Hodgkins Disease & Non Hodgkins Lymphoma

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Background
Overview
The malignant lymphomas, Hodgkins disease (HD) and non-Hodgkins lymphoma (NHL), comprise a
group of clinically and pathologically diverse malignant lymphomas of largely unknown cause. Their
successful management involves a multidisciplinary approach, proceeding from an accurate diagnosis to
a comprehensive staging evaluation and appropriate therapeutic recommendation and regimen.
Etiology / Pathogenesis
In 1832, Thomas Hodgkin presented a paper entitled On Some Morbid Appearances of the Absorbent
Glands and Spleen. His report was an autopsy description of seven patients with an entity he described
as a primary process involving the lymph nodes and spleen rather than a reactive inflammatory condition.
Independent reports by Sternberg and Reed described the giant cells characteristic of Hodgkins disease,
which are known today as Reed-Sternberg (RS) cells.

The RS cell is characterized by its large size and classic binucleated structure and large eosinophilic
nucleoli. It is the tumor cell characterizing HD and must be identified within the appropriate cellular milieu
of lymphocytes, eosinophiles and histiocytes in order for the diagnosis to be established. Hodgkins
disease is unique pathologically because the tumor cells comprise a minority of the cell population in
which normal inflammatory cells are the major cellular components. The RS cell is characterized as both
a macrophage and lymphocyte and has the ability to phagocytose. RS cells are not absolutely specific for
HD and have been noted in infectious mononucleosis4 and in other malignancies including lymphomas,
carcinomas and sarcomas.

In the years that have followed the initial identification of Hodgkins disease as a neoplastic entity, a
heterogeneous group of over 20 additional and discrete non-Hodgkin lymphomatous neoplasms have
been described with characteristic morphologic, immunophentypic, genetic and clinical features. This
group has been classified as non-Hodgkin lymphomas (NHL) and, with an ever-increasing incidence, now
is the sixth most common cause of cancer in the United States.
The precise etiology and pathogenesis of both HD and NHL are unknown. There is, however, convincing
evidence that most types of HD and non-Hodgkins lymphoma are derived from germinal center or post-
germinal center B-cells (bone marrow) and that the B-cell germinal center plays a key role in both normal
B-cell differentiation and in the genesis of B-cell neoplasms. Lymphoid neoplasms of T-cell (thymus) origin
constitute less than 15% of NHL group, the vast majority being of B-cell origin.
The exact mechanism that triggers the transformation to malignancy is unknown, but over the years a
variety of infectious agents, congenital and acquired immunodeficiency states, autoimmune disorders and
physical and chemical agents have been associated with an increased risk of these disorders.

The arguments for an infectious etiology of HD date back to its early descriptions. Mycobacterium
tuberculosis was the first organism to be suspected of causing HD. However, once it was realized that HD
is associated with immune defects, M. tuberculosis was recognized as a consequence of HD rather than
a cause of the disease. Reports of clustering of cases tended to support the infectious etiology, but these
reports were subsequently recognized as chance occurrence.
The Epstein-Barr virus (EBV) has been another proposed cause of Hodgkins disease, and the
circumstantial evidence is impressive. The incidence of HD is elevated in patients with a history
of EBV infection. The E-B virus, which infects and immortalizes B-lymphocytes in vitro, has been
implicated in the pathogenesis of African Burkitts lymphoma and B-cell malignancies in immuno-
compromised patients such as those that occur after organ transplantation. Using molecular biological
techniques, EBV genome fractions have been found in Reed-Sternberg cells.
The possibility that an abnormal immune response is related to the development of HD has been given
support by reports that there is as much as a twenty-fold increase in HD among HIV-infected individuals.
The data are even more impressive for the incidence of non-Hodgkins lymphoma; patients with long-
standing human immunodeficiency virus (HIV) infection are also estimated to have a 100-fold increased
risk for the development of NHLs. In the early 1980s, an increase in intermediate and high-
grade NHL was noticed among young homosexual men. Analysis of a series of 90 such cases revealed
that their age distribution was identical to that of AIDS, with the highest percentage seen between ages
30 and 39, in contrast to NHL in the general population where the median age was between 55 and 60
years. In this and subsequent series, 30% to 40% of patients had a lymphoma similar in histology to
Burkitts lymphoma, a tumor that is epidemic in equatorial Africa and rare in the United States.
Helicobacter pylori infection of the stomach results in chronic gastritis and the development of mucosa-
associated lymphoid tissue (MALT) and associated gastric lymphomas. This link between H. pylori
infection and primary gastric MALT lymphomas had prompted the development of treatment strategies
based on the eradication of the H. pylori infection. The human T-cell leukemia virus (HTLV) and the
Kaposis sarcoma-associated herpes virus (KSHV) are two rare viruses that have also been associated
with NHL. Additionally, certain chemical and physical agents have been associated with an increased risk
of NHL, as is the case with the survivors of nuclear explosions or reactor accidents and in patients with
other tumors that have been treated with certain chemotherapies and/or radiation.
The idea that HD may represent an uncommon host response to a common agent has received support
from a study of monozygotic and dizygotic twins. Monozygotic twins, who would be expected to have
similar immune responses, had a 99-fold increased risk of being concordant for having HD, supporting a
role for genetic susceptibility and/or an abnormal immune response in the etiology of HD.

Accurate classification of the malignant lymphoid neoplasms is essential for the correct diagnosis and for
the evaluation of prognosis and treatment of patients. Hodgkins disease has been classified into four
histological subtypes. Each subtype classification is based on the number and appearance of Reed-
Sternberg cells as well as the background histological milieu.

Several classifications have been proposed for the complex array of non-Hodgkins lymphomas. These
have been based on the degree of differentiation of the tumor and on whether the growth pattern is
nodular or diffuse. Other classifications have been based on the cell of origin of the malignancy. The
International Panel Working Formulation of the National Cancer Institute has separated NHL into
categories, each incorporating the above-mentioned items and having therapeutic implications18. Their
generally accepted NHL classification identifies four subtypes and their respective incidences:
Low grade or favorable prognosis lymphomas (38%)

Diffuse, well differentiated

Nodular, poorly differentiated

Nodular, mixed types

Intermediate grade or intermediate prognosis lymphomas (40%)

Nodular, histiocytic

Diffuse, poorly differentiated

Lymphocytic

Diffuse mixed types

High grade or unfavorable prognosis lymphoma (20%)

Diffuse histiocytic lymphoma (diffuse large cell cleaved, noncleaved, and immunoblastic types)

Diffuse, undifferentiated (Burkitts and non-Burkitts type)

Miscellaneous lymphomas (2%)

