Hodgkin's Disease is a "malignant lymphoma" virtually always starting in lymph nodes, formerly called
"reticulum, cell sarcoma". It is a "lympho-reticular disease" that was first recognized by Thomas
Hodgkins in 1832, who noted enlarged lymph nodes in patients not attributable to inflammation. Since
then, there has been a continual sub-classification of the malignant lymphoma's, most notably into
Hodgkin's and Non-Hodgkin's types. The classic binuceated "owi's eyes" cells, termed "Reed-Stemberg"
are believed derivedfrom lymphoctyes or the monocyte-macrophage "antigen presenting" cells, and are
pathognemonic for Hodgkin's Disease, which comprises 40% of malignant lymphomas.
Epidemiology and Risk Factors for Hodgkin's Disease:
There are 7400 new cases of Hodgkin's in the U.S.A. each year, causing 1500 deaths. The incidence of
Hodgkin's has remained fairly constant over the past 50 years. A small male predominance is seen, the
male to female ratio is 1:3:1. In childhood cases, 85% are male. A "bimodal" age distribution is
seen for Hodgkin's, with one cluster of cases in the 2nd to 3rd decade, and a second cluster in the
7th decade. In industrials countries, the disease tends to occur at a later age than in underdeveloped
countries. The disease is rare in children under 10 years old. There are proportionately more cases in
the older age group peak than in the younger age group. It accounts for 0.75 of the new cancer cases in
the U.S.A./year.
Risk Factors:
While the reason a particular person gets Hodgkin's is unknown, clusters of the disease in certain
regions have been noted, and both genetic and infectious processes have are suspected. People at
increased risk for developing Hodgkin's include:
1) Inborn immune deficiency diseases, such as Wiscott-Aldrich, Ataxia Teiangectasia, and T-cell
function disorders.
2) Acquired immunodeficiency from AIDS or immunosuppressive drugs.
3) Living in Western countries, being of higher social class, more educated.
4) Genetic pre-disposition, clusters are noted in siblings with similar HLA genotypes.
5) Infection with Epstein-Barr Virus (EBV) history is noted in up to 40% of patients developing
Hodgkin's. Elevated levels of the IgG and IgA immunoglobulins against the EBV capsid antigen
are noted 3 months to 12 years prior to clinical Hodgkin's development. Components of the EBV
genome have been noted in the cellular DNA of the Reed-Stemberg cell (Ref. Weiss NEJM 320:
502 1989). However, the EBV is not noted in all patients and may be merely a marker of the
poorer cellular immunity (but intact humoral immunity) seen in Hodgkin's patients.
While the pathogenesis of Hodgkin's still remains unknown, it is likely that a combination of
enviromental and genetic factors are at work, such as the EBV precipitating the dis-
ease in a genetically susceptible individual.
Molecular Biology:
The Reed-Stemberg (RS) cell likely arises from either lymphocytes or antigenpresenting cells of the
monocyte-macrophage line. Regarding lymphocytic origin, 60% of RS cells have T or B cell specific
antigens, and B cells are the usual target for EBV. Furthermore. RS cells express IL-2 receptors,
HLA-DR antigens, and Ki-1, which are all features of activated lymphoctyes.
On the other hand, RS cells have la antigen, and Fc and C3 receptors which are all found in
antigen-presenting cells. It is important to note that RS-like cells are found in several infectious,
inflammatory and neoplastic conditions including infectious mononucleosis, reactive lymphoid
hyperplasia and immunoblastic lymphoma. Thus, diagnosing Hodgkin's depends on finding the RS cells in
the appropriate backround millieu. The lymphocytes within Hodgkin's are usually predominantly CD-4
positive T-cells, recall that poorer cellular immunity (but intact humoral immunity) charactizes
Hodgkin's. This defective cellular immunity persists even after clinical cure!
The BCL2 Oncogene is found in 1/3 of Hodgkin's patients, and p53 suppressor gene is found in almost
all Hodgkin's patient's except those with Lymphocyte predominant disease. The common tl4:18
translocation of B cell lyphomas is rare in RS cells. We Conclude that different subtypes of
Hodgkin's may be derived from different immune cells, sothe RS cell may arise from more than one type
of precursor (Ref. Devita Clinical Oncology c. 1994 4th ed.p. 1824).
Clinical Presentation and Modes of Spread:
Hodgkin's appears to always arise in lymph nodes, cervical and/or supraclavicular node involvement
occurs in over 80% of patients, while mediastinal lymph nodes are noted in 50% of patients. lnguinal
lymph nodes are seen in 10% of patients. Common signs and symptoms include:
1) Painless lymphadenopathy. The enlarged lymph nodes have a rubbery texture. Spread is usually
axial and contiguous, that is proceeds in smooth order from one lymph node group to the next.
Generalized lymphadenopathy is unusual.
2) Unexplained Fever (>38o C), Weight Loss (> 1 0% body weight in 6 months) and/or drenching Night
Sweats constitute the accepted "B" symptoms. One- Third of patients present with "B" symptoms.
Generalized pruritis and alcohol induced tissue pain are common but do not represent "B" symptoms.
