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EXAMINING THE

POTENTIAL OF
REDUCING LATE SIDE
EFFECTS IN HODGKINS
LYMPHOMA

9 December 2015

Alex Kozak

It has been determined from years of research that one of the possible side effects from
radiation exposure is cancer. It almost seems counterintuitive, but one of the ways in which to
treat cancer is also to administer doses of radiation to tumors. However, even though radiation is
used to treat cancer, it can also result in a later formation of other tumors. This is due to the fact
that even though radiation kills cells, some cells are either not entirely killed off by radiation
exposure, or they are more resistant to radiation exposure. When either of these occurs, the cells
they fail to die and secondary tumors can be formed. Usually these secondary tumors present
years after the initial radiation was delivered. The possibility of these secondary tumors forming
depends on the dose of radiation initially given and the type of cells and aggressiveness of the
cells. Another major factor is the age at which a patient first received the dose of initial radiation.
This is because the cells in younger individuals are more sensitive to radiation and any of the
associated effects. The effects of ionizing radiation are seen particularly in the form of secondary
malignancies seen in individuals who received radiation treatments for Hodgkins lymphoma as
children. Although the cure rate for low stage Hodgkins lymphoma is about 95%, the occurrence
of secondary malignancies later in life is high. It is evident that even though cancers, such as
Hodgkins lymphoma, are considered curable, further research needs to be conducted in order to
limit late term side effects such as secondary malignancies.
There has been an important discussion among oncologists and researchers as to whether
or not to treat patients presenting with Hodgkins lymphoma with radiation therapy, or simply
with chemotherapy alone. An article in The New England Journal of Medicine discussed the
results of a study pertaining to this subject and overall, the researchers were able to conclude that
treating patients with chemotherapy results in better 12-year outcomes for patients in contrast to
treating patients with a treatment involving subtotal nodal irradiation. The current practice is to

treat stages IA and IIA, non-bulky disease with ABVD chemotherapy regimen and involved-field
radiation therapy to 20 Gy3. This is effective in 90% of patients for long-term control 3. However,
stage III or IV disease is treated with ABVD alone and this is proven effective in 65 to 70% of
patients3. Based on this information, a need to compare and contrast the two methods of
treatment in the same stage of disease needed to be performed. Thus, a trial was formed of 399
participants in which 180 patients were randomized to receive ABVD treatment alone and 178
were randomized to receive sub-total nodal radiation treatment3. Of the 178, 53 patients with
favorable prognoses received sub-total nodal radiation alone, and 125 patients with less
favorable prognoses received ABVD along with radiation therapy3. 56 patients of the initial 399
were lost to follow-up. All patients included in the study had stage IA or IIA non-bulky disease 3.
The study was a 12 year study and the results were that the patients treated with ABVD alone
had a better 12 year survival (87%) than those treated with any radiation therapy 3. This was
slightly different than what the researchers expected because a meta-analysis was done prior to
the study and overall, the results were in favor of a combination of chemotherapy and radiation
therapy3. Upon further review, it was noted that not all of the studies used ABVD, but rather a
less effective chemotherapy regimen was used in some of the studies and some of the trials had
included stages IIB and IIA disease along with bulky disease3. Meyer et al was able to confirm
that the toxicity associated with radiation therapy results in a shortened survival.
Due to the variety of treatment options and diagnoses of Hodgkins lymphoma, it can be a
challenge to compare and contrast the effect that radiation therapy has on secondary tumor
development in individuals who were treated for the disease as children. However, a
retrospective study was able to be comprised in Australia because in Australia it was/is common
practice to treat with chemotherapy alone, regardless of the stage of the cancer 1. Therefore,

performing an analysis of children who developed secondary malignancies after receiving


radiation therapy verses children who were treated with chemotherapy alone was possible. Of the
group of 142, 14 patients developed 16 secondary solidary tumors: 12 of these individuals
received radiation therapy and 2 did not1. Of the 12, 75% of their tumors were in the field of
treatment, but the actual number may be larger because the origin of those who developed
melanoma could not be determined1. It had been previously discovered that young females
treated for Hodgkins lymphoma have a greater risk of developing secondary breast
malignancies, but this review did not have any patients that developed breast cancer. However, it
is notable that only 11 female patients had radiation treatments involving the breast tissue, 4 of
which were treated with a mantle field 1. In addition, all the female patients were treated with
alkylating agents which have been proven to protect against breast cancers 1. Barbaro and
colleagues1 mentioned that there was no significant difference in the number of chemotherapy
cycles in the patients that presented with secondary tumors nor was there a difference in those
that were administered doses of < 25 Gy. One unexpected discovery of the retrospective study
was that the presence of B symptoms did border on significance for developing secondary
tumors later in life1. This factor, however, needs to be researched further. Even though the
evidence for the 5 year overall survival is slightly more promising in patients that received
radiation therapy (96.5%) in contrast to those treated with chemotherapy alone (92.9%), it is the
late effects with which the oncology community is primarily concerned. Based on this
retrospective study, it is apparent that there should be a strong push to only treat Hodgkins
lymphoma, in pediatric patients, with chemotherapy alone.
The review composed by Khafga and Belgaumi 2 discusses the current treatment and
previous and on-going clinical trials regarding the roles of chemotherapy and radiation therapy in

