Author: Dr Joseph Connors British Columbia Cancer Agency 2008-07-28
Introduction
Hodgkin lymphoma is a cancer that originates from B-lymphocytes of the immune system and the most common type is marked by the presence of a very specific type of cell known as the Hodgkin Reed-Sternberg cell. Once a uniformly fatal disease, today Hodgkin lymphoma is routinely curable. This knol provides a history of the disease and then goes on to describe the typical symptoms, diagnosis, treatment options, and prognosis after treatment.The history of Hodgkin lymphoma
In
1832, Thomas Hodgkin first published a small series of cases describing
enlargement of lymph nodes or the spleen in which he described “… some
morbid appearances of the absorbent glands and spleen.” [1] This
is traditionally considered the seminal description of the disease that
carries his name. Throughout the rest of the 1800s more detailed
microscopy was used to describe the abnormal cells within the diseased
lymph nodes and spleen of patients with Hodgkin lymphoma. At the turn of
the century, amidst much debate whether Hodgkin lymphoma was an
infection or a cancer, Dorothy Reed Mendenhall and Carl Sternberg
published elegant drawings of the distinctive giant cells that came to
bear their names (Figure 1), Reed-Sternberg cells.[2, 3].
In the first half of the twentieth century, the identification and classification of this lymphoma was further refined, eventually leading to the names used today for the major types of Hodgkin lymphoma: nodular sclerosis; mixed cellularity; lymphocyte depleted and nodular lymphocyte predominant. A fifth type, lymphocyte rich, was added in 1998 and at the same time a distinction drawn between the uncommon nodular lymphocyte predominant type and the other four, now grouped together as classical Hodgkin lymphoma. (Table 1)[4]
In the first half of the twentieth century, the identification and classification of this lymphoma was further refined, eventually leading to the names used today for the major types of Hodgkin lymphoma: nodular sclerosis; mixed cellularity; lymphocyte depleted and nodular lymphocyte predominant. A fifth type, lymphocyte rich, was added in 1998 and at the same time a distinction drawn between the uncommon nodular lymphocyte predominant type and the other four, now grouped together as classical Hodgkin lymphoma. (Table 1)[4]
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Table 1. World Health Organization Classification of Hodgkin lymphoma types
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Name Frequency (%)*
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Classical Hodgkin lymphoma
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Nodular sclerosis 77
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Mixed cellularity 10
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Lymphocyte rich 4
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Lymphocyte depleted 1
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Nodular lymphocyte predominant Hodgkin lymphoma 8
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* frequency based on all new cases (n = 862) seen in British Columbia since January 1998 when the new category of lymphocyte rich classical Hodgkin lymphoma started to be used.
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Initial
progress in the treatment of Hodgkin lymphoma was slow consisting of
little more than minimally useful surgical resection of superficial
tumors. However, soon after the discovery of X-rays by the Curies and
Roentgen William Pusey [5] and Nicholas Senn [6] separately described
shrinkage of advanced lymph nodal disease in response to brief exposure
to radioactive radium. Disappointingly, the disease always grew back and
through the 1950s Hodgkin lymphoma was considered incurable. Vera
Peters [7] and Henry Kaplan [8, 9] subsequently demonstrated that
Hodgkin lymphoma could be cured with radiation from radioactive cobalt
or, even better, using the newly invented linear accelerator.
Chemotherapy, the use of mildly poisonous chemicals to treat cancer, came to the field of treating Hodgkin lymphoma later than radiation, but has had a profound effect. Studies into the multiple effects of mustard gas, the poison gas frequently used in World War I, led to the discovery of chemicals such as mechlorethamine and cyclophosphamide with the ability to bind methyl and other alkyl groups to DNA (deoxyribonucleic acid), the chemical with which chromosomes are made. Other chemicals capable of disrupting normal intra-cellular metabolism such as the corticosteroids (chemicals similar to adrenalin, the fight-flight hormone made in the adrenal glands) and the vinca alkaloids vinblastine and vincristine (noxious chemicals made by the periwinkle plant to deter consumption by animals), were found to cause shrinkage of Hodgkin lymphoma tumors, but the effects were transient. The real potential of chemotherapy was not realized until combinations of drugs were explored. In pioneering work at the United States National Cancer Institute, a team led by Dr. Vincent DeVita, Jr. made the remarkable discovery that a four drug combination called MOPP (mechlorethamine, vincristine {trade name Oncovin}, procarbazine and prednisone) could cure far advanced Hodgkin lymphoma.[10] This observation transformed the approach to cancer treatment. For the first time doctors had shown that at least some cancers, no matter how widely spread in the body, could be cured with medications. Even patients with cancer that had spread beyond the reach of surgery or radiation, which can only be given in effective doses to small regions of the body, could be cured. It is no exaggeration to say that the entire field of modern cancer chemotherapy was built on this initial observation and the contemporaneous one showing that similar chemicals could cure childhood leukaemia. Today we use newer drugs such as the antibiotics doxorubicin and bleomycin, both derivatives of natural defence chemicals made by fungi or bacteria, as well as other more recently discovered chemicals instead of the original MOPP combination because they are more effective and cause fewer side effects. Nevertheless, the principle of using combinations of chemotherapy drugs remains the keystone of Hodgkin lymphoma treatment.