3) Anterior Mediastinal mass on Chest X-ray. "Bulky" mediastinal disease is defined as measuring
equal or greater than 1/3 of the thoracic diameter. Pulmonary involvement may occur by either
direct extention from hilar nodes or by hematogenous dissemination. It may be seen as discreet
nodules or infiltrates on X-Ray. Pleural effusion is occasionally seen and are transudates.
4) The eadiest abdominal sites for Hodgkin's are the spleen, splenic hilar and celiac lymph nodes.
Clinical enlargement of the spleen is an unreliable detector of di- sease there, as 25% of
patients with no spienomegally will have occult spleen involvement increases. As the disease
becomes disseminated, the likelihood of spleen involvement increases. Mesenteric nodes are rarely
involved. Hepatomegaly is also uncommon, without spleen involvement, but not vice-versa.
Periaortic lymph nodes are involved late in supradiapragmatic Hodgkin's but early in inguinal
presentations.
5) Disseminated disease is marked by hematogenous spread. to bone marrow, and to bone cortex causing
osteolytic or blastic lesions. Disease extending from the retropehtoneal lymph nodes to the
vertebrae may cause radiographic 'ivory vertebrae" appearance. Hodgkin's rarely involves the gut
lymphoid tissues and very rarely spread to the CNS.
6) Patients with Hodgkin's are at higher infection risk with viruses and funguses due to poorer
cellular immunity and occasionally present with ITP, Coomb's positive anemia, or invoivment of the
skin, breast or kidneys.
Pathologic Types of Hodgkin's Disease:
Hodgkin's disease is grouped into 4 basic, pathologic types, in the Rye system:
1) Nodular Sclerosis (NS) is about 75% and is characterized by large RS cells (60 um) who's cytoplasm
retracts during fixation, leaving "lacunar" spaces around the nuclei. The RS cells are
"occasional" and in a backround of neutophils, eosinophils and birefringent bands of collagen.
This type tends to arise in the cervical nodes and anterior mediastinum in late adolescent
patients, and is of intermediate prognosis. Subtypes include lymphocyte-depleted NS with marked
necrosis, and a syncitial variant with bulky masses.
2) Lymphocyte Predominant (LP) is about 1 0% of Hodgkin's and is characterized by rare RS cells,
which makes the diagnosis difficult. As the name suggests, there are plentiful lymphocytes. It
occurs in patients under 35 years old with localized disease. It is usually asymptomatic and early
stage at presentation with a good prognosis. Subtypes include nodular and diffuse patterns, the
diffuse type being related to B-cell lymphoma and characterized by an indolent course with
frequent late relapeses.
3) Mixed Cellularity (MC) accounts for 30% of cases and is characterized by a mixed infiltrate of
neutrophils, eosinophils and plasma cells. A moderate number of RS cells are noted. It is the most
common type in middle-aged patients between 30-50 years old, and often has a retro-peritoneal
presentation. It is intermediate in prognosis.
4) Lymphocyte Depleted (LP) represents less than 5% of cases and has lots of RS cells and few
lymphocytes. It often has diffuse fibrosis, and causes minimal adenopathy. The reticular subtype
is difficult to distinguish from high-grade Non-Hodgkin's lymphoma. Most patients. are over 50
years old, and have diffuse abdominal disease. Bone marrow and liver involvment are more common
than in the other types, and most patients present with advanced stage disease. It carries the
poorest prognosis.
Staging: (Given by the Ann Arbor System)
| Stage I | Involves a single lymph node region (on either side of the diaphragm) |
| Stage II | Involves two or more lymph node regions on the same side of the
diaphragm (i.e. either "supra" or "sub" diapragmatic disease, not both) |
| Stage III | Involves nodal regions on both sides of the diaphragm. |
| Stage IV | Means diffuse involvement of extralymphatic tissues, with or
without simultaneous lymph node involvement. |
**Stages I-III may be subclassified into 'E" subtype to indicate the presence of extranodal disease, either alone or in combination with nodal disease depending upon the stage and "S"
subtype to indicate spleen involvement, which is treated as a large lymph node. Subtype "X'
indicates bulky disease of > 1/3 thoracic diameter or > 10 cm.
**All stages may be further subdivided into "A" and "B" disease, depending upon the presence or
absence of uB' symptoms of fever, night sweats and/or weight loss.
Staging Work-up and Evaluation:
It is crucial to do a complete staging work-up in the patient since the recommended treatments follow
the stages. However, this is balanced by the the realization that some tests (i.e. staging
laparotomy) are unneccessary if the mode of therapy is a forgone conclusion, or if there is a minimal
chance it would be positive. Also, some tests ( bipedal lymphangiography) are highly operator
dependent and some institutions may have insufficient experience to really benefit the patient from
the test. Thus, while all patients will get routine radiographs and blood tests, sound judgement as
to whether the benefits of the test will outweigh the risks and costs is mandatory for invasive
procedures.
Routine diagnostic procedures include:
1) Physical exam concentrates on the clinical lymph node groups, detailing the location and size of
any enlarged nodes. Also looks for any signs of organomegaly or cardiorespiratory problems.