Composite lymphoma

Mycosis fungoides

True histiocytic, other, and unclassifiable types

The obvious complexity of the current classification of NHLs has taxed the ability of hematopathologists.
The diagnosis of a non-Hodgkins lymphoma is unquestionably one of the most difficult tasks confronting
a general surgical pathologist. The difficulties involved have resulted in many institutions routinely
referring new cases ofNHL to expert hematopathologists for review and consultation.
Demographics / Epidemiology
Approximately 7,500 new cases of Hodgkins disease are diagnosed annually in the United States. In
contrast to the increasing incidence of non-Hodgkins lymphoma, the annual incidence of HD has
remained stable over the last several decades. The male to female ratio of HD incidence is 1.3 1.4 to 1.
In most economically developed countries, there is a bimodal age distribution with one peak occurring in
the third decade of life (age range 15-39 years) and a second smaller peak occurring after age 50. The
second peak may be an artifact of histologic misclassification because recent studies have demonstrated
that many of the older-age cases originally diagnosed as HD turned out to be NHLs. The age-specific
incidence is low, no early incidence peak occurs. In some developing countries, the peak shifts into
childhood, mostly boys.
In contrast to the stable and relatively static incidence of Hodgkins disease, non-Hodgkins lymphoma is
emerging as a worldwide epidemic. More than 50,000 new cases were diagnosed annually in the United
States during the 1990s and there is evidence that the incidence is increasing. Some of this increase is
undoubtedly related to the predilection for the development of NHL in patients with AIDS. However, a
large number of other factors may be contributing to the increase in incidence since NHL was manifesting
a steady increase of 3% to 4% per year in the 1970s prior to the emergence of the AIDS crisis. The rise
in NHLincidence is faster and higher than that of all other malignancies except lung cancer in women and
prostate cancer.
The incidence of NHL increased 86.6% in males from 1973 to 1991 with an estimated annual change of
3.8%. As a result, NHL now constitutes about 6% of all malignancies in the United States.
The incidence of the various non-Hodgkins lymphomas is age-dependent, has a variable distribution, and
is more common in males than females. Lymphomas represent approximately 10% of all childhood
cancers in developed countries and are third in relative frequency behind acute leukemias and brain
tumors. They are more common in adults than in children and manifest a steady increase in incidence
from childhood through age 80. The mean age at diagnosis of NHL is 45 to 55 years and the median age
is 60 to 65 years. The greatest rise in new cases of NHL has been in elderly white males and the least
increase has been seen in young white females. The increase in incidence of NHL has been
accompanied by an increase in extra and diffuses involvement such as involvement of the gastrointestinal
tract and oropharynx. Other common extranodal sites include the brain, skin, bone, thyroid, lung, breast
and testis.
Diagnosis
History
It is important that the history include any occurrence of lymphoma in the family
and a history of previous infectious mononucleosis or exposure to radiation or toxic
chemicals by the patient. Stigmata suggesting the presence of an immunodeficiency
disorder should be sought because of the predilection for patients with AIDS to
develop non-Hodgkins lymphoma.
Key aspects of the medical history of HD or NHL patient include the determination of whether he/she has
symptoms that have a prognostic significance as well as a possible influence on the therapeutic regimen.
The physician should focus on symptoms that suggest a specific extranodal site (e.g., bone pain), as well
as symptoms such as fever, night sweats and a weight loss equal or greater than 10% of the patients
body weight, since these complaints usually signal the presence of diffuse disease and have a significant
influence on prognosis and future therapy. In lymphomatous malignancies fever may be manifest in any
pattern including a low-grade continuous fever or occasional high spikes of fever. The pattern of recurrent
episodes of daily high fever separated by days without fever is known as Pel-Epstein fever. Pain at the
site of Hodgkins disease involvement in association with the ingestion of alcohol has been well
recognized. Its mechanism is unknown and its presence does not have prognostic significance.
Physical Examination
A meticulous examination of all lymph node-bearing sites is mandatory. In
addition to the frequently encountered cervical and supraclavicular sites, the axillae
and groins merit careful palpation. Splenomegaly is another frequent physical finding
in lymphomatous malignancies.
Hodgkins disease almost always presents with lympadenopathy and the involved nodes are usually
freely movable and have a rubbery consistency. Cases in which the histology demonstrates fibrosis or
sclerosis can be associated with hard and firm adenopathy. Although any lymph node group can be
involved, cervical and supraclavicular adenopathy are the most common physical findings, although
axillary adenopathy is not rare. Mediastinal disease is often present, but rarely is the only site of
involvement because it usually occurs in association with cervical and supraclavicular adenopathy. HD
can also present with iliac, inguinal and femoral adenopathy, and in approximately 3% of cases, there
may be only subdiaphragmatic disease. Splenomegaly is noted at presentation in approximately 10% of
cases of HD. However, splenomegaly may occur as a nonspecific manifestation of HD and in only half of
the cases is there actual splenic involvement with HD found at laparatomy. Additionally, splenic
involvement has been reported in 30% of HD cases in the absence of splenomegaly.

Extranodal HD can occur at any site. Lung, liver, bone and bone marrow are the most common sites of
extranodal involvement and each of these sites is seen in approximately 5% to 10% of cases.

Hodgkins disease tends to spread in a contiguous fashion. For example, because of contiguity with the
thoracic duct, left supraclavicular nodal involvement is often seen in association with mediastinal
involvement.

As is the case with Hodgkins disease, most patients with non-Hodgkins lymphoma present with painless
lymphadenopathy, most commonly in the cervical and supraclavicular regions. Systemic symptoms occur
in less than 25% of patients in most large series. When present, they are usually associated with
advanced disease.

Gastrointestinal lymphoma occurs in less than 3% of NHL, with stomach and colon the most common
sites of involvement, and with vague abdominal pain the most common presentation. Obstruction,
specifically intussusception in children, or perforation, may be complications of intestinal lymphoma.
Genitourinary presentations include renal mass, ureteral obstruction, testicular and ovarian masses and
vaginal bleeding. Neurological signs and symptoms include headache, cranial nerve palsies and signs of
leukoencephalopathy. Unusual metabolic presentations include hyperuricemia, renal failure,
hypercalcemia and severe hypoglycemia.
Disease Staging
The symptoms and physical findings play key roles in the important process of the staging of Hodgkins
disease and non-Hodgkins lymphoma, a process which is of utmost value in the prognosis of the disease
and in the planning of a therapeutic program. Several staging classifications have been proposed for both
HD and NHL. Table 4 presents the widely used Cotswald classification for HD.
Table 4-Cotswald Staging Classification for Hodgkins Disease

The staging classification of HD into A (asymptomatic) and B (symptomatic) has a relationship to

prognosis. The presence of symptoms is a suggestive indication of advanced disease. Symptoms are
found in fewer than 10% of patients with Stage I disease and in approximately 65% of patients with Stage
IV disease.

The purpose of clinical evaluation is not only to determine the stage of the disease and the therapeutic
regimen, but also to establish an appropriate clinical baseline so that success or failure of therapy can be
assessed.

