2007 ANNUAL
SITE STUDY
HODGKIN’S
LYMPHOMA
SUSQUEHANNA
HEALTH
David B. Nagel, M.D.
April 11, 2008
Hodgkin’s
lymphoma was first described by Thomas Hodgkin in 1832. It remained an incurable malignancy until the
early 1960’s when the concept of extended field radiotherapy encompassing nodal
regions above and below the diaphragm, in addition to the spleen and in some
cases even the liver and lungs, was used with success in curing a percentage of
patients stage I through III Hodgkin’s disease.
The development of systemic chemotherapy by DeVita and colleagues in the
mid-1960’s with the development of MOPP chemotherapy enabled a percentage of
patients with advanced Hodgkin’s disease to be cured. By the 1980’s, MOPP had given way to ABVD
chemotherapy and a number of patients were being treated with combined modality
therapy utilizing various combinations of chemotherapy and radiation therapy in
an attempt to increase the cure rate over what had been seen with single
modality therapy. Success has been seen
with combined modality therapy to the point that it has become the accepted
treatment for both favorable and unfavorable stages I and II Hodgkin’s disease
and various subsets of stage III Hodgkin’s disease, i.e. bulky mediastinum
involvement.
Staging of
Hodgkin’s disease is based on the Ann Arbor staging system with the Cotswolds
modification.[1] In addition to this, a number of prognostic
factors have been identified that are not a part of this staging system. These include: the number of involved
regions, size of tumor mass (primarily mediastinal), “B” symptoms, age greater
than 50 years, male gender, elevated ESR, cytology (mixed cellularity), anemia
and low serum albumin.2,3
These risk factors have been used in various combinations to separate
patients into the following 3 groups:
early stage favorable, early stage unfavorable, and advanced stage by
the cooperative groups investigating treatment of Hodgkin’s disease.[2],3
Our study
encompasses the dates from January 1, 1990 through December 31, 2001. During the early part of this trial, stages I
and II Hodgkin’s disease were commonly treated with subtotal nodal radiotherapy
alone. At the end of this period the
same stages were treated either with chemotherapy alone or combined modality
therapy usually involving initial chemotherapy followed by radiotherapy to
involved sites of disease. The
treatment for stages III and IV Hodgkin’s disease during this period saw less
change and remained either chemotherapy alone or combined modality therapy on a
case-by-case basis. Controversies remain
in the optimal treatment of the various stages of Hodgkin’s disease, however,
combined modality therapy has emerged as the standard preferred treatment for
favorable and unfavorable early stage Hodgkin’s lymphoma.2,6,9,11 There is less agreement as to the optimum
treatment strategy for those patients with advanced stage Hodgkin’s lymphoma.9
Our 63 analytic patients over 11 years at
Susquehanna Health give us an average of approximately 6 new patients with
Hodgkin’s disease per year. We analyzed
various aspects of the patient group including additional malignancies: those
occurring prior to presentation of Hodgkin’s disease and those that occurred
after Hodgkin’s disease treatment. The
latter have frequently been termed “secondary malignancies” some of which may
be attributed to the treatment, some of which may have developed irrespective
of the treatment. Because of our small
number of patients, we are not able to perform statistical analysis of this
data, however, table 2 does show disposition of the malignancies occurring
after the treatment of Hodgkin’s disease in each patient.
|
Table
2 |
|
|
Second
Primary |
Status |
|
Large
Cell Lymphoma, Colon |
Alive and
disease-free |
|
Larynx,
Melanoma |
Alive and
disease-free |
|
Colon |
Deceased
from Colon CA |
|
Penis |
Deceased
from ESRD |
|
Nerve
Sheath Tumor |
Alive
with disease |
|
Wilms,
Kidney |
Deceased
from other causes |
Tables 3 through 6 detail various attributes
of our patient cohort. Table 3 shows the
age at diagnosis exhibiting the bimodal peaks in age distribution
characteristic of Hodgkin’s disease.
