Page 1382 - Hematology_ Basic Principles and Practice ( PDFDrive )

1228 Part VII Hematologic Malignancies

LONG-TERM COMPLICATIONS OF TREATMENT IN also been implicated in the development of late cardiac diseases
including coronary artery disease, valvular dysfunction, myocardial
HODGKIN LYMPHOMA dysfunction, pericarditis, and conduction defects, and radiation-
related cardiac toxicity remains a major factor compromising overall
The high cure rate associated with HL translates to a significant outcome in HL survivors. Optimal screening methods for cardiovas-
proportion of patients who are at increased risk for a range of long- cular disease are not clearly established and therefore close monitoring
term sequelae of treatment. Data on the cumulative incidence of of these patients is warranted, including strict control of cardiac risk
cause-specific mortality in HL survivors show that although the rate factors (including hypertension, diabetes, hypercholesterolemia, and
of lymphoma-related deaths plateaus after the first 10−15 years fol- smoking).
lowing therapy, the rate of death because of late complications con-
tinues to rise.
The management of late toxicities associated with chemotherapy Gonadal Dysfunction
and/or RT is often more challenging than acute, with effects in some
cases being irreversible and life threatening. Long-term treatment- A number of agents used in the treatment of HL can result in gonadal
related complications in patients previously treated for HL include dysfunction, which is of particular relevance given the young age of
hypothyroidism, peripheral neuropathy, gonadal dysfunction, sec- this patient population. Pelvic RT and intensive alkylating-based
ondary malignancy, and cardiovascular disease. Of these, secondary frontline chemotherapy regimens such as MOPP and escalated
malignancy and cardiovascular complications occur most frequently, BEACOPP have been shown to induce male and female sterility
with risk continuing even beyond 25 years from diagnosis, and rep- whereas the risk is reduced with baseline BEACOPP and reduced
resent the two most common entities determining quality of life, further still with less aggressive combinations such as ABVD where
long-term morbidity, and mortality in this patient population. it is usually only transient. Unsurprisingly, however, the risk rises
significantly among patients with relapsed or refractory disease fol-
lowing high-dose salvage chemotherapy. It is therefore recommended
Secondary Malignancy that all patients with newly diagnosed HL, who are of reproductive
age, should be offered fertility preservation before commencing
It is well described that intensive RT with extended field size and therapy.
certain chemotherapy agents, such as cyclophosphamide, nitrogen The significance of long-term sequelae following treatment for
mustard, procarbazine, and etoposide may increase the risk of devel- HL has become more apparent over recent years given the growing
oping secondary malignancies. Solid tumors appear to account for number of young survivors. However, it is important to remember
the majority of cases of secondary malignancy, with breast cancer, that a significant proportion of the data surrounding late effects relate
lung cancer, and gastrointestinal cancer occurring most frequently. to patients who were treated with chemotherapy and RT approaches
This risk has been shown to be significantly greater among patients that no longer feature in current practice. Increased awareness of
treated for HL during childhood or during teenage years. Among the long-term complications can account for many of the important
female population, secondary breast cancer predominates, with treatment modifications which have been made over the past two
extended radiation field size and the administration of RT to those decades, and provides the current rationale for ongoing development
under the age of 30 years representing the two most significant risk with regards to novel agents as well as RT technique. Current and
factors. Time to development of breast cancer is usually about 10−15 future follow-up approaches for these individuals requires vigilance,
years. Therefore for all female patients receiving radiation to the focusing on strategies that enable both early detection and primary
mediastinum or axillae, annual breast screening with mammography prevention wherever possible for the impact of these sequelae to be
is recommended 8−10 years after treatment or from the age of 40 reduced. Guidelines for the optimal monitoring of adult HL survivors
years, whichever occurs first. 5 years out of treatment have been issued by the National Compre-
The risk of secondary hematologic malignancy, including leuke- hensive Cancer Network (NCCN).
mia and myelodysplasia, has been particularly associated with prior
exposure to alkylating chemotherapy, especially when delivered in
combination with large-field RT. Although this risk has fallen with CONCLUSION
the use of more modern chemotherapy, the exact choice of regimen
still appears to be significant, with the incidence of AML or myelo- The treatment of HL over the last 50 years has been one of the great
dysplasia being significantly greater among those treated with more success stories in oncology. Developments in combination chemo-
intensive chemotherapy, such as BEACOPP, than with ABVD. 12,14 therapy and its use in association with RT have resulted in cure rates
Time to development of treatment-related leukemia after HL is about of greater than 80%, for a disease that was once usually fatal. For
3−5 years, and the prognosis of these patients is poor, with an esti- some patients, however, cure is still unachievable, and for others,
mated OS of 7.2 months. survival is limited by late complications of cancer therapy. At present,
the key objective in the ongoing management of HL is to increase
efficacy without increasing the risk of unnecessary toxicity. Future
Cardiovascular Disease approaches to management, not only in the relapsed and refractory
setting, but also at earlier stages of disease are going to involve the
The risk of cardiovascular disease may be three- to fivefold increased use of targeted therapies. The best example so far is brentuximab
in survivors of HL compared with the general population. Cardiac vedotin, the first FDA-approved drug for HL since 1977, and its
complications tend to present approximately 10−15 years after success is likely to revolutionize treatment. As more specific targets
exposure, although actual disease onset may in fact be well before emerge based on advances in molecular tumor biology, further
this, given the lack of early symptoms in many cases. The association antibody and small molecule targeting, including for example PD-1
between anthracycline-based chemotherapy and cardiac toxicity is inhibitors, are likely to be developed. In addition, PET-directed
well established and is particularly relevant to the setting of HL given approaches and the identification of more specific predictive bio-
the chemotherapy combinations currently used in standard practice. markers should help define which patients need more, or less,
Anthracycline-induced cardiac toxicity typically manifests as arrhyth- intensive treatments. The future management of HL is therefore
mias or congestive cardiac failure as a result of ventricular dysfunction likely to shift toward an approach that is no longer according to
secondary to direct myocardial damage. The severity of cardiac toxic- prognostic group, but rather according to the specific needs of the
ity is directly correlated to the cumulative dose that is delivered and, individual. This marks a pivotal moment in the treatment of a disease
as such, both individual dosage and the number of cycles are signifi- for which the development of new drugs had, until recently, remained
cant considerations when planning treatment. Radiation exposure has static for more than 30 years.