Table 5 shows the classification of HD cases with respect to Stage and Symptomatic Status.
Table 5-Distribution of Hodgkins Disease Cases with Respect to Stage and Symptomatic Status

A number of staging classifications have been proposed for the non-Hodgkins lymphomas. In essence,
they parallel those of Hodgkins disease in respect to Stages I and II with only minor modifications of
Stages IIIand, if present, Stage IV.
Testing Procedures for HD and NHL
Office and Laboratory Studies

Hodgkins disease and non-Hodgkins lymphoma patients are prone to develop a

variety of hematologic and blood chemistry abnormalities and blood specimens
should be withdrawn for appropriate baseline values.
A slight to moderate polymorphonuclear leukocytosis may be present. Lymphocytopenia may occur early
and become pronounced with advancing disease. Eosinophilia is present in about 20% of patients and
thromocytosis may be observed. Anemia, often hypochromic and microcytic, usually develops with
advancing disease. Defective iron utilization is characterized by low serum iron levels and low iron-
binding capacity. Hypersplenism may occur producing cytopenias alone or in any combination in the
presence of marked splenomegaly.

Lymphomatous infiltration of bones and liver is characterized by elevations of serum levels of the
respective isoenzymes of alkaline phosphatase. Other blood chemistry studies should include levels of
blood glucose, urea nitrogen and creatinine. Serum bilirubin levels and measurements of hepatic
enzymes are helpful in assessing liver involvement. Serum uric acid should be monitored especially
during therapy to detect increases that may predict hyperuricemic renal shutdown. Serum electrolytes
should also be checked to monitor fluid and electrolyte balance in patients who are often depleted by the
underlying disease as well as therapy.

Serum levels of lactic dehydrogenase (LDH) and beta-2 microglobulin (beta 2-M) represent surrogate
quantitative measures of metastatic potential and tumor burden respectively. They have been used as
indicators and serological staging agents to predict freedom from relapse and survival. Patients at low risk
for disease recurrence have normal levels of both markers whereas elevations predict shortened
remission and survival.
Radiologic Studies

Radiologic studies are particularly valuable in assessing disease extent. The

specific studies to be performed will vary with the individual patient and depend on
the physicians assessment of the likelihood of diffuse disease involvement.
A chest radiograph is indicated in all patients with HD and NHL primarily to assess lung status and in
particular, mediastinal disease involvement. Most authorities also recommend computerized tomographic
(CT) studies of the chest, abdomen, pelvis and neck to assess the presence of disease not readily
assessable by physical examination. Other radiologic procedures are performed as deemed clinically
appropriate and include gallium scanning, magnetic resonance imaging (MRI), ultrasound and bone and
liver scans. Lymphangiography is occasionally performed when there is a strong suspicion of periaortic
and retroperitoneal nodal involvement.
Invasive Procedures
 The diagnosis of both HD and NHL requires a biopsy that contains sufficient tissue
to permit an accurate microscopic diagnosis by an experienced hematopathologist.
Biopsy specimens are usually obtained from palpable lymph nodes but may
occasionally be obtained from other tissues. Needle aspirations or biopsies are
inadequate for the primary histologic diagnosis.
A bone marrow aspiration and biopsy should be performed as part of the initial staging procedure
although these tests are rarely positive unless other evidence of advanced disease (at least Stage III) is
present. The majority of patients with bone marrow involvement will be symptomatic; nevertheless, a
bone marrow biopsy should be obtained at baseline in all patients because the results may not only
influence the use of initial therapy but might affect future decisions at the time of relapse (e.g., a decision
on the feasibility of an autologous bone marrow transplantation).
A major controversy surround the performance of a staging laparatomy. A staging laparoscopy can only
be justified when the results will influence therapy. Some physicians recommend the procedure whenever
therapeutic planning includes radiation. Others reserve it for those cases where clinical staging is
equivocal. When performed, it should include inspection of the liver and spleen and liver and nodal
biopsies.

Currently, laparoscopy is being performed far less frequently because chemotherapy is incorporated in
many clinical settings and because retrospective studies provide a basis for determining the likelihood of
intraabdominal disease with different clinical perspectives. Several studies have demonstrated that
laparotomy had no significant impact on survival or relapse rate in patients with a favorable prognosis
who were randomized to staging with laparotomy or clinical staging. The risk of occult subdiaphragmatic
disease can be estimated on the basis of sex, age, erythrocyte sedimentation rate (ESR), number of
involved lymph node sites, and histologic subtype. A bone marrow biopsy is included in the routine
staging of patients who have advanced-stage disease, constitutional symptoms, or both.
Differential Diagnosis
The differential diagnosis of both Hodgkins disease and non-Hodgkins lymphoma
involves the ruling out of obvious and common conditions as well as other
malignancies. The exact diagnosis hinges on the histological findings and the opinion
of an experienced hematopathologist.
In patients with cervical adenopathy, infections, including bacterial or viral pharyngitis, infectious
mononucleosis and histoplasmosis must be excluded. Other malignancies, such as nasopharyngeal and
thyroid cancers, can present with localized cervical adenopathy and axillary adenopathy is a common
metastatic manifestation of breast cancer. Mediastinal lymphomatous involvement must be distinguished
from infections, sarcoidosis and other thoracic neoplasms.

In other patients, the differential diagnosis includes tumors of the lung and mediastinum, specifically of
small cell and non-small cell type. Reactive mediastinitis and hilar lymphadenopathy from histoplasmosis
can be confused with lymphoma since it occurs in otherwise asymptomatic patients.

The pathologic diagnosis of HD has traditionally been considered to be easier and safer than that of the
more complex non-Hodgkins lymphomas. However, a 1968 review of the histopathologic material of 600
patients in whom an initial diagnosis of HD had been made revealed a mistaken diagnosis in an
astonishing 47% of cases. The most common error in pathological diagnosis was the confusion of
inflammatory or other non-neoplastic conditions with HD (32%). The high rate of error was attributed to
the relative inexperience of the contributing general pathologists in the diagnosis of hematopathologic
malignancies. In a study reported by the Southwest Oncology Group (SWOG) in 1982, the rate of
misdiagnosis in 575 cases of HD was again high, but the most common class of error was confusion of
HD with NHL. In subsequent similar studies of HD, the confusion with NHL was always found to be the
most common diagnostic error. Although the incidence of misdiagnosis has decreased, major errors still
exist in up to 10% of cases.
The correct diagnosis of both Hodgkins disease and non-Hodgkins lymphoma is completely dependent
on a correct interpretation of the histopathology of the biopsy material and it is mandatory that assistance
in this area be obtained from experienced hematopathologists.

Treatment
The currently successful treatment of Hodgkins disease is one of the triumphs of modern cancer
therapeutics. The death rate due to Hodgkins disease has decreased by two-thirds in the last 40 years
because of the introduction of effective diagnostic and therapeutic modalities. All patients regardless of
the stage of the disease can and should be treated with curative intent.