Table 4 shows that approximately two-thirds of our patients presented
with multiple nodal regions involved with Hodgkin’s disease. Table 5 shows nodular sclerosing is the dominant
histology occurring in almost two-thirds of our patients with mixed cellularity
found in the majority of the remaining patients. Indeed, lymphocyte predominance and
lymphocyte depletion are uncommon pathologic entities. An additional 4 patients were found to have
nodular lymphocyte predominant Hodgkin’s disease (NLPHD), but these patients
were not included in this analysis since NLPHD follows a distinctly different
natural history and is excluded in most analyses of treatment of Hodgkin’s
disease. Table 6 shows the distribution of
symptoms at presentation with stage II predominating in 46% of our patient
cohort followed by stage III and IV, each representing approximately 20% of the
cohort. 
Staging of
Hodgkin’s disease during this time period of 1990 to 2001 is represented in
table 7. Ninety-eight percent of the
patients had CT scans including chest, abdomen and pelvis, 71% of these patients
had a gallium scan. Bone marrow biopsies
(table 8) were done in 86% of the patients.
They were positive in 10%, negative in 76%, not performed in 11% and 3%
unknown if it was performed. 
Treatment
of Hodgkin’s disease can be divided into 3 categories: chemotherapy, radiation therapy and combined
modality therapy consisting of a combination of chemotherapy and radiotherapy. Combined modality therapy generally consists
of several cycles of chemotherapy followed by different radiotherapy strategies
which evolved over the time of this study from subtotal nodal radiotherapy to
extended field radiotherapy and most recently to involved field radiotherapy
treating only the involved site with a small margin around it. Table 9 shows the 63 cases analyzed by
treatment and arranged by stage. Three
of the 63 patients received no treatment. Of the remaining 60 patients, 31
received chemotherapy, 7 received radiotherapy and 22 received combined
modality therapy. Forty-nine patients
treated achieved complete remission and 11 patients were never disease
free. Twenty-five of 31 patients
receiving chemotherapy treatment, 5 of 7 receiving radiation therapy and 19 of
22 receiving combined modality therapy achieved a complete remission.
Thirty-four patients of the 49 complete responders remained disease free and 15
failed. Recurrence data is further
delineated in the paragraph below table 9.
The initial stage of disease for the fifteen patients who failed their first course of therapy was as follows: 3-IA, 3-2A, 1-2B, 2-3B, 1-4A and 5-4B. Fourteen of the 15 recurred in the same lymph node chain as at diagnosis. Ten of 25 chemotherapy, 2 of 5 radiotherapy and 3 of 19 combined modality therapy complete responders failed their first course of therapy. The average number of months to first failure in this recurrence group was 32 months from initial diagnosis. All of these patients received salvage therapy; either chemotherapy alone, radiotherapy alone or combined chemo/radiation modality. Six patients received therapy with a bone marrow transplant, 2 being still alive. Of these 15; 8 patients are currently disease-free, 6 are deceased from Hodgkin’s lymphoma and 1 deceased from other causes.
Survival data was
examined for the 60 patients receiving treatment and graphed on tables 10, 11
and 12. Tables 10 and 11 show overall
5-year survival and disease-free survival respectively. To date 25 patients are deceased; 17 from
this disease and 8 from other causes.
Both graphs show superiority of combined modality therapy over either
chemotherapy or radiation therapy alone.
Table 12, detailing overall survival analyzed by AJCC stage, shows our
stage I 5-year survival is lower than that seen for stages II through IV. We feel that this result is anomalous and may
be explained by the small number of patients in this group (8) as well as their
advanced age. Six of the 8 patients were
age 49 or greater with an average age of 54.2.
Age greater than 45 is considered an adverse prognostic factor in the
International Prognostic Score (IPS) system for Hodgkin’s lymphoma.[3],[4]
In addition, only 3 of the 7 treated Stage I patients received combined
modality therapy. 
Table 13 breaks
down treatment of stage I and II patients by modality. This graph shows superiority in treatment by
combined modality therapy over chemotherapy and radiotherapy only patients. 
