and subcarinal shielding, have been
demonstrated to reduce the risk of cardiac mortality.42 However, mortality from coronary heart disease was not modified, likely due to the continued
irradiation of proximal cardiac vessels. This risk is
favorably influenced by reducing the dose of cardiac
irradiation to 30 to 36 Gy.42 Current practices implementing these risk-modifying treatment techniques
have also been shown to favorably impact on surrogate measures of cardiac function, suggesting that
successful prospective risk modification has been
achieved.44,45 These observations mandate careful
technical considerations during the treatment planning of mantle field irradiation. Despite these successes, concern remains with regard to the potential
cardiotoxicities associated with current doxorubicin-containing chemotherapy regimens and their
potential adverse synergistic interactions with mantle field irradiation.
As cardiac complications are influenced also by
other risk factors such as diet and cigarette smoking,
vigilance and appropriate therapeutic interventions
are prudent and reasonable recommendations.46
However, supporting evidence outlining the significance of these interventions in this population of
patients is unavailable. The role of prospective
screening remains to be evaluated.
449
Pulmonary Complications
Several treatment-related pulmonary complications
may lead to both morbidity and mortality in HD survivors. These include chronic pulmonary fibrosis
and acute interstitial pneumonitis secondary to lung
irradiation, exposure to bleomycin-containing regimens, and their potential adverse synergistic interaction. Factors contributing to radiation-induced pulmonary toxicity include the irradiation of large
volumes, often the result of an attempt to encompass
prechemotherapy bulky tumor volumes, and the use
of large fraction sizes.47 Several chemotherapy regimens, including ABVD47 and VBM (vinblastine,
bleomycin, and methotrexate),48 have been associated with significant pulmonary toxicity and mortality. The ABVD regimen has been shown to increase
radiologic49 and functional measures9 of lung damage, with a restrictive pattern observed. This may be
due to the effects of bleomycin- or doxorubicininduced radiation recall pneumonitis.50 The VBM
regimen was the subject of a British National Lymphoma Investigation study and is noteworthy for
premature study termination due to a high and unexpected rate of severe pulmonary toxicity seen in 47
percent of the patients.48
Currently, risk-modification strategies include
restriction of radiotherapy fields to the postchemotherapy tumor volume and the reduced use of wholelung irradiation, particularly in combination with
chemotherapy. Attention to the use of bleomycincontaining regimens and the cumulative dose are
also important considerations.
Infectious Complications
An increased risk of infectious complications results
not only from the underlying immune deficits
observed in HD patients but also from the consequences of various diagnostic and therapeutic interventions. These iatrogenic causes include the formerly common use of staging laparotomies with
splenectomy and the myelosuppressive effects of
both chemotherapy and radiation therapies. Of the
various infectious complications, overwhelming
bacterial sepsis is associated with a grave prognosis
and contributes to the majority of infectious mortalities. These often involve gram-positive encapsu-
450
MALIGNANT LYMPHOMAS
lated organisms following a splenectomy but may
also occur after splenic irradiation. This risk has
been reduced with prior immunization and the use of
antibiotic prophylaxis.
Herpes zoster infections are commonly encountered during treatment or within 1 to 2 years following therapy, but they are rarely fatal with the prompt
initiation of antiviral therapy. Other infections may
include pneumonia, skin infections, and meningitis.
With the emphasis on current clinical staging practices, the recognition of very-low-risk groups
amenable to involved-field radiotherapy alone, and
the introduction of less intensive combination
chemoradiotherapy regimens, the incidence of fatal
infectious complications will continue to decrease.
Thyroid Complications
Various thyroid complications arising in patients
treated for HD may be observed. These may commonly include primary hypothyroidism, Graves’ disease, autoimmune thyroiditis, benign cysts, and thyroid malignancies. The most frequent complication
is primary biochemical hypothyroidism, which represents the most common problem necessitating follow-up and intervention. In a large contemporary
series reported from Stanford, the 20-year cumulative risk of biochemical and overt/biochemical
hypothyroidism was 43 percent and 52 percent,
respectively, with nearly one-half manifesting within
5 years of therapy.51 Radiation exposure is the principal etiologic risk factor. A dose-response relationship has been demonstrated.51–53 Although the precise nature of this dose-response relationship
remains to be defined, dose and treatment-field
reductions should lessen this risk. The influence of
age is difficult to assess due to its association with
radiotherapy doses and potential confounding
effects from chemotherapy. However, among
patients less than 16 years of age, radiotherapy dose
continues to be important. For patients greater than
16 years, of female gender, and additionally undergoing chemotherapy, an increase in radiotherapy
doses appears to further increase the risk of thyroid
complications. This risk appears to decrease modestly with advancing age. Although current practices
with reduced radiotherapy doses are likely to reduce
the risk of hypothyroidism, the impact of introducing less intensive but combined modality therapy in
early-stage disease remains to be determined.