Lymphoid tissues in the head and neck (Waldeyees ring) are checked.
2) Biopsy of the presenting lymph node to establish the diagnosis. The largest and most central lymph
node of a given group is most likely to be diagnostic. Neck nodes are prefered to axillary or
inguinal nodes, since the later more often harbor chronic inflammatory changes that can confuse
the diagnosis. Finding of RS cells is necessary but not sufficient for the diagnosis. RS cells may
be very hard to find, or they may be plentiful but represent a benign condition. It can take an
expert pathologist to find the RS cells and make sure that they are in the appropriate milleau
to diagnose Hodgkin's.
3) Hematologic tests: include CBC with differential and reticulocyte count to check for anemia, which
is commonly microcytic, and a Coomb's antiglobulin test if anemia is found. Lymphocytopenia is
found in advanced disease. ESR elevation parallels disease activity in Hodgkin's. Chemistries
include routine SMA panel for liver and kidney function, serum copper, and protein
electrophoresis. Diffuse (broad band) hypergammaglobuline- mia is commonly seen in Hodgkin's and
NHL. Monoclonal spikes are rare in Hodgkin's. Bone marrow biopsies are obtained in any patient
with "B' symptoms. if there is evidence of bone involvement 'on imaging studies or from elevated
alkaline phosphatase, or for any patient with stage III or IV disease.
4) Imaging procedures: If a chest X-Ray is normal, then a CT scan is usually unneccessary (DeVita).
However, in practice a Chest CT is almost always obtained (Rubin 7th ed. 1993 p. 220). Chest CT
gives details about intrathoracic lymph nodes, lung parenchyma, pericardium, pleura, and chest
wall, and can alter eventual treatment in 10% of cases (Rubin p.221). Also, obtaining a baseline
study gives a chance for comparison with later studies. Nodes >1 cm. are suspicious, while nodes
>2 cm. are abnormal. Abdominal CT will show spienomegaly and overt liver involvement, and can show
enlarged paraaortic or mesenteric nodes. Special attention is given to the celiac and porta
hepatis regions, versus the paraaotic and mesenteric nodes. An important modification of the Ann
Arbor staging system for stage III was developed by the Univ. of Chicago. In this modification,
multiple spienic nodules (>4) or involvement of the lower abdominal lymph nodes (paraaotic and
mesenteric) is substaged as 1112, while patients with less spienic nodules and only involvement of
the spienic. celiac and portal nodes ( all closer to the spleen) is III l
Lymphangiography was popularized at Stanford where large series were reviewed by Dr.
Castellino and Hoppe (Ref. Invest. Rad. 9:155 1974). The test, a 'bipedal lymphangiogram" involves
injection of contrast into the lower leg veins, where it migrates into the lymph system and
travels cephalad. The contrast is taken up by certain lymph nodes in the pelvis and abdomen, and
when a plain flat-plate X-Ray is taken of these areas, these lymph nodes can be visualized.
Enlargement and subtle changes in architecture (particularly a "foamy' appearance) alludes to
lymphomatous disease in these nodes. The external iliac and paraaortic nodes are well visualized
by this method, Unfortunately many nodes are not well visualized can be remembered by the
acronym'MIHOP':
| M = Mesenteric |
| I = Internal iliac |
| H = Hypogastric |
| 0 = Obturator |
| P = Parasacral |
This is of course the same for lymphangiography in Prostate CA) -The experts at
Stanford were able to get an accuracy of 92% in identifying positive lymph nodes by lymphangiogram
(no false negatives but 25% false positives). Overall, 30% of clinically early stage patients had
disease below the diaphragm showed by lymphangiogram. Specifically, 15% of pts. with only cervical
disease had positive abdominal nodes, while 80% of those with stage IIB disease had positive nodes
(Ref. Rubin 7 ed. 1993.). This made lymphangiogram a very valuable test for upstaging patients to
stage III and disqualifying radiotherapy as the only treatment (at least for 1112 disease). This
could also then obviate a laparotomy, as described below, since the treatment (chemotherapy) was a
forgone conclusion. Furthermore, the contrast dye stays for many months in the lymph nodes, and so
the effects of therapy can often be gauged by getting subsequent abdominal X-rays and
re-visualizing the nodes. However, current radiologists rarely have the experience to do a proper
lymphangiogram, and the results are very "operator dependent". Also, it is an uncomfortable test
and has possible complications of venous thrombosis. Thus many centers rarely, if ever, do this
test today, despite it's utility at Stanford. However, the POC (Hanks) recommends it for all pts.
not laparotomized! Gallium Scaning is useful for following response of bulky disease in the thorax
(it's far less reliable for disease below the diapragm, or for nodular lymphoma).
5) Anatomic Staging:
Laparotomy is a surgical evaluation to help determine the stage of Hodgkin's Disease, it is not a
therapeutic procedure. It's utility is the ability to objectively determine whether disease exists
below the diaphragm, which may then preclude radiotherapy only (since some will still treat
1111AMth XRT only).