The final and most recent major contribution to Hodgkin lymphoma treatment was the demonstration that the use of very high doses of chemotherapy drugs can cure otherwise refractory (nonresponsive) Hodgkin lymphoma, as long as patients are rescued from these drugs’ extreme toxicity by being given back special blood forming stem cells removed from their blood or bone marrow before the high dose chemotherapy.[11] This technique of high dose chemotherapy with stem cell rescue gives patients a second chance, even if the Hodgkin lymphoma comes back despite standard dose chemotherapy.
The remarkable progress over just a few decades in the treatment of Hodgkin lymphoma, changing it from a uniformly fatal disease into one that can be routinely cured, exemplifies the fundamental reliance of modern medicine on careful scientific and clinical research. Basic laboratory research led to the discovery of therapeutic radiation, chemotherapy, stem cell transplantation, and the special types of scans that we use routinely to monitor the effects of treatment. Teams of clinical researchers have treated thousands of volunteer patients in clinical trials that have allowed us to define the most effective and least toxic treatments for this now reliably curable cancer. Hematopathologists, diagnostic radiologists, radiation and medical oncologists, specially trained oncology nurses and pharmacists work together as a multimodality team, the approach that is at the heart of modern cancer treatment. The history of Hodgkin lymphoma encompasses almost two centuries of progress and continues to serve as a guiding paradigm for curing cancer.
Chemotherapy, the use of mildly poisonous chemicals to treat cancer, came to the field of treating Hodgkin lymphoma later than radiation, but has had a profound effect. Studies into the multiple effects of mustard gas, the poison gas frequently used in World War I, led to the discovery of chemicals such as mechlorethamine and cyclophosphamide with the ability to bind methyl and other alkyl groups to DNA (deoxyribonucleic acid), the chemical with which chromosomes are made. Other chemicals capable of disrupting normal intra-cellular metabolism such as the corticosteroids (chemicals similar to adrenalin, the fight-flight hormone made in the adrenal glands) and the vinca alkaloids vinblastine and vincristine (noxious chemicals made by the periwinkle plant to deter consumption by animals), were found to cause shrinkage of Hodgkin lymphoma tumors, but the effects were transient. The real potential of chemotherapy was not realized until combinations of drugs were explored. In pioneering work at the United States National Cancer Institute, a team led by Dr. Vincent DeVita, Jr. made the remarkable discovery that a four drug combination called MOPP (mechlorethamine, vincristine {trade name Oncovin}, procarbazine and prednisone) could cure far advanced Hodgkin lymphoma.[10] This observation transformed the approach to cancer treatment. For the first time doctors had shown that at least some cancers, no matter how widely spread in the body, could be cured with medications. Even patients with cancer that had spread beyond the reach of surgery or radiation, which can only be given in effective doses to small regions of the body, could be cured. It is no exaggeration to say that the entire field of modern cancer chemotherapy was built on this initial observation and the contemporaneous one showing that similar chemicals could cure childhood leukaemia. Today we use newer drugs such as the antibiotics doxorubicin and bleomycin, both derivatives of natural defence chemicals made by fungi or bacteria, as well as other more recently discovered chemicals instead of the original MOPP combination because they are more effective and cause fewer side effects. Nevertheless, the principle of using combinations of chemotherapy drugs remains the keystone of Hodgkin lymphoma treatment.