Analysis: Aside from our overall survival of this small
group of stage I patients, comparison of our stage II, III and IV patients with
the All NCDB Facilities observed 5-year survival table 14 and All Pennsylvania State
Facilities observed 5-year survival Hodgkin’s lymphoma table 15 is very similar
for stage II patients, and is better than either of the comparison groups for
stage III patients and stage IV patients.
Recent
published literature of treatment for early stage Hodgkin’s disease clearly
favors combined modality therapy over either chemotherapy or radiotherapy
alone. The German Hodgkin’s Study Group
HD-10 study for patients with favorable Hodgkin’s disease receiving 2 to 4
cycles of ABVD combined with involved field radiation therapy showed an overall
survival of 97% and freedom from treatment failure of 94% at a median follow up
of 4 years.[5] Another recent study was the EORTC-GELA H-8
trial, which treated early stage favorable and unfavorable patients with 3
cycles of MOPP-ABVD plus involved field radiation therapy. This showed a 5-year event free survival rate
of 98%. The recommendation from this
paper dated December 5, 2007 was for patients with early stage Hodgkin’s
disease to be treated with chemotherapy plus involved field radiation therapy
as standard treatment.[6] The current NCCN guidelines also recommend
combined modality therapy for early stage Hodgkin’s disease.
Future Directions: FDG-PET scanning has emerged as a powerful imaging tool for the staging of lymphomas and PET is now strongly recommended before treatment of Hodgkin’s disease. It is now also being used for post treatment assessment since a complete response is required for cure of this disease.[7] Nearly all-ongoing trials of early stage Hodgkin’s disease incorporate FDG-PET/CT for assessment of the response to treatment after 1 or 2 cycles of ABVD.[8] It is hoped that this information will lead to “adaptive” treatment strategies according to response by PET scan. Since our study preceded the general use of PET scanning for Hodgkin’s lymphoma, none of the 63 patients in this study received PET scan during their initial workup and treatment.
Future studies will continue to try to resolve various controversies in the treatment of Hodgkin’s disease:
1. What is the optimal chemotherapy regimen and number of cycles in early and advanced Hodgkin’s disease?
2. What is the optimal radiation therapy dose and extent of coverage in involved field radiation therapy?
3. What is the role of radiation therapy in advanced Hodgkin’s disease?[9]
4. Are there subsegments of favorable Hodgkin’s disease that can be treated with chemotherapy only?[10]
5. How can “adaptive therapy strategies” be used with FDG-PET CT scanning after 1 to 2 cycles of chemotherapy?8
6. What is the risk of second malignancy with the current radiation therapy utilizing involved field with the current dose recommendations of 20 to 30 Gy?[11]
A recent article from February 1,
2006 in the JCO shows no second cancers observed in the CMT group with median
follow up of 8.1 years, but longer term follow up is still needed to assess the
risk of second malignancy in this group of patients.11
Conclusions: Excluding our small group of stage I patients, the treatment of Hodgkin’s disease at Susquehanna Health for stages II through IV compared very favorably with all Pennsylvania State facilities data and all NCDB facilities data for years 1998 through 1999. Due to the small number of our stage I patients and the fact that their average age at 54 placed them in a negative prognostic category, a comparison of our stage I patients with the larger databases is not valid. Although our number of patients in any one-treatment group is small, it is interesting to note the superiority in terms of local recurrence and overall survival and disease free survival of our combined modality group compared to chemotherapy or radiotherapy alone. FDG-PET/CT scanning should now be a standard part of the work-up of any patient presenting with Hodgkin’s disease, and should also be used as a follow up test to assure complete response to therapy. Mature data is still not available as to how PET scanning should be used during treatment to form “adaptive treatment strategies”. Until these data are available we should refrain from the use of PET scan for this purpose. Our own data is in agreement with the current recommendations by the NCCN2 and recent literature showing a superiority of combined modality therapy in the treatment of early stage Hodgkin’s disease.5,6
References