A standard staging laparotomy includes:
a) Sampling of all anatomic nodal stations in the abdomen, including the spienic, portal,
celiac, periaaotic and mesenteric. Clips are placed by enlarged nodes.
Splenectomy, the spleen is "finely sliced" by the pathologist. The splenic pedicle is marked
with clips for easy localization by the radiation oncologist.
c) Oophoropexy in females to get the ovaries out of the way if XRT is possible.
d) Biopsy of both lobes of the liver (its positivity is less than 5% if the spleen is
negative).
e) Bilateral Bone Marrow Biospy from the Iliac wings.
Complications of Lapartomy include death rate of 1%, surgical infection rate of 10% Patients
with massive mediastinal disease have an increased death rate and may be difficult to wean from a
ventilator. Possible later complications include asplenic sepsis with encapsulated bacteria (i.e
streptococcus, pneumococcus, and salmonella) especially in children, and late bowel obstruction
from adhesions. Laparotomy is not an innocuous procedure and must be justified. In general, any
patient for whom chemotherapy is primary treatment should not get laparotomized. This includes
patients with stages IIIB and IV disease, and those with massive mediastinal disease. Any patient
with "B" symptoms will receive chemotherapy in some institutions, so this obviates laporatomy for
them. Also, for pediatric Hodgkin's it is seldom indicated as children usually will get chemotherapy
with low dose XRT if it is indicated, and they have a greater risk of sepsis after spenectomy.
Another class of patients for whom lapamtomy is not justified are those who's chance of being
upstaged by laparbtomy is very low. In general, the chance that a patient with stage I or 11
disease will be upstaged at lapatomy is 30%, thus justifying the procedure. However, according to
the extensive Stanford series, some classes of patients with stage I or 11 disease have a less
than 5% chance of being upstaged so for them laparotomy is not justified. This includes:
1) All females with stage I disease
2) Females less than 27 years old with less than 4 sites of disease.
3) All males with stage I lymphocyte predominant or interfollicular
histology.
4) All patients with Clinical Stage I disease limited to the thorax, axilia or high
cervical nodes.
The remaining patients who are usually laparotomized are those with IB, IIB or IIIAL disease,
and those with IA and IIA disease with higher risk factors for disease under the diaphragm,
which includes male sex and having positive supraclavicular nodes.
Prognostic Factors:
Factors having an adverse effect on prognosis include:
1) "B" symptoms. especially weight loss and night sweats.
2) Higher Stage, especially with bone-marrow or organ invovement.
3) Patients with greater spienic involvement (>5 nodules) have a worse
prognosis when treated with primary XRT.
4) Bulky disease with large tumor burden. This includes large mediastinal lymphadenopathy, which is: >1/3 of maximal thorax diameter.
5) Worrisome labs include ESR>70 and high serum copper.
6) Older Age, Lymphocyte Depleted Histology and Male sex all worse.
Treatment of Hodgkin's Disease:
While Hodgkin's Disease used to be uniformly fatal, long term survival for all stages now exceeds
75%, and for early stages over 90%. The whole idea of the extensive staging procedures above is to
select the appropriate treatment, as neither over nor under treatment is optimal. In general, stages IA, IIA,
and IIIAL can be treated with Radiation alone, while many clinicians choose chemotherapy for patients with "B'
symptoms, stage II IA2 and any stage IV patients. Patients with more extensive disease such as large
mediastinal mass or lung parenchymal involvement get combined treatment with both chemotherapy and radiation,
while some with stage IV or relapsed disease are getting high-dose chemotherapy followed by autologous bone
marrow transplantation. Each of these therapies for Hodgkin's has evolved, and some history, methods of
current administration. and side effects and latest usage of each of these is now discussed.
Radiation Therapy Alone:
The responsiveness of lymphomas to radiation was noted as early as 1902 by Pusey (Ref. JAMA 1902; 38:166).
Only orthovoltage was available, so treating deep tumors were difficult to treat without excessive skin
reaction. Another pioneer named Gilbert developed the basic principles of modem radiation therapy, suggesting
that treatment of all involved areas was essential for cure. Gilbert treated adjacent sites that had a high
probability of involvement, as we do today. His work resulted in the first verifiable cures from Hodgkin's
with radiation alone, as shown by no recurrences 10 years after treatment. The *guru" who had the most
influence on our current use of radiation for Hodgkin's was Henry Kaplan of Standford University (Ref. NEJM
1968 278 892). His work layed the foundation for modem radiation treatment for cure of Hodgkin's. Kaplan
provided anatomical evidence. through staging techniques, of the "orderliness and continuity" of the initial
presentation of Hodgkin's and subsequent spread (Ref. DeVita 4th ed. p. 1829). He also was able to use the
newly developed supervoltage machines to adequately treat deep disease. Later researchers refined the
dose-response cure for Hodgkin's.
In general, local gross disease should get 44 Gy, but contingous areas with treated for subclinical disease
should get no more than 35 Gy, and possibly as low as 30 Gy. Doses are ideally fractionated at 1.5 - 2.0 Gy/
fraction, 5 days per week. (Ref. Hanks Cancer Treatment Reports 1982: 66 805).