The final and most recent major contribution to Hodgkin lymphoma treatment was the demonstration that the use of very high doses of chemotherapy drugs can cure otherwise refractory (nonresponsive) Hodgkin lymphoma, as long as patients are rescued from these drugs’ extreme toxicity by being given back special blood forming stem cells removed from their blood or bone marrow before the high dose chemotherapy.[11] This technique of high dose chemotherapy with stem cell rescue gives patients a second chance, even if the Hodgkin lymphoma comes back despite standard dose chemotherapy.
The remarkable progress over just a few decades in the treatment of Hodgkin lymphoma, changing it from a uniformly fatal disease into one that can be routinely cured, exemplifies the fundamental reliance of modern medicine on careful scientific and clinical research. Basic laboratory research led to the discovery of therapeutic radiation, chemotherapy, stem cell transplantation, and the special types of scans that we use routinely to monitor the effects of treatment. Teams of clinical researchers have treated thousands of volunteer patients in clinical trials that have allowed us to define the most effective and least toxic treatments for this now reliably curable cancer. Hematopathologists, diagnostic radiologists, radiation and medical oncologists, specially trained oncology nurses and pharmacists work together as a multimodality team, the approach that is at the heart of modern cancer treatment. The history of Hodgkin lymphoma encompasses almost two centuries of progress and continues to serve as a guiding paradigm for curing cancer.
Biology of Hodgkin Lymphoma
All cancers, including Hodgkin lymphoma, consist of a clone of cells derived from one which underwent malignant transformation (became a cancer cell). Initially every cell derived from the original one is a nearly exact duplicate. However, because they are genetically unstable, cancer cells make copying errors in passing genetic information from parent cell to offspring, thus disrupting their normal behavior and allowing them to accumulate abnormally and spread (metastasize) to other parts of the body where they do not belong, forming new tumors (metastases). Even though they change and develop new behaviors, all cancer cells retain some of the characteristics of their original parent cell, making it possible to determine what type of cell gave rise to the cancerous clone by examining the cells in metastatic tumors. Such scientific detective work has revealed that Hodgkin lymphoma is derived from one of the white blood cells called a lymphocyte.Lymphocytes are the circulating white blood cells that move throughout our blood and lymph fluid and are stored within structures called lymph nodes and the bone marrow, spleen, and other organs. These lymphocytes, which defend the body against infection, come in two types. T-lymphocytes – named because they spend some time developing in the thymus, a small gland in the chest deep behind the breast bone – have the ability to destroy cells that have germs hiding inside them. B-lymphocytes, which start out in the bone marrow, make antibodies that adhere avidly to germs, neutralizing and often killing them. Each B-lymphocyte makes just one type of antibody and if that antibody does not bind to anything nearby, the B-lymphocyte commits suicide by undergoing a process called programmed cell death, known to scientists as apoptosis. Only the B-lymphocytes that make useful antibodies are left behind.
Until the mid-1990s the cell of origin of Hodgkin lymphoma remained obscure. However, techniques based on laser-guided microdissection of single cells allowed isolation of malignant Reed-Sternberg cells, the characteristic abnormal cells of Hodgkin lymphoma.[12] The genetic structure of these cells was analyzed demonstrating that not only are they are derived from a B-lymphocyte that lost its ability to make antibodies but, even more importantly, these cells are unable to undergo programmed cell death.[13, 14] They persist in an expanding clone that gradually acquires increasingly malignant behavior over time.
Who develops Hodgkin lymphoma?
Hodgkin lymphoma is uncommon, but not rare. It is usually seen in younger patients; this is quite different from most cancers, which typically increase in frequency with age. It occurs more often in men and is seen more frequently in whites, with the highest incidence rates observed in the United States, Canada and Northern Europe. It is much less frequently observed in populations derived from southeastern Asia and Eastern Europe.[15] It is unclear why this geographic and racial variation occurs.The cumulative lifetime risk of developing Hodgkin lymphoma in North America is approximately 1 in 250. Around 8000 to 9000 new cases are seen in the United States and Canada each year. The incidence of Hodgkin lymphoma has declined modestly, but significantly over the past 20 years at an annual rate of approximately 0.9 %. http://www.cancer.org/docroot/stt/stt_0.asp) Although the age-adjusted annual incidence is approximately 2.7 per 100,000, the age-adjusted annual mortality is less than 0.5 per 100,000, indicating that many patients are cured.
What causes Hodgkin lymphoma?