Fertility Complications
As the majority of patients with HD are young at initial presentation, late fertility complications pose a
major concern in the treatment decision-making
process. Radiation therapy and chemotherapy may
result in temporary or permanent risks of infertility.
The risks of fractionated radiotherapy on ovarian
function are dependent not only on the minimum
ovarian dose but also on the age of the patient. In general, for women between the ages of 15 and 40 years,
a dose of 2.5 to 5.0 Gy is associated with a 30 to 40
percent risk of permanent infertility.54 Standard doses
and subtotal nodal irradiation portals are associated
with minimal risks of infertility based on phantom
measurements.55 If pelvic field irradiation is indicated, a midline oophoropexy or heterotopic transplantation may be required. Combination chemotherapy, particularly with alkylating agents, has been
demonstrated to adversely affect ovarian function,
with lower doses being less toxic and younger women
being less likely to become infertile.56
A similar dose-dependent relationship exists for
permanent azoospermia with fractionated radiotherapy. A total dose of 1 to 2 Gy is associated with a
low risk of permanent azoospermia and is achievable with standard doses and field sizes57,58 Pelvic
radiotherapy requires testicular shielding and various physical considerations to minimize the scatttered dose. Although the majority of patients are
likely to experience short-term azoospermia, more
than 85 percent of such treated patients may be
expected to recover spermatogenesis function. Alkylating agent–based regimens (eg, MOPP) also may
result in permanent sterility in a dose-dependent
fashion. The use of ABVD appears to significantly
reduce this risk, with the majority of patients subsequently recovering spermatogenesis.59 Current
strategies of less intensive combination chemotherapy with limited-field radiotherapy and combination
chemotherapy regimens minimizing alkylating
agent exposure are likely to be associated with low
risks of infertility. The importance for this is under-
Late Complications after Treatment of Hodgkin’s Disease
scored by the observation that one-half of all
patients with pretreatment sperm banking demonstrated abnormal sperm at the time of cryopreservation, limiting the available subsequent material for
insemination.60
Other Complications
Various other organ-specific treatment-related complications warrant consideration. This may include
radiation-induced xerostomia resulting from irradiation of the Waldeyer lymphoid tissues, necessitating
subsequent lifelong dental prophylaxis and care. The
risk of complete and permanent xerostomia is dose
related and is reduced with current employed doses.
Pretreatment dental evaluation is recommended. A
prophylactic role for the aminothiols, such as amifostine, remains to be defined. Radiation-induced
gastric and duodenal ulcer disease, gastritis, and
small bowel obstructions and perforations have been
reported. These risks appear to be increased with
prior abdominal surgery and large radiotherapy dose
fractions.9 Total doses greater than 35 Gy have been
shown to increase the risk of major bowel complications.61 Current practices with an emphasis on clinical staging and limited radiotherapy fields are likely
to reduce the risk of these complications. Cyclophosphamide-related bladder fibrosis, hemorrhagic
cystitis, and carcinoma are well described and can
be prevented with adequate hydration. In the pediatric population, radiation-related bone and soft tissue damage are age and dose dependent. In general,
the use of higher doses is associated with a higher
risk of skeletal deformity and soft tissue atrophy
when given in younger patients. Corticosteroids are
associated with avascular necrosis of the femoral or
humeral heads and osteoporosis. Hodgkin’s disease
survivors also are more likely to be fatigued and to
report higher levels and longer duration of fatigue62;
they subsequently are prone to depression.63 Survivors also experience an increased risk of problems
in psychosocial adaptation that have included elevated levels of psychologic distress, continued conditioned nausea and vomiting, poorer body image,
decreased sexual interest and activity, and increased
difficulties returning to work (including various
forms of job discrimination). Survivors also have
451
experienced difficulties in obtaining life and health
insurance, higher divorce rates, and a perceived negative socioeconomic effect.63–66
MANAGEMENT PRINCIPLES TO
MINIMIZE THE RISK
The management of HD is now based largely on various clinical prognostic factors that direct riskappropriate therapy. This has given rise to risk-stratification schemas that have identified an early-stage
favorable risk group, an intermediate-risk group,
and an advanced-risk group. An understanding of
the risk factors associated with various late complications recently has permitted further tailored therapy, attempting to maximize the therapeutic ratio.
Several randomized trials are ongoing and are summarized in Table 27–3. The roles of molecular-based
prognostic factors and indicators of minimal residual disease offer the promise of identifying further
homogeneous risk groups.