The machine energy is ideally 4 to 8 MV, This gives the best depthodose characteris@ tics, Cobalt@60 has less
well defined beam edges and since its energy is only 1.25 MV, it normally gives less dose delivery at depth,
and even poorer depth dose when the SSD is less than the standard 80 cm. If higher energy is used (i.e, 15 or
20 MV) then the superficial tissues like the neck subdermis (vath its abundance of lymph nodes) will then
be undertreated (unless complex bolus techniques are used).
There are several basic radiation fields to know clearly for treating Hodgkin's. Each has a particular eponym,
such as umantle 0 t 4 spade p , "paraaortic" or @ivica, Combim nations of these fields allow for *total nodal
irradiations the lesser "subtotal nodal irradiation or the lower body "inverted Y.
The most widely used field is the mantle." It's design is critical since it radiates large amounts of normal
tissue. The idea of the mantle is to treat the lymph nodes in the neck (cervical, occipal, pre-articular and
supraclavicular regions), the upper torso (axillary, infraclavicular and pectoral regions) and the midchest
(mediastinum and hilar areas), The idea is to give dose to these regions while protecting radiation sensitive
normal tissue in the area (like lung, heart, soinal cord and humeral head).
The mantle starts from just below the earlobes, wnicn corresponds to the inferior mandibular margin with the
head extended. A mouth and trapezoidal larynx block are placed, Note the shape of the anterior and posterior
blocks are slightly different. The anterior lung blocks are slightly smaller, to allow greater treatment of
the axillary and infraclavicular areas. They start with rounded tops 2 cm below the clavicle, and gently curve
down to parallel the chest wall at about T6 (see diagram). The medial portion of each block flares out to
encompass the hila. By contrast, the posterior lung blocks start out just 1 cm from the clavicles (as seen on
the posterior port view) and are squared off on top to parallel the clavicle image. These posterior lung
blocks directly abut the chest wall from the outset (instead of gradually tapering to meet it at T6 like the
anterior blocks). The hilar area, as seen from the posterior view, is treated similar to the anterior port.
When a dose of 40 Gy or more is prescribed, a 5 HVL posterior cord block is placed over the cervical cord from
the outset of treatment. The posterior cord block is then extended to the thoracic cord area to limit the
thoracic cord dose to 36 Gy. Also very important is the addition of "subcarinal" blocking after 30 Gy has been
delivered to the mediastinum, placed 5 cm below the carina, to limit the dose to the pericardium and the
heart. Finally, note the humeral head blocks to avoid getting a dry joint as a late effect.
Special situation mantle modifications:
1) In patients with known mediastinal involvement treated with primary irradiation, the entire cardiac
silhouette is treated to 15 Gy (with lung blocks shaped to expose the entire cardiac silhouette),
afterwhich regular lung blocks are used. Devita (4th ed. p. 1830) says the whole heart should only be
treated if there is known pericardial disease.
2) For patients with massive mediastinal disease (>I/3 the thoracic diameter at T6) when treated with XRT
alone we start with very small or even no lung blocks and treat to 1 0 Gy in 1 Gy/day fractions. We give a
2 week treatment break (to allow the mass to shrink) and then progressively increase the size of the blocks
as the mass decreases (Ref. Perez 2nd ed. p. 1315 - 1316). If laparotomy is planned, patients may have
their mediastinal masses shrunk in this manner to avoid anesthesia problems.
3) In patients with hilar adenopathy or pulmonary parenchymal involvement we treat the whole pulmonary
parenchyma (given the increased risk of coexisting lung disease). We omit the lung blocks on the side of
the hilar node(s) for the first 15 Gy, then use "partial transmission" (aka "thin") lung blocks giving
37%.transmission for the remainder of the mantle treatment, so the total dose to the entire lung is about
25 Gy over 5 weeks, which is full tolerance (Ref. Perez 2nd ed. table pg. 151).
4) Larynx blocking is appropriate unless there is known disease directly adjacent to it.
5) A "supradiaphragmatic" or "minimantle" merely cuts off the lower portion of the mantle from the clavicles
downward. It is used for retreatment of axillary and supra- clavicular nodes, and possibly for lymphocyte
predominant disease localized to the high cervical region, which has a less than 5% chance of mediastinal
involvment.
Dosimetric considerations when irradiating a mantle field include getting an irregular field point dose
calculation for each nodal group within the field. If the to any of of the nodal groups are outside the
prescribed range, special blocking or bolus will be neccessary. Spinal cord doses must be especially watched,
since the mantle often abuts other fields (i.e. paraaortic, spade or preauricular fields). A brief review of
how to do a gap calculation follows.
"The Simple Way to Calculate A Gap"
I recommend you stick with the symbols in Johns (the guy who invented TAR, TPR. wrote on'the subject
long before Kahn and speaks the queen's English)
| "The Formula" (memorize it) |
| For each field: |
S = dW
______
2 F |
S = Separation (for each field)
W = how long the field is on the skin
d = depth at calculation point
(i.e. how deep the spinal cord is)
F = Distance from collimator to skin (SAD) |
Then just add both together: GAP= SI + S2
Example: You are adjoining 2 fields, at 120 cm SAD, with the spinal cord at a depth of 6 cm. The upper field
is 30 cm long, and the lower field is 20 cm long. How big should the gap be?