The cause of Hodgkin lymphoma remains unclear. There is a rapid rise in incidence between childhood and early adulthood with an increased incidence in siblings and parts of the world where crowding is common, suggesting that some type of infection might cause Hodgkin lymphoma. However, no virus or any other germ has been clearly implicated. The leading candidate remains the Epstein Barr virus (EBV). Approximately 90 % of people around the world are infected by EBV by early adulthood. In the developed countries infection with EBV is often delayed into the teens, when it causes infectious mononucleosis in up to 30 % and can increase the likelihood of developing Hodgkin lymphoma threefold. Despite this apparent association, however, less than one-half of cases of Hodgkin lymphoma can be linked to EBV, making it clear that other factors must be important.Although there is no clear-cut association between Hodgkin lymphoma and environmental factors or chemical exposure, there are strong hints of a genetic link. First degree relatives of individuals with the disease have up to a five-fold increased risk of developing the lymphoma. Identical twins of an affected individual are 100 times more likely to develop Hodgkin lymphoma compared to fraternal twins.[16] No specific gene has been linked to Hodgkin lymphoma but it is possible that when genetically predisposed individuals are exposed to EBV or other unknown viruses this exposure induces a greater chance of developing the lymphoma.
How is the diagnosis of Hodgkin lymphoma made?
Most patients with Hodgkin lymphoma come to the doctor because of painless swelling of the lymph nodes in the neck or chest or, less commonly, the lower part of the body. Occasionally the involved lymph nodes become sore immediately after drinking alcohol. Approximately 25 % of patients notice weight loss, heavy sweating at night, or persistent fever. These symptoms, referred to as “B” symptoms of Hodgkin lymphoma, usually signal that the lymphoma is causing a large tumor mass in one place or has spread widely throughout the body. Sometimes patients notice persistent unexplained itching, which can start long before the diagnosis of the lymphoma. When the swollen lymph nodes are inside the chest they can cause unexplained cough or difficulty breathing.Hodgkin lymphoma only spreads outside the lymph nodes and spleen about 20 % of the time. It may spread into the bones and cause pain; into the bone marrow (the hollow center of our large bones where new blood cells are formed) where it may cause low blood counts (low levels of the red cells that carry oxygen (anemia), the white cells that fight infection, or platelet cells that help our blood to clot properly); into the liver, where it can cause a blockage of the channels that run from the liver into the intestine causing jaundice (a yellowish discoloration of the skin); or into the lungs where it may cause cough.
If the diagnosis of Hodgkin lymphoma is suspected, an enlarged lymph node or a piece of tissue (biopsy) from an area of swelling is removed to be carefully examined under the microscope by a specialist called a pathologist who looks for the typical malignant cells called Reed-Sternberg, or sometimes Hodgkin cells scattered against a background of the type of cells that are typically seen in areas of inflammation (Figure 2). In addition to taking a careful medical history and examining the patient for the presence of localized swellings or areas of pain, once the doctor makes a diagnosis of Hodgkin lymphoma he or she then arranges for additional tests to be done to establish the extent of disease, a process called staging.
What is staging?
In
order to tell how best to treat Hodgkin lymphoma the cancer specialist
needs to understand where the disease has spread within the body.
Medical scientists have found that the disease usually first develops in
lymph nodes in the upper part of the body and then spreads from one
lymph node group to another. Eventually, after it has spread to the
lymph nodes in the upper abdomen, it can invade the spleen and then
other organs such as the liver and bone marrow. In addition, the
malignant cells can move from lymph nodes into nearby organs such as the
lungs or bones. A striking aspect of Hodgkin lymphoma is how faithfully
it stays within certain parts of the body. In most cases it does not
reach beyond the lymph nodes and even when it does it only spreads to
the lungs, liver, bone or bone marrow.
Knowing about this regular pattern of dissemination helped experts who
met in Ann Arbor, Michigan in the early 1970s to develop a system (named
after that city) to describe the extent of or, as doctors refer to it,
the stage of the disease.[17] This system works very well at predicting
which treatment will be best so it is still used today (Table 2).
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Table 2. Ann Arbor staging system for Hodgkin lymphoma
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Stage
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Involvement
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I
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Single lymph node region (I) or one extralymphatic site (IE).
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II
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Two
or more lymph node regions, same side of the diaphragm (II) or local
extralymphatic extension plus one or more lymph node regions same side
of the diaphragm (IIE).