Treatment options for early-stage favorable risk
groups, stages IA and IIA, traditionally have
included extended-field radiotherapy (EFRT) alone
or combination chemoradiotherapy. Patients treated
with radiotherapy are at an increased risk of disease
relapse that is more amenable to salvage chemotherapy when compared with the risk of patients treated
with combination chemoradiotherapy as initial treatment.3 Patients treated with more aggressive upfront combined modality therapy may be at an
increased risk of late complications.3
Recent efforts by the German Hodgkin’s Study
Group (GHSG) attempting to minimize the risk of
radiotherapy late complications demonstrated that
although a reduced dose of 30 Gy is sufficient to treat
subclinical disease, it was associated with a 5-year
relapse-free survival of 82 percent, despite the benefits of pathologic staging.67 Salvage chemotherapy
was successful in the vast majority, with a 5-year
overall survival of 97 percent. Despite this success, it
has been argued that for the 15 to 20 percent of
patients relapsing following up-front radiation therapy alone, exposure to salvage chemotherapy significantly increases the risk of late complications. Efforts
to reduce the risk of relapse have incorporated abbreviated cycles of chemotherapy in combination with
452
MALIGNANT LYMPHOMAS
Table 27–3. CURRENT TREATMENT STRATEGIES
ATTEMPTING TO DEFINE THE MAXIMUM
THERAPEUTIC RATIO IN THE TREATMENT
OF HODGKIN’S DISEASE
Study
Early stage—
favorable prognosis
GHSG HD-10
EORTC H9-F
Early stage—
unfavorable prognosis
GHSG HD-11
EORTC H9-U
NCI HD6
ECOG-E2496
Advanced stage—
GHSG HD-12
ECOG-E2496
Treatment Arms
ABVD × 2* + IFRT (20 Gy)
ABVD × 2 + IFRT (30 Gy)
ABVD × 4 + IFRT (20 Gy)
ABVD × 4 + IFRT (30 Gy)
EBVP × 6
EBVP × 6 + IFRT (20 Gy)
EBVP × 6 + IFRT (36 Gy)
ABVD × 4 + IFRT (20 Gy)
ABVD × 4 + IFRT (30 Gy)
BEACOPP basic × 4 + IFRT (20 Gy)
BEACOPP basic × 4 + IFRT (30 Gy)
ABVD × 4 + IFRT (30 Gy)
ABVD × 6 + IFRT (30 Gy)
BEACOPP basic × 4 + IFRT (30 Gy)
ABVD × 2 + EFRT (35 Gy)
ABVD × 4–6
ABVD × 6 + IFRT (36 Gy)
Stanford V × 3 months + IFRT (36 Gy)
BEACOPP escalated × 8
BEACOPP escalated × 8 + RT of
residual disease (30 Gy)
BEACOPP escalated × 8 +
BEACOPP basic × 4
BEACOPP escalated × 8 +
BEACOPP basic × 4 + RT of
residual disease (30 Gy)
ABVD × 6 + IFRT (36 Gy)
Stanford V × 3 months + IFRT (36 Gy)
GHSG = German Hodgkin’s Lymphoma Study Group; RT = radiation therapy;
ABVD = doxorubicin, cyclophosphamide, vinblastine, and dacarbazine;
IFRT = involved-field radiation therapy; EORTC = European Organization
for Research and Treatment of Cancer; EBVP = epirubicin, bleomycin,
vinblastine, and prednisone; BEACOPP = bleomycin, etoposide, adriamycin,
cyclophosphamide, vincristine, procarbazine, and prednisone; NCI = US
National Cancer Institute; EFRT = extended-field radiation therapy; ECOG =
Eastern Cooperative Oncology Group; Stanford V = doxorubicin, vinblastine,
mechlorethamine, vincristine, bleomycin, etoposide, and prednisone.
*Number of cycles.
†
Patients with large mediastinal mass or with bulky tumors > 10 cm are
excluded.
increasingly less intensive radiotherapy volumes and
doses, based on the recognition of a dose-dependent
relationship between chemotherapy and radiation
with several late complications (Table 27–4).