The therapy of Hodgkins disease and non-Hodgkins lymphoma involves three main modalities:

Radiation
Chemotherapy
Combination radiotherapy and chemotherapy
In the case of Hodgkins disease, staging is critical in choosing the therapeutic modality. In non-Hodgkins
lymphoma, the histologic tissue type, as well as staging, is a major determinant of therapy.

Radiation Therapy
Radiation is the standard approved therapy in Hodgkins disease stages I and II.

In disease limited to lymph nodes above the diaphragm, therapy is usually directed only to the involved
area (limited field radiation). Before the advent of effective salvage chemotherapy, radiotherapy was often
directed at both involved and uninvolved lymphoid areas (extended field radiation involving total or
subtotal lymphoid radiation). The tendency today is to limit the field of radiation to the mantle of
involvement if the disease is confined to the upper chest (above the carina) with a resultant cure rate in
excess of 80% (reaching as high as 92% when causes of death other than Hodgkins disease are
excluded.

Radiotherapy alone remains an option in some patients with minimal splenic, splenic hilar or celiac node
involvement (stage IIIA). In these patients, it is possible to effect a cure in 60% to 70% of patients using
total nodal irradiation, but those with extensive splenic involvement will require systemic therapy because
of the high rate of recurrence with radiation therapy alone. Most relapses (75%) occur within the first 3
years after completing therapy; late relapses thereafter are uncommon. There is a tendency to offer such
patients combined modality therapy because it is associated with the lowest recurrence rate.
An alternative treatment applicable to early-stage disease is to use both radiation and chemotherapy in
selected patients such as those with bulky mediastinal disease and significant B symptoms. Other
candidates are those at a high risk for subdiaphragmatic involvement, mixed cellularity or lymphocytic
depleted Hodgkins Disease histology, or over 40 years-old.
The radiation dose required to eradicate Hodgkins disease in demonstrably involved nodes is 40 to 45
Gy (1 Gy=100 rads). A standard regimen is a total dose of 36 Gy delivered in 20 daily functions of 1.8 Gy
over a period of 4 weeks.

Chemotherapy
It is important to note that more than half of the patients with Hodgkins disease who experience relapse
after radiation therapy alone have disease that is still curable with chemotherapy.

Until recently, MOPP (mechlorethamine, Oncovin, procarbazine and prednisone) was the
chemotherapeutic combination of choice but is now used much less frequently because of its side effects
including myelosuppression, susceptibility to infection, infertility and autonomic and peripheral
neuropathy.
The combination chemotherapy of choice today is ABVD (doxorubicin) [Adriomycin], bleomycin,
vincristine, and dacarbazine). It has been shown to be both more effective as well as less toxic
than MOPP. A cycle ofABVD therapy includes:
Advanced Hodgkins disease is classically defined as stages IIIB and IV. In these stages, Hodgkins
disease is curable only with a systemic approach. ABVD is the standard combination chemotherapy
generally administered for 6 cycles. It remains controversial whether post chemotherapy adjuvant
radiotherapy improves the outcome in advance Hodgkins disease. If it is to be utilized, the radiotherapy
field should be kept minimized, doses kept low and sites to be eradicated limited to bulky disease.
ABVD is generally well tolerated. Its primary side effects are nausea, fatigue, moderate hair loss, some
increased susceptibility to infections, neuropathy secondary to vincristine and pulmonary fibrosis
secondary to bleomycin. Pulmonary function should be monitored and bleomycin withheld if there is a fall
of 25% or more in pulmonary diffusion capacity. Doxorubicin cardiotoxicity is rare; however, it is
recommended that all patients have left ventricular ejection fraction measured before therapy. Infertility is
not a major problem with ABVD but all men should be advised to bank sperm. ABVD had rarely been
administered during the second and third trimesters of pregnancy; no adverse effects have been noted in
the few such cases where it was administered. All women of childbearing age should have a pregnancy
test before therapy and be advised to delay pregnancy for 2 years after treatment to avoid the
coincidence of pregnancy and relapse.
In the case of non-Hodgkins lymphoma, the choice of therapy depends not only on the staging of the
disease, but also on the histological classification of the tumor.

Low-grade lymphomas (indolent or favorable) are usually small lymphocytic or follicular center
lymphomas. Grade I and II low grade lymphomas are uncommonly diagnosed, but may be curable with
involved field radiation. One study reported a relapse-free survival rate of 62% at 5 years in all patients
and 80% in 15 years or later in patients 40 years of age or younger. Generally, no benefit from additional
adjuvant chemotherapy has been documented.

Usually low-grade lymphomas are diagnosed in stages III or IV (75% to 90%) and there is bone marrow
involvement in approximately 70%. The median survival of this group is 5 to 7 years with an initial
response to radiotherapy or chemotherapy and then relapse eventually leading to death. Some have
adopted a watch and wait approach to this advanced stage, but in one study, 5 year survival was only
12% with this approach compared to 51% for aggressive therapy.
Intermediate grade lymphomas are more aggressive than low-grade lymphomas with untreated survival
times measured in months rather than in years. The most common intermediate grade lymphomas are
the large cell lymphomas, which are curable in about 50% of cases. Most are treated similarly, even those
with apparent stage I and II disease because of the now-recognized systemic nature of these stages.
Recommended therapy consists of standard anthracycline combination chemotherapy, usually in the form
of CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone) administered in three cycles (CHOP-3)
and followed by radiotherapy. This regimen has produced a 4-year survival as high as 97% on stage I
patients less than 60 years of age and with a normal performance status. In advanced (stage III or IV)
intermediate grade non-Hodgkins lymphoma, CHOP has been shown to produce long-term complete
remission rates of up to 75%.
High-grade lymphoma, including precursor lymphoblastic lymphoma, Burkitts lymphoma and Burkitts-like
lymphoma, tend to occur in younger age patients and have an untreated survival time usually measured
in weeks. They usually present with advanced stage disease and are always treated with systemic
chemotherapy. Many have CNS involvement and require intrathecal therapy. Low risk patients, i.e., those
with a serum LDL level less than 300 IU/L and without bone marrow or CNS involvement, may have a 5
year remission rate as high as 94%.
Monoclonal antibody (MAb) therapy for non-Hodgkins lymphoma

Studies have revealed that more than 90% of lymphomas of B-cell origin express the CD20 antigen, thus
identifying CD20 as a potential target for monoclonal antibody (MAb) therapy. In 1987, the first such MAb,
rituximab, was approved by the FDA for the treatment of patients with relapsed or refractory low-grade or
follicular, CD-20 positive, B-cell non-Hodgkins lymphoma. This was followed by the approval of
tositumomab in 1998.
Rituximab is a mouse-human chimeric IgG1-kappa immunoglobulin that selectively binds the CD20
antigen on lymphoma cells inducing complement-and antibody-dependent cytotoxicity. It has also been
shown to induce apoptosis in the tumor cell. Several phase I and phase II trials suggest an approximate
50% response rate in the therapy of indolent and relapsed or refractory low-grade or follicular-B
lymphoma, but imply no change in survival. Significantly lower response rates were seen in patients with
lymphocytic histology or in patients with bone marrow involvement and with two or more extranodal sites
of disease.