Answer:
| For first field S1 = |
6 cm 30 cm
__________
2 X 120 cm |
= 0.75 cm |
| For the second field S2 = |
6 cm X 30cm
___________
2 X 120 cm |
= 0.50 cm |
Therefore, total GAP = S1 + S2 = 0.75 cm + 0.50 cm = 1.25 cm
**Always be sure your adjacent Hodgkin's fields do not directly abutt on the skin suiface!
The Preauricular Field:
If there are positive nodes in the preauricular area, they will not be treated properly with the mantle field,
since it ends below these at the jawline. Thus, if there are positive nodes above the thyroid notch, or
involvement ' or Waideyees ring (rare), this field is appropriate. It is treated unilaterally with electrons
(6 - 9 MeV) to spare parotid or bilaterally with photons (4 - 6 MV) for deep disease.
SubDiaphragmatic Fields:
If one is treating all of the major lymph node groups under the diaphragm, this will include the paraaortic,
spienic, and pelvic, and femoral nodes (even "total nodal irradiation" doesn't treat the popliteal nodes). If
one is treating all these nodal groups, they will set up a classical "Inverted Y"' field, named for ft's shape
(see diagram below). **Unless there is actual evidence of disease in the inguinal region, or the patient has a
subdiaphragmatic presentation of Hodgkin's (less than 10%) the above field is truncated at the L4/L5
interspace to omit the inguinal and femoral nodes, while still covering the common iliac nodes. This spares
the substantial amount of marrow in the pelvis and reduces radiation dose to the gonads. This is called a
"paraaortic/spienic pedicle field' or more common the "spade" field.
The splenic pedicle is always irradiated if a lapamtomy has been done, idven though the spleen was completely
negative pathologically. It should be marked by the surgeon with clips for easy localization at simulation. If
a laparotomy has not been done, but the patient is being treated with primary irradiation anyway, then the
entire spleen is treated.
Combining the mantle with the inverted-Y field yields "total nodal irradiation" which is rarely done, given
the very low incidence of failures in the inguinal region for a supradiaphragmatic presentation (less than
I%). If it is done, then the supradiaphragmatic and subdiaphragmatic fields are treated independently, waiting
2 - 4 weeks after the mantle is completed to allow for bone marrow recovery before starting the abdominal and
pelvic fields. More commonly patient's recieve a mantle followed by the spade field, which together comprise
"'subtotal nodal irradiation". This is the current treatment of choice for patient's with IA and IIA disease.
Involved Field:
When there is a bulky site of disease such as in the neck. "involved field" treatment can be given the the
local site, in combination with chemotherapy for systemic disease. Chemotherapy must be given if the goal is
cure when involved field treatment is used. Basically,- the field is set up at simulation with a 2 - 3 cm
margin to shrink the tumor, and field reductions are used as appropriate. This is discussed in "combination
therapy".
Side Effects of Radiation:
Are divided into early and late reactions. and of course depends upon the fields treated.
Acute Effects:
1) Nausea/Vomiting with abdominal fields, we can reduce this with daily dose reduction.
2) Bone marrow depression- common for WBC to drop to 2000 when treated subtotal nodal irradiation. We
wait 2 -4 weeks between the upper and lower fields to allow for bone marrow recovery.
3) Sialidenit is from irradiation to the salivary glands is transient.
Subacute and Late Effects:
1) Radiation pneumonitis incidence is less than 5% with mantle, but radiographic lung rxn.
seen in 20%. This is increased when bleomycin containing chemotherapy is given, and can occur with
bleomycin even with no radiation given.It is also more common in smokers. If pneumonitis occurs, then
it manifests 6 - 12 weeks after treatment by cough, shortness of breath, pleuritic chest pain, fever.
and infiltrates on chest X-ray. It is treated with oxygen and systemic steroids.
2) Thyroid dysfunction is seen as elevation in TSH in up to 2/3 of paitnes, but only 1 0%
manifest clinical thyroid problems- treated with levothyroxine supplement.
3) Xerostomia from mantle irradiation dose of over 20 Gy to salivary glands, see as
increased caries and decreased salivary, IgA. Can use salivart, water spray bottle, humidifier,
baking soda mouthwash and excellent dental hygeine.
4) Cardiac problems- asymptomatic pericardial effusion or acute pericarditis (3%) treated
with indomethacin, constrictive pe6carditis (2%) treated with surgical pericardial window,
increased atherosclerosis and late coronary disease (20%) seen especially with whole heart XRT
or in combination with chemotherapy. While 50% of patients may have late abnormalities on
echocardiogram, less than 1 0% have clinical problems with decreased left ventricular function
(Devita)
5) Lhermitte's syndrom caused by demyelinization of spinal cord tracts seen in 25% of pts.
12 weeks after treatment, shock-like sensations with neck flexion but is transient and does not
lead to transverse myelopathy.