Several combination chemoradiotherapy regimens have been reported with promising relapsefree rates. The results of the recently completed
EORTC-GELA (European Organization for Research
and Treatment of Cancer–Groupe d’Etude des
Lymphomes de l’Adulte) H8-F randomized trial,
reported in abstract form, have confirmed a significantly improved relapse-free survival with three
cycles of a MOPP/ABV (doxorubicin, bleomycin,
vinblastine) hybrid and involved-field (36 to 40 Gy)
irradiation (IFRT) compared with that of EFRT
alone.68 Interim analysis of the GHSG HD-7 trial
suggests comparable efficacy between EFRT and
two cycles of ABVD and IFRT.69 The ongoing
GHSG HD-10 is evaluating the efficacy of this
abbreviated chemoradiation strategy but with
reduced doses ranging from 20 to 30 Gy. Significant
improvements in the therapeutic ratio will depend on
eventual demonstration of a lower cumulative risk of
late complication mortality resulting from the exposure of all low-risk patients to an abbreviated
chemoradiotherapy regimen. The EORTC H9-F trial
is evaluating not only reduced doses of IFRT (20 Gy
versus 36 Gy) but also the relative efficacy and toxicity associated with chemotherapy alone.
Patients with early-stage disease but presenting
with other adverse risk factors such as bulky disease
constitute an intermediate-risk group and have been
treated traditionally with combination chemoradiotherapy using EFRT. Efforts to reduce the radiotherapy intensity with involved fields and dose reductions have been the subject of recent investigations.
The results of the EORTC-GELA H8-U trial were
reported in abstract form demonstrating comparable
and high response rates, 4-year treatment failure-free
survival and 4-year overall survival between four
cycles of a MOPP/ABV hybrid and IFRT versus
EFRT (36 to 40 Gy).70 An additional two cycles of
MOPP/ABV did not appear to improve the results of
the involved-field arm. Hence, the toxicities associated with para-aortic and splenic irradiation may be
avoided in this group of patients. Several other comparable randomized trials are ongoing including the
GHSG HD-11 trial addressing the dose of the IFRT
(20 Gy versus 30 Gy).69
For more unfavorable risk groups, the optimal
treatment remains to be defined. The treatment strategy may involve ABVD-based chemotherapy regimens alone or sequential chemoradiotherapy. Recent
efforts have focused on strategies attempting to overcome drug resistance with either broad-exposure
hybrid regimens, dose-escalation strategies, or
Late Complications after Treatment of Hodgkin’s Disease
453
Table 27–4. ESTABLISHED RISK FACTORS FOR MAJOR LATE COMPLICATIONS AFTER TREATMENT OF HODGKIN’S DISEASE
Late
Complication
Established
Major Risk Factors
Dose-Response
Relationship Suggested?
Other Risk Factors*
Leukemia
Alkylating chemotherapy†
Yes
RT, splenectomy
Lung cancer
RT, smoking
Yes
Chemotherapy
Breast cancer
RT, age < 30 yr
at presentation
Yes
Alkylating chemotherapy + RT, splenectomy or
splenic RT
Coronary artery
disease
RT
Yes
Possible doxorubicin-based chemotherapy,
cigarette smoking, hypertension,
hypercholesterolemia, diabetes mellitus, obesity
Infertility
Alkylating chemotherapy, RT
Yes
—
RT = radiation therapy.
*Less established or controversial, often with a weak association resulting in inconsistent reporting.
†
For example, MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) combination chemotherapy regimen.
accelerated schedules minimizing the overall treatment time. Various studies remain ongoing. The
accelerated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) dose-escalated regimen has
been demonstrated to have significant efficacy and
has been adopted as the standard regimen by the
GHSG.69,71 Interestingly, early success also has been
observed with the accelerated Stanford V regimen.72
Hence, these patients will continue to be heavily
treated, with the risks of late complications to be
defined. It is noteworthy that the recent meta-analysis of trials in advanced-stage HD with and without
radiation therapy demonstrated that the benefits of
radiotherapy depended on the adequacy of the
chemotherapy delivered.73 As such, the volume,
dose, and use of radiotherapy should be applied judiciously in this group of patients who are at risk of
late complications due to the necessity to achieve
up-front disease control. Currently, radiotherapy is
reserved for the treatment of initial bulky disease or
subsequent postchemotherapy residual disease.
CONCLUSION
The success achieved in the management of HD is a
testament to the collaborative efforts of institutions
and cooperative groups committed to improving the
management of this disease. Management strategies
of the past 20 to 30 years may now pose a considerable risk of delayed complications to HD survivors.
Through meticulous delineation of prognostic factors
and risk factors for complications, the ability to provide tailored up-front risk-appropriate effective ther-
apy with the lowest risk of subsequent late complications should yield the greatest therapeutic ratio for
patients with HD. To date, significant gains have been
achieved toward this goal. Although therapeutic modifications likely will yield the greatest risk reduction,
screening and preventive strategies, including participation in mammography screening and smoking cessation, are highly recommended despite their
unproven value. As well, long-term follow-up and
evaluation clearly are warranted in HD survivors.
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