Rituximab was well tolerated in multiple infusions of 375 mg/m2. The most common adverse effects were
low-grade fever, chills, nausea and headache. These were not commonly seen after the initial infusion
and were much less frequent or absent with subsequent infusions. The objective of multiple clinical trials
in progress is to incorporate MAb therapy in primary management strategies in combination with other
cytotoxic therapies. Anti-CD20 therapy has produced favorable results when used in combination with
chemotherapy. In one trial, patients with newly diagnosed or relapsed/refractory CD20-positive low-grade
or follicular lymphomas received 6 cycles of ADVP (cyclophosphamide, doxorubicin, vincristine and
prednisone) administered every three weeks with 6 infusions of rituximab. There was a complete
remission response rate of 55% and partial response rate of 40%. Several studies have evaluated
rituximab in the treatment of aggressive non-Hodgkins lymphoma.
The results were significantly less favorable than those with indolent lymphoma with overall response
rates of 30% to 40%. The greater the tumor burden, the less was the response Rte with no response
seen in patients with tumors larger than 10 cm.

Another aspect of MAb therapy is its in conjugation with radioactive materials such as the radioisotopes
iodine-131 and yttrium-90. The follicular lymphomas are extremely sensitive to irradiation and these
agents have the advantage that the radiotherapy is targeted to tumor cells, thereby limiting toxic effects
on normal cells. Results have been encouraging.

Developing Therapies
Stem cells

A recent development has been the use of stem cell transplantation. Significantly higher response rates to
cytotoxic agents have been reported in patients who had received prior stem cell transplantation than in
those who had not (78% vs. 34%, respectively, p<0.01.

Vaccines

The idiotype, the molecular determinant of the variable region of the surface immunoglobulin, of a B-cell
lymphoma can function as a tumor-specific marker. Immune responses against the idiotype have been
induced in patients by tailor-made vaccines. Lymphoma vaccines are prepared by isolating the idiotype
protein from the lymphoma tissue, conjugating it to a protein carrier and mixing it with an immunologic
adjuvant in vitro.

Complications
Early complications of Hodgkins disease and non-Hodgkins lymphoma are usually related to therapy

Complications of radiotherapy depend on the radiated volume of tissue, dose administered and the
technique employed. The acute effects are usually mild and transient and may include dryness of the
mouth, changes in taste, pharyngitis, nausea, dry cough, dermatitis, and fatigue. Six weeks to 3 months
after radiation therapy, patients may note an electric shock sensation in the lower extremities on flexion of
the neck. This so-called Lhermittes syndrome is related to transient demyelinization of the cervical spinal
cord. Radiation pneumonitis and pericarditis are other rare delayed complications of radiotherapy.

Acute and subacute adverse effects to chemotherapy are fairly common. In fact, MOPP therapy, which
was widely used up until recently, has been discontinued in many cancer clinics due to its association with
myelosuppression (particularly thrombocytopenia), susceptibility to infections, infertility and autonomic
and peripheral neuropathy. The current gold standard chemotherapy, ABVD is better tolerated although
associated with hair loss, nausea and vomiting, fatigue and myelosuppression (particularly neutropenia).
Delayed and long-term complications include hypothyroidism secondary to thyroid gland radiation,
pericardial fibrosis, focal carcinoma or sarcoma secondary to radiation therapy, sterility, anemia and
hematological complications of chemotherapy such as thrombocytopenia. Late-appearing infections may
occur due to the chronic state of immune depression following therapy and patients who have had
splenectomy may have a predilection for bacterial infections.

Special Considerations
Lymphomatous malignancies occurring in children, the elderly, patients with HIV infection and during
pregnancy have special therapeutic needs. These patients should be referred to health providers with
training and experience in these specialized areas.
In patients with low-grade lymphomas, age does not usually make a difference in type of therapy or
prognosis and nonaggressive therapy is usually broken. However, in the treatment of diffuse aggressive
lymphomas, age is an important prognostic factor. The Southwest Oncology Group (SWOG) has reported
a complete response rate of 65% and a median survival of 101 months in patients under 40 years-old in
comparison with a response rate of 37% and a median survival of only 16 months in patients over the age
of 65. Similarly, the European Organization for Research and Treatment of Cancer Lymphoma
Cooperative Study Group reported superior results in elderly patients with the use of aggressive
chemotherapy (CHOP) compared to the results obtained with a less aggressive anthracycline regimen.
Patients with HIV infection also constitute a special group of lymphoma patients because of their
predilection for the development of non-Hodgkins lymphoma, usually of high-grade B-cell type
(immunoblastic or small uncleaved cell types); about 30% unusual extranodal involvement. Studies have
demonstrated that aggressive chemotherapy induces remissions and prolongs life. However,
chemotherapy toxicity has been reported to shorten survival in these seriously ill patients.
When to Refer
For the primary physician, determination of the presenting signs and symptoms should be followed by
biopsy of the most accessible tissue, usually a peripheral node. Following examination and the
determination of a definitive diagnosis by an experienced hematopathologist, referral to an oncologist is
advisable for recommendations for appropriate therapy. Lymphomatous neoplasms occurring in children,
the elderly, during pregnancy or in patients with HIV infection will require specialists experienced in those
fields and who are prepared to anticipate the increased demands that these special populations will
impose.
Radiotherapy requires the availability of modern appropriate facilities and administration by trained
radiotherapists. Chemotherapeutic protocols are best administered by experienced medical oncologists.

Prognosis
All patients with both localized and disseminated Hodgkins disease should be treated with curative intent.

The prognosis of patients with stage IA and IIA disease treated by radiotherapy is excellent with 10-year
survivals in excess of 80%. Patients with disseminated disease (IIIB, IV) have a 5-year survival rates of
50% to 60%. Poorer results are seen in patients who are older, those who have bulky disease and those
with lymphocytic depletion or mixed cellularity on histologic examination. Patients whose disease recurs
after radiation may still be curable with chemotherapy. The treatment of choice for patients who relapse
after initial chemotherapy is high-dose chemotherapy with autologous stem cell transplantation. This
offers a 35% to 50% chance of cure in patients whose disease is still chemotherapy sensitive. Although
early stage non-Hodgkins lymphoma share the same prognosis as Hodgkins disease patients, those with
more complex patterns fare less well. The median survival of indolent lymphomas is 6 to 8 years. These
diseases ultimately become refractory to chemotherapy, often associated with histologic progression of
the disease to a more aggressive form.
The International Prognostic Index is now widely used to categorize patients with intermediate grade
lymphomas into risk groups. Factors that confer an adverse prognosis include:

Over 60 years-old
 Elevated serum LDH
Advanced stage (III or IV) disease
Poor performance status
Patients with no or one risk factor may have a complete (80%) response to standard chemotherapy and
most responses (80%) are durable. Patients with two risk factors have a complete 7% complete response
and 70% are long-lasting. Patients with higher risk disease have lower response rates and poor survival
with standard regimens of treatment and alternative therapies are needed. Early treatment with high-dose
therapy and autologous stem cell transplantation improves the outcome. For patients who relapse after
initial chemotherapy, the prognosis depends on whether the lymphoma is still partially sensitive to
chemotherapy. If so, autologous transplantation offers a 50% chance of long-term salvage.