6) Peptic ujcers/hemorrhage/chronic diarrhea/obstruction seen in 1 % with less than 35 Gy
and 3% with 45 Gy. Use H2 blockers, lomotil, possible surgery.
7) Fertility decrease- when ovaries >2 cm from block their dose is 8% (2.4 Gy) which is
enough in a single dose to cause permanent sterilization (2.5 - 6.0 Gy) but usually not enough
to do so when the dose is fractionated-- so oophorapexy helps, but women over 30 may get
menopausal symptoms.
8) Males will recieve up to 10% of the delivered dose to their testes if the inguinal
region is treated with no testicular shielding. If shielding is used, the gonadal dose
drops to about 2%, mostly from internal scatter of radiation. When fractionated, this shielded total
0.8 Gy or so should not effect sperm count.
9) Second cancers- are mostly a concern with chemotherapy or combined therapy, being predominantly
non-lymphocytic lymphomas. The occurance of a leukemia after radiation alone is extremely rare
(Perez). However, there is a also a risk of solid tumors occuring with a latentey of 7 - 1 0 years
after XRT, expecially in smokers, with a long term risk of perhaps 10%.
10) Herpes Zoster (Shingles) outbreaks in the irradiated field occur in up to 20% of patients in the
first 2 years after treatment. It's generally self-limited.
11) Psychosocial problems are being recognized in survivors of Hodgkin's in general, with difficulties in
marriage, higher unemployment, and alcoholism.
Results of Radiation Alone:
Overall, the results of radiation in early stage disease are excellent (Stanford data):
| Stage | 1O year disease-free survival | 10 yr. total survival |
| IA | 80% | 90% |
| IIA | 70% | 80% |
| IIIA1&2 (all comers) | 50% | 70% |
| IIIAL (by laparotomy) | 80% | 80% |
The actual 10 year survival rates are higher due to salvage with chemotherapy.
Chemotherapy Alone:
Hodgkin's Disease is curable by combination chemotherapy (Ref. Devita 4th ed. p. 1836). Historically, the
first evidence that chemotherapy was effective in Hodgkin's came from 1943 when Goodman used nitrogen mustard
gas analogues (developed by the Germans for chemic ' al warfare) in patients with lymphomas, and noted marked
resolution of lymphadenopathy (Ref. JAMA 1946 132:126). Early studies in the 1940's did not show good cure
rates with single agent chemotherapy, median survival was only about 1 year! Since many new drugs were being
discovered in this era, it was natural to try combination chemotherapy for Hodgkin's, and a 4 drug regimen
methotrexate, vincristine, cyclophosphamide and prednisone (MOMP) showed 80% initial responses when patients
were treated for 2.5 months (Ref. Devita Proc Am Assoc CA 1967 8:13).
In 1964, this regimen was modified to substitute procarbazine for methotrexate, and, the treatment was given
for 6 months. This was called the MOPP regimen, and has become the standard to which all other chemotherapy is
compared. It's combination of Mechlorethamine, Oncovir (vincristine), Procarbazine, and Prednisone was based
upon the individual activity of each of these drugs, and their differing toxicities. A complete cycle of MOPP
takes 29 days, and is two weeks of treatment then 2 weeks rest.
The MOPP regimen is given for a minimum of 6 cycles, or unless the tumor grows in spite of treatment. The
doses of each drug are titrated for each patient to mitigate bone-marrow suppression, using a "sliding scale",
and vincristine doses are modified to avoid excessive neurotoxicity. These principles have made the MOPP
regimen a model for developing chemotherapy for other cancers. NCI study: (Ref. Devita vide supra) was a
landmark study confirming the efficacy of MOPP in curing Hodgkin's Disease, with durable remissions noted over
20 years. They evaluated 188 patients with stages III and IV Hodgkin's and found that 84% had complete
response, while 16% failed induction therapy. After 20 years, 54% of the patients were "continuously free of
disease" (36% had actually died of Hodgkin's). Most patients who died of Hodgkin's did so in the first 4 years
after treatment, and only 5 patients (2.5%) died of treatment related complications. Three major prognostic
factors were noted by the NCI, being "B' symptoms, advanced stage disease, and male sex. These patients were
treated for 6 months. Further NCI studies showed that "maintainanc e chemotherapy was ineffective" (Ref. Frie
An. Int Med 1973:79 376)
The Classic MOPP Regimen and Doses Include (Ref. Longo Sem Onc. 1990 17:716):
| Nitrogen Mustard | 6.0 mg/m2 | I.V. | Days 1,8 |
| Vincristine | 1.4 mg/m2 | I.V. | Days 1,8 |
| Procarbazine | 100 mg/m2 | P.O | Days 1-14 |
| Prednisone | 40 mg/m2 | P.O. | Days 1-14 |
Overall, the cure rate for "advanced" Hodgkin's Disease with MOPP is 55%. Over the past 2 decades,
modifications of MOPP have been attempted to increase the cure rate and decrease the toxicity from the MOPP
agents. The most concerning toxicities of the MOPP regiment include:
| Nitrogen Mustard: | sterility (almost 100% in males, and in females over 30 years old, loukemogenesis
(non-lymphocytic leukemia in about 7% of patients, 3-1 0 years after treatment,
associated with loss of chromosomes 5 and 7, more common in patients over 40 and very
fatal) and myelosuppression |
| Vincristine: | Peripheral neuropathy |
| Procarbazine: | Nausea/Vomiting, myelosuppression |
| Prednisone: | Gastric ulcers, aseptic necrosis of the femoral heads. |
Modifications in MOPP included sustituting Chlorambusil for Nitrogen mustard the "LOPP" regimen at Stanford
University and exchanging vinblastine for vincristine, or exchanging cyclophosphamide for mechorethamine
("CVPP"). None of these were shown definitely superior to MOPP.