the treatment of Hodgkins lymphoma. Discussed are both lymphoma in adults and children, but
the primary focus is on pediatric cases and their long-term outcomes. It is evident that previous
treatment protocols using radiation resulted in a significant number of late toxicities such as
cardiac, pulmonary, and gonadal toxicities as well as secondary malignancies. One of the major
secondary malignancies is breast cancer in females who as children were treated for Hodgkins
lymphoma and particularly with extended field radiation therapy. Females treated with a mantle
field have a 2.7 times higher risk for developing breast cancer over others who were treated with
mediastinal radiation2. Although extended field radiation therapy has been replaced by involved
field radiation therapy, there is still concern in the medical oncology community regarding the
intensity and late side effects of the standard toxic treatments. Currently, the standard practice of
care is a combination of chemotherapy agents and involved field radiation. The cure rate is
above 95% for early stage cancers and 85% for later stage disease2. Even though the cure rates
are high, secondary malignancies and late effects are still of great concern. It is for this reason
that current studies are looking into other chemotherapy regimens, reduced radiation dose, and
even looking into excluding radiation from the course of care altogether. A study conducted
through Stanford, Dana-Farber, and St. Judes Childrens Research Hospital examined VAMP, a
non-alkylating regimin that replaces bleomycin and dacarbazine with methotrexate and
prednisone in stage I and II non-bulky Hodgkins lymphoma 2. Patients then received either 15
Gy or 25.5 Gy and this study was able to confirm that that use of alkylating agents could be
avoided while having a successful cure rate 2. The review itself states that there is no
demonstrable survival advantage for the use of radiation in Hodgkins lymphoma trials 2 This
suggests that radiation is only used in order to prevent relapses in the disease. In summary, it is
stated that there needs to be a great reduction or even an omission of therapy treatments in

pediatric Hodgkins lymphoma patients due to the toxicities and late effects caused by such
therapies.
When treating cancers with radiation therapy, an oncologist needs to keep in mind the
late term side effects that patients can experience as a result of radiation exposure. This concept
is particularly of importance when treating pediatric patients because their cells are more
sensitive to radiation and because they have long lives ahead which should not include a
diagnosis of a secondary malignancy. The treatment of Hodgkins lymphoma is unfortunately
associated with long term side effects, particularly of secondary cancers that develop later in life.
With an initial cure rate of 90% for stages IA and IIA non-bulky disease, it is evident that further
research needs to be conducted to reduce toxicity levels to normal structures. There is great
promise with treating Hodgkins disease with chemotherapy alone, but further research needs to
examine which chemotherapy routine is best. In addition, this needs to be long term and all the
participants need to have early stage disease. In dealing with cancers that are more common in
pediatric patients, it is crucial to remember that whatever dosage children receive, the effects of
that dosage stay with them the remainder of their lives. Hopefully, this can prevent children from
having to experience another cancer diagnosis later in life.

Bibliography
1. Barbaro PM, Johnston K, Dalla-Pozza L, Cohn RJ, Wang YA, Marshall GM, Ziegler DS.
Reduced incidence of second solid tumors in survivors of childhood Hodgkins lymphoma
treated without radiation therapy. Annals of Oncology. 2011;22(12):2569-2574.
http://journals.ohiolink.edu.proxy.lib.ohio-state.edu/ejc/pdf.cgi/Barbaro_P._M.pdf?
issn=09237534&issue=v22i0012&article=2569_riossthltwrt. Accessed [4 December 2015].
2. Khafaga YM, Belgaumi AF. Pediatric Hodgkins lymphoma: Changing concepts and moving
points in radiation therapy. Transfusion and Apheresis Science. 2013;49(1):56-62.
http://journals.ohiolink.edu.proxy.lib.ohio-state.edu/ejc/pdf.cgi/Khafaga_Yasser_M.pdf?
issn=14730502&issue=v49i0001&article=56_phlccampirt. Accessed [4 December 2015].
3. Meyer M.D. RM, Gospodarowicz M.D. MK, Connors M.D. JM, et al; for NCIC Clinical
Trials Group and the Eastern Cooperative Oncology Group. ABVD Alone versus RadiationBased Therapy in Limited-Stage Hodgkin's Lymphoma. The New England Journal of Medicine.
2012;366(5):399-408. http://www.nejm.org.proxy.lib.ohiostate.edu/doi/full/10.1056/NEJMoa1111961#t=articleTop. Accessed [5 December 2015].

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