Patient Education
Patients should be informed of the nature of their disease, its course and prognosis. Most patients with
Hodgkins disease and non-Hodgkins lymphoma have some degree of familiarity with the nature, course
and prognosis of their disease. As with other conditions, this knowledge has been reinforced by the ready
availability of medical information supplied by the Internet and other sources.

The physician should independently provide the patient with accurate and factual information, correcting
any misconceptions the patient may have acquired from other sources. The excellent prognosis of
Hodgkins disease and non-Hodgkins lymphoma and their actual curability with todays therapeutic
armamentarium should be emphasized. This will not alone maintain morale on the part of the patient, but
also will support his/her compliance with the program.

As with any disease, the physician should alert the patient to potential therapeutic side effects and
significant signs and symptoms that may herald a relapse.

Follow up
Long term survivors of successful therapy should be followed for long-term. Complications such as
hypothyroidism, pericardial fibrosis, focal carcinoma or sarcoma secondary to radiation therapy, sterility,
anemia and hematological complications of chemotherapy such as thrombocytopenia. The chronic state
of immune depression following therapy can result in late-appearing infections such as herpes zoster.
Patients who have had splenectomy may have a predilection for bacterial infections.

About The Brain

The brain is a soft, spongy mass of tissue. It is protected by:

- The bones of the skull

- Three thin layers of tissue (meninges)

- Watery fluid (cerebrospinal fluid) that flows through spaces between the meninges and through spaces
(ventricles) within the brain

This picture shows the brain and nearby structures. (Image courtesy of the National Cancer Institute)

This picture shows the brain and nearby structures. (Image courtesy of the National Cancer Institute)

The brain directs the things we choose to do (like walking and talking) and the things our body does
without thinking (like breathing). The brain is also in charge of our senses (sight, hearing, touch, taste,
and smell), memory, emotions, and personality.

A network of nerves carries messages back and forth between the brain and the rest of the body. Some
nerves go directly from the brain to the eyes, ears, and other parts of the head. Other nerves run
through the spinal cord to connect the brain with the other parts of the body. Within the brain and
spinal cord, glial cells surround nerve cells and hold them in place.

The three major parts of the brain control different activities:

- Cerebrum: The cerebrum uses information from our senses to tell us what is going on around us and
tells our body how to respond. It controls reading, thinking, learning, speech, and emotions. The
cerebrum is divided into the left and right cerebral hemispheres. The right hemisphere controls the
muscles on the left side of the body. The left hemisphere controls the muscles on the right side of the
body.

- Cerebellum: The cerebellum controls balance for walking and standing, and other complex actions.

- Brain stem: The brain stem connects the brain with the spinal cord. It controls breathing, body
temperature, blood pressure, and other basic body functions.

This picture shows the major parts of the brain. (Image courtesy of the National Cancer Institute)

This picture shows the major parts of the brain. (Image courtesy of the National Cancer Institute)

Tumor Grades and Types

When most normal cells grow old or get damaged, they die, and new cells take their place. Sometimes,
this process goes wrong. New cells form when the body doesn't need them, and old or damaged cells
don't die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor.

Primary brain tumors can be benign or malignant:

Benign brain tumors do not contain cancer cells:

- Usually, benign tumors can be removed, and they seldom grow back.

- Benign brain tumors usually have an obvious border or edge. Cells from benign tumors rarely invade
tissues around them. They don't spread to other parts of the body. However, benign tumors can press on
sensitive areas of the brain and cause serious health problems.

- Unlike benign tumors in most other parts of the body, benign brain tumors are sometimes life
threatening.

- Benign brain tumors may become malignant.

Malignant brain tumors (also called brain cancer) contain cancer cells:

- Malignant brain tumors are generally more serious and often are a threat to life.

- They are likely to grow rapidly and crowd or invade the nearby healthy brain tissue.

- Cancer cells may break away from malignant brain tumors and spread to other parts of the brain or to
the spinal cord.

- They rarely spread to other parts of the body.

Tumor Grade

Doctors group brain tumors by grade. The grade of a tumor refers to the way the cells look under a
microscope:

- Grade I: The tissue is benign. The cells look nearly like normal brain cells, and they grow slowly.

- Grade II: The tissue is malignant. The cells look less like normal cells than do the cells in a Grade I
tumor.

- Grade III: The malignant tissue has cells that look very different from normal cells. The abnormal cells
are actively growing (anaplastic).

- Grade IV: The malignant tissue has cells that look most abnormal and tend to grow quickly.

Cells from low-grade tumors (grades I and II) look more normal and generally grow more slowly than
cells from high-grade tumors (grades III and IV).

Over time, a low-grade tumor may become a highgrade tumor. However, the change to a high-grade
tumor happens more often among adults than children.

Types of Primary Brain Tumors

There are many types of primary brain tumors. Primary brain tumors are named according to the type of
cells or the part of the brain in which they begin. For example, most primary brain tumors begin in glial
cells. This type of tumor is called a glioma.

Among adults, the most common types are:

Astrocytoma: The tumor arises from star-shaped glial cells called astrocytes. It can be any grade. In
adults, an astrocytoma most often arises in the cerebrum.
- Grade I or II astrocytoma: It may be called a low-grade glioma.

- Grade III astrocytoma: It's sometimes called a high-grade or an anaplastic astrocytoma.

- Grade IV astrocytoma: It may be called a glioblastoma or malignant astrocytic glioma.

Meningioma: The tumor arises in the meninges. It can be grade I, II, or III. It's usually benign (grade I)
and grows slowly.

Oligodendroglioma: The tumor arises from cells that make the fatty substance that covers and protects
nerves. It usually occurs in the cerebrum. It's most common in middle-aged adults. It can be grade II or
III.

Among children, the most common types are:

Medulloblastoma: The tumor usually arises in the cerebellum. It's sometimes called a primitive
neuroectodermal tumor. It is grade IV.

Grade I or II astrocytoma: In children, this lowgrade tumor occurs anywhere in the brain. The most
common astrocytoma among children is juvenile pilocytic astrocytoma. It's grade I.

Ependymoma: The tumor arises from cells that line the ventricles or the central canal of the spinal cord.
It's most commonly found in children and young adults. It can be grade I, II, or III.

Brain stem glioma: The tumor occurs in the lowest part of the brain. It can be a low-grade or high-grade
tumor. The most common type is diffuse intrinsic pontine glioma.

You can find more information about types of brain tumors at

http://www.cancer.gov/cancertopics/types/brain. Or, you can call the NCI Cancer Information Service at
1-800-4-CANCER (1-800-422-6237).