The first exciting new regimen developed for Hodgkin's after MOPP was "ABVD" by Dr. Bonadonna in
Italy. It contains:
| Addamycin | 25 mg/m2 | I.V. | Days 1, 1 5 |
| Bleomycin | 10 mg/m2 | I.V. | Days 1, 1 5 |
| Vinblastine | 6 mg/m2 | I.V. | Days 1, 1 5 |
| Dacarbazine | 375 mg/m2 | I.V. | Days 1, 1 5 |
**The Overall Cure Rate for ABVD in "advanced" Hodgkin's is also 55%, no diffence was noted in disease free or
overall survival from MOPP. (Ref. Santoro and Bonadonna Cancer. Chemother. Pharm. 1979 2: 101). However, they
noted:
1) The toxicities of ABVD were different. Adriamycin and Bleomycin have cardiac limiting toxicity,
pulmonary toxicity and alopecia, but do not cause the nearly universal sterility and almost lO%
non-lymphocytic leukemias seen with nitrogen mustards.
2) ABVD was found to be an effective salvage regimen for MOPP failures, as discussed under "salvage
therapy".
To try to improve the disease-free survival rates in advanced Hodgkin's, and as a general test of the
Goldie-Coldman hypothesis about the increased utility of using multiple non cross-resistant drugs to cure
cancer, MOPP and ABVD were combined:
Bonadonna Study (Ref. NEJM 1982: 306:770) randomized 88 patients with stage IV Hodgkin's to either alternating
cycles of MOPP/ABVD or MOPP alone. Patients got twice the usual duration of treatment - 12 months total- and
results were compared to 8 years post-treatment. Results showed theat complete remissions were obtained in 89%
of pts. treated with alternating MOPP/ABVD compared to 74% getting MOPP alone, which wasn't significant.
However, at 8 years, freedom from progression (disease4ree survival) was was 65% for MOPP/ABVD versus just 36%
for MOPP alone, which was significant. The conclusion was that alternating MOPP/ABVD significantly reduced
deaths from stage IV Hodgkin's.
**Caveat: toxicity of the combined regimen was greater that either MOPP ' or ABVD alone. For the alternating
MOPP/ABVD treatment, 22% of the patients refused to complete therapy versus just 7% for those getting MOPP
alone. Furthermore, notice the poorer results in the MOPP alone group compared to the NCI study. This was
because these patients had significant dose reductions when being treated for 12 months in Bonadonna's study,
due to vincdstine neuropathy.
Connom and Klimbo study (Ref. J. Clin. Onc. 1985; 3:1174) omitted dacarbazine from the MOPP/ABVD hybrid and so
treated with alternating courses of the seven remaining drugs- This was called the "MOPP/ABV hybrid". In their
original study, patients received XRT to areas of bulk disease, and actuarial relapse-free survival was 90% at
5 years for 74 evaluable patients- although they had more favorable histology patients, and the long-term
results were in line with other drug combinations (Devita 4th ed. p. 1 842). Importantly, it was as effective
as MOPP/ABVD but easier for patients to tolerate, and MOPP/ABV is now a standard therapy.
This is the full transcript, offered freely in the spirit of internet sharing, of CancerAnswers' report on Hodgkin's Disease. Much more, including latest additional treatments for Hodgkin's Disease can be found on our order page. Thank you for using CancerAnswers as your information resource.
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ADDITIONAL TOPICS
Acute Leukemia
Anal Cancer
Bladder Cancer
Bone Cancer
Brain Cancer
Breast Cancer: Early
Breast Cancer: Advanced
Cartilage Cancer
Cervical Cancer
Chronic Leukemia
Colo-rectal Cancer
Esophagus Cancer
Fat Cancer
Gall-Bladder Cancer
Hodgkin's disease
Kidney Cancer
Larynx Cancer
Liver Cancer
Lung Cancer
Lung "small cell" Cancer
Lymphoma
Melanoma
Mesothelioma
Mouth Cancer
Multiple Myeloma
Muscle Cancer
Muscle and Fat Tumors
Nasal Cavity Cancer
Nasopharynx Cancer
Ovarian Cancer
Pancreas Cancer
Penile Cancer
Plasmacytomia
Prostate Cancer
Skin Cancer
Stomach Cancer
Testicle Cancer
Thyroid Cancer
Tongue Base and Tonsil
Cancer of Unknown Origin
Uterine Cancer
Vaginal Cancer
Vulvar Cancer
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