Risk Factors
When you're told that you have a brain tumor, it's natural to wonder what may have caused your
disease. But no one knows the exact causes of brain tumors. Doctors seldom know why one person
develops a brain tumor and another doesn't. Researchers are studying whether people with certain risk
factors are more likely than others to develop a brain tumor. A risk factor is something that may increase
the chance of getting a disease. Studies have found the following risk factors for brain tumors:

Ionizing radiation: Ionizing radiation from high dose x-rays (such as radiation therapy from a large
machine aimed at the head) and other sources can cause cell damage that leads to a tumor. People
exposed to ionizing radiation may have an increased risk of a brain tumor, such as meningioma or
glioma.

Family history: It is rare for brain tumors to run in a family. Only a very small number of families have
several members with brain tumors.

Researchers are studying whether using cell phones, having had a head injury, or having been exposed to
certain chemicals at work or to magnetic fields are important risk factors. Studies have not shown
consistent links between these possible risk factors and brain tumors, but additional research is needed.

Symptoms

The symptoms of a brain tumor depend on tumor size, type, and location. Symptoms may be caused
when a tumor presses on a nerve or harms a part of the brain. Also, they may be caused when a tumor
blocks the fluid that flows through and around the brain, or when the brain swells because of the
buildup of fluid. These are the most common symptoms of brain tumors:

Headaches (usually worse in the morning)

Nausea and vomiting

Changes in speech, vision, or hearing

Problems balancing or walking

Changes in mood, personality, or ability to concentrate

Problems with memory

Muscle jerking or twitching (seizures or convulsions)

Numbness or tingling in the arms or legs

Most often, these symptoms are not due to a brain tumor. Another health problem could cause them. If
you have any of these symptoms, you should tell your doctor so that problems can be diagnosed and
treated.

Diagnosis

If you have symptoms that suggest a brain tumor, your doctor will give you a physical exam and ask
about your personal and family health history. You may have one or more of the following tests:

Neurologic exam: Your doctor checks your vision, hearing, alertness, muscle strength, coordination, and
reflexes. Your doctor also examines your eyes to look for swelling caused by a tumor pressing on the
nerve that connects the eye and the brain.

MRI: A large machine with a strong magnet linked to a computer is used to make detailed pictures of
areas inside your head. Sometimes a special dye (contrast material) is injected into a blood vessel in your
arm or hand to help show differences in the tissues of the brain. The pictures can show abnormal areas,
such as a tumor.

CT scan: An x-ray machine linked to a computer takes a series of detailed pictures of your head. You may
receive contrast material by injection into a blood vessel in your arm or hand. The contrast material
makes abnormal areas easier to see. Your doctor may ask for other tests:

Angiogram: Dye injected into the bloodstream makes blood vessels in the brain show up on an x-ray. If a
tumor is present, the x-ray may show the tumor or blood vessels that are feeding into the tumor.
Spinal tap: Your doctor may remove a sample of cerebrospinal fluid (the fluid that fills the spaces in and
around the brain and spinal cord). This procedure is performed with local anesthesia. The doctor uses a
long, thin needle to remove fluid from the lower part of the spinal column. A spinal tap takes about 30
minutes. You must lie flat for several hours afterward to keep from getting a headache. A laboratory
checks the fluid for cancer cells or other signs of problems.

Biopsy: The removal of tissue to look for tumor cells is called a biopsy. A pathologist looks at the cells
under a microscope to check for abnormal cells. A biopsy can show cancer, tissue changes that may lead
to cancer, and other conditions. A biopsy is the only sure way to diagnose a brain tumor, learn what
grade it is, and plan treatment. Surgeons can obtain tissue to look for tumor cells in two ways:

However, if the tumor is in the brain stem or certain other areas, the surgeon may not be able to remove
tissue from the tumor without harming normal brain tissue. In this case, the doctor uses MRI, CT, or
other imaging tests to learn as much as possible about the brain tumor.

Biopsy at the same time as treatment: The surgeon takes a tissue sample when you have surgery to
remove part or all of the tumor.

Stereotactic biopsy: You may get local or general anesthesia and wear a rigid head frame for this
procedure. The surgeon makes a small incision in the scalp and drills a small hole (a burr hole) into the
skull. CT or MRI is used to guide the needle through the burr hole to the location of the tumor. The
surgeon withdraws a sample of tissue with the needle. A needle biopsy may be used when a tumor is
deep inside the brain or in a part of the brain that can't be operated on.

A person who needs a biopsy may want to ask the doctor the following questions:

- Why do I need a biopsy? How will the biopsy results affect my treatment plan?

- What kind of biopsy will I have?

- How long will it take? Will I be awake? Will it hurt?

- What are the chances of infection or bleeding after the biopsy? Are there any other risks?

- How soon will I know the results?

- If I do have a brain tumor, who will talk with me about treatment? When?

Treatments

People with brain tumors have several treatment options. The options are surgery, radiation therapy, and
chemotherapy. Many people get a combination of treatments. The choice of treatment depends mainly
on the following:

- The type and grade of brain tumor

- Its location in the brain

- Its size

- Your age and general health

For some types of brain cancer, the doctor also needs to know whether cancer cells were found in the
cerebrospinal fluid.

Your doctor can describe your treatment choices, the expected results, and the possible side effects.
Because cancer therapy often damages healthy cells and tissues, side effects are common. Before
treatment starts, ask your health care team about possible side effects and how treatment may change
your normal activities. You and your health care team can work together to develop a treatment plan
that meets your medical and personal needs.

You may want to talk with your doctor about taking part in a clinical trial, a research study of new
treatment methods.

Your doctor may refer you to a specialist, or you may ask for a referral. Specialists who treat brain tumors
include neurologists, neurosurgeons, neuro-oncologists, medical oncologists, radiation oncologists, and
neuroradiologists. Your health care team may also include an oncology nurse, a registered dietitian, a
mental health counselor, a social worker, a physical therapist, an occupational therapist, a speech
therapist, and a physical medicine specialist.

You may want to ask your doctor these questions before you begin treatment:

- What type of brain tumor do I have?

- Is it benign or malignant?

- What is the grade of the tumor?

- What are my treatment choices? Which do you recommend for me? Why?

- What are the expected benefits of each kind of treatment?

- What can I do to prepare for treatment?

- Will I need to stay in the hospital? If so, for how long?

- What are the risks and possible side effects of each treatment? How can side effects be managed?

- What is the treatment likely to cost? Will my insurance cover it?

- How will treatment affect my normal activities? What is the chance that I will have to learn how to
walk, speak, read, or write after treatment?

- Would a research study (clinical trial) be appropriate for me?

- Can you recommend other doctors who could give me a second opinion about my treatment options?
- How often should I have checkups?

Surgery

Surgery is the usual first treatment for most brain tumors. Before surgery begins, you may be given
general anesthesia, and your scalp is shaved. You probably won't need your entire head shaved. Surgery
to open the skull is called a craniotomy. The surgeon makes an incision in your scalp and uses a special
type of saw to remove a piece of bone from the skull. You may be awake when the surgeon removes part
or all of the brain tumor. The surgeon removes as much tumor as possible. You may be asked to move a
leg, count, say the alphabet, or tell a story. Your ability to follow these commands helps the surgeon
protect important parts of the brain. After the tumor is removed, the surgeon covers the opening in the
skull with the piece of bone or with a piece of metal or fabric. The surgeon then closes the incision in the
scalp.

Sometimes surgery isn't possible. If the tumor is in the brain stem or certain other areas, the surgeon
may not be able to remove the tumor without harming normal brain tissue. People who can't have
surgery may receive radiation therapy or other treatment.

You may have a headache or be uncomfortable for the first few days after surgery. However, medicine
can usually control pain. Before surgery, you should discuss the plan for pain relief with your health care
team. After surgery, your team can adjust the plan if you need more relief. You may also feel tired or
weak. The time it takes to heal after surgery is different for everyone. You will probably spend a few days
in the hospital.

Other, less common problems may occur after surgery for a brain tumor. The brain may swell or fluid
may build up within the skull. The health care team will monitor you for signs of swelling or fluid buildup.
You may receive steroids to help relieve swelling. A second surgery may be needed to drain the fluid. The
surgeon may place a long, thin tube (shunt) in a ventricle of the brain. (For some people, the shunt is
placed before performing surgery on the brain tumor.) The tube is threaded under the skin to another
part of the body, usually the abdomen. Excess fluid is carried from the brain and drained into the
abdomen. Sometimes the fluid is drained into the heart instead.

Infection is another problem that may develop after surgery. If this happens, the health care team will
give you an antibiotic.

Brain surgery may harm normal tissue. Brain damage can be a serious problem. It can cause problems
with thinking, seeing, or speaking. It can also cause personality changes or seizures. Most of these
problems lessen or disappear with time. But sometimes damage to the brain is permanent. You may
need physical therapy, speech therapy, or occupational therapy.

You may want to ask your doctor these questions about surgery:

- Do you suggest surgery for me?

- How will I feel after the operation?

- What will you do for me if I have pain?

- How long will I be in the hospital?

- Will I have any long-term effects? Will my hair grow back? Are there any side effects from using metal
or fabric to replace the bone in the skull?

- When can I get back to my normal activities?

- What is my chance of a full recovery?

Radiation Therapy

Radiation therapy kills brain tumor cells with high-energy x-rays, gamma rays, or protons. Radiation
therapy usually follows surgery. The radiation kills tumor cells that may remain in the area. Sometimes,
people who can't have surgery have radiation therapy instead.

Doctors use external and internal types of radiation therapy to treat brain tumors:

External radiation therapy: You'll go to a hospital or clinic for treatment. A large machine outside the
body aims beams of radiation at the head. Because cancer cells may invade normal tissue around a
tumor, the radiation may be aimed at the tumor and nearby brain tissue, or at the entire brain. Some
people need radiation aimed at the spinal cord also. The treatment schedule depends on your age, and
the type and size of the tumor. Fractionated external beam therapy is the most common method of
radiation therapy used for people with brain tumors. Giving the total dose of radiation over several
weeks helps to protect healthy tissue in the area of the tumor. Treatments are usually 5 days a week for
several weeks. A typical visit lasts less than an hour, and each treatment takes only a few minutes.

Some treatment centers are studying other ways of delivering external beam radiation therapy:

Intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy: These types of

treatment use computers to more closely target the brain tumor to lessen the damage to healthy tissue.

Proton beam radiation therapy: The source of radiation is protons rather than x-rays. The doctor aims
the proton beam at the tumor. The dose of radiation to normal tissue from a proton beam is less than
the dose from an x-ray beam.

Stereotactic radiation therapy: Narrow beams of x-rays or gamma rays are directed at the tumor from
different angles. For this procedure, you wear a rigid head frame. The therapy may be given during a
single visit (stereotactic radiosurgery) or over several visits.

Internal radiation therapy (implant radiation therapy or brachytherapy): Internal radiation isn't
commonly used for treating brain tumors and is under study. The radiation comes from radioactive
material usually contained in very small implants called seeds. The seeds are placed inside the brain and
give off radiation for months. They don't need to be removed once the radiation is gone.

Some people have no or few side effects after treatment. Rarely, people may have nausea for several
hours after external radiation therapy. The health care team can suggest ways to help you cope with this
problem. Radiation therapy also may cause you to become very tired with each radiation treatment.
Resting is important, but doctors usually advise people to try to stay as active as they can.

Also, external radiation therapy commonly causes hair loss from the part of the head that was treated.
Hair usually grows back within a few months. Radiation therapy also may make the skin on the scalp and
ears red, dry, and tender. The health care team can suggest ways to relieve these problems. Sometimes
radiation therapy causes brain tissue to swell. You may get a headache or feel pressure. The health care
team watches for signs of this problem. They can provide medicine to reduce the discomfort. Radiation
sometimes kills healthy brain tissue.
Although rare, this side effect can cause headaches, seizures, or even death.

Radiation may harm the pituitary gland and other areas of the brain. For children, this damage could
cause learning problems or slow down growth and development. In addition, radiation increases the risk
of secondary tumors later in life.

You may want to ask your doctor these questions about radiation therapy:

- Why do I need this treatment?

- When will the treatments begin? When will they end?

- How will I feel during therapy? Are there side effects?

- What can I do to take care of myself during therapy?

- How will we know if the radiation is working?

- Will I be able to continue my normal activities during treatment?

Chemotherapy

Chemotherapy, the use of drugs to kill cancer cells, is sometimes used to treat brain tumors. Drugs may
be given in the following ways:

By mouth or vein (intravenous): Chemotherapy may be given during and after radiation therapy. The
drugs enter the bloodstream and travel throughout the body. They may be given in an outpatient part of
the hospital, at the doctor's office, or at home. Rarely, you may need to stay in the hospital. The side
effects of chemotherapy depend mainly on which drugs are given and how much. Common side effects
include nausea and vomiting, loss of appetite, headache, fever and chills, and weakness. If the drugs
lower the levels of healthy blood cells, you're more likely to get infections, bruise or bleed easily, and feel
very weak and tired. Your health care team will check for low levels of blood cells. Some side effects may
be relieved with medicine.

In wafers that are put into the brain: For some adults with high-grade glioma, the surgeon implants
several wafers into the brain. Each wafer is about the size of a dime. Over several weeks, the wafers
dissolve, releasing the drug into the brain. The drug kills cancer cells. It may help prevent the tumor from
returning in the brain after surgery to remove the tumor. People who receive an implant (a wafer) that
contains a drug are monitored by the health care team for signs of infection after surgery. An infection
can be treated with an antibiotic.