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III
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Lymph node regions on both sides of the diaphragm (III) which may be accompanied by local extralymphatic extension (IIIE).
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IV
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Diffuse involvement of one or more extralymphatic organs or sites.
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Symptoms
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A =
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no B symptoms
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B =
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presence of at least one of these symptoms
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1) unexplained weight loss > 10 % baseline during 6 months prior to staging
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2) recurrent unexplained fever > 38oC
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3) recurrent night sweats
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E lesion.
Localized extranodal extension of Hodgkin lymphoma from a contiguous or
nearby nodal site is noted with the designation E, for example stage IIEA for asymptomatic disease in the mediastinum with contiguous extension into nearby lung.
| |
Stages I through III indicate the extent of lymph node disease. In stage I, a single cluster of lymph nodes is involved.
In stage II two or more groups of lymph nodes are involved but they are
either above (90% of cases) or below (10% of cases) the diaphragm, the
thin muscle that separates the chest from the abdomen. In stage III the
involved lymph nodes are both above and below the diaphragm. In this
system the spleen counts as a large lymph node, which is quite
reasonable because that is how it functions, as a large reservoir of
lymphocytes as they do their work for the immune system. Stage IV is
reserved for disease that has spread well outside the lymph nodes into
the bone marrow, lung, bone or liver. A small amount of localized spread
outside the lymph nodes into the nearby tissues is allowed without
changing the stage and for this type of extension a special designation
of “E” for extranodal is used. In addition to the number of the stage, I
through IV, doctors use a letter A or B to designate whether any of
three distinctive symptoms is present. If a patient has lost more
than 10% of normal body weight, is having a persistent unexplained
fever, or has heavy sweating episodes at night, the letter B is put
after the number of the stage; A is used if the symptoms are absent.
Thus, in the shorthand that doctors use to accurately describe the
spread of the lymphoma, if a patient has Hodgkin lymphoma only in the
lymph nodes on one side of the neck and in the central tissues of the
chest (the mediastinum) and no fever, weight loss or sweats, the stage
is II A. On the other hand, a patient with many swollen lymph nodes and
spread of the lymphoma into the liver who is experiencing drenching
sweats at night is said to have stage IV B.
Specialists determine the stage of Hodgkin lymphoma with a standard set of tests including blood tests to check how well new blood cells are being made in the body and to determine if the liver and kidneys are working properly. Most important in determining the extent of the lymphoma, however, are a physical examination, chest X-Ray (Figure 3) and a computerized tomographic (CT) scanning of the neck, chest, abdomen and pelvis. Staging is so important to treatment that before CT scanners were invented many patients had to have exploratory surgery to take biopsies throughout the abdomen to determine if any lymphoma was hiding there. Fortunately, such staging laparotomies are no longer needed. Finally, if patients have lower than normal blood counts or if they are experiencing B symptoms, it is necessary to use a thin coring needle to take a specimen from the bone marrow, usually from the posterior portion of the pelvic bones, in a simple out-patient procedure. When the physical examination, blood tests, CT scans and, if necessary, bone marrow biopsy are complete the specialist has a very clear picture of the full extent of the lymphoma and can plan treatment. In doing so both the extent and the size of the enlarged lymph nodes are considered. Thus, stage II with a very large mass of enlarged lymph nodes is treated differently from stage II with only modestly swollen nodes. Usually the largest diameter of the biggest mass is used to characterize the bulk of the lymphoma and many experts consider any mass greater than 10 cm in any diameter to be bulky, although differing measurement criteria are sometimes used.
Armed with the stage and a measurement of the most bulky tumor mass the specialist can decide if the Hodgkin lymphoma is limited or advanced in extent, the two groups most commonly distinguished for treatment planning. Those with stages I or II, without any bulky tumors (larger than 10 cm in greatest diameter) and free of B symptoms are considered to have limited stage disease. Those with stage III or IV or bulky disease or with B symptoms have advanced disease. Using these definitions approximately 40 % of patients have limited and 60 % advanced disease.
Recently a new way of detecting cancer has been developed called positron emission tomography (PET), which performs a scan of the entire body looking for areas of abnormal uptake of glucose (sugar) labeled with a radioactive tracer to detect malignant cells. (http://en.wikipedia.org/wiki/Positron_emission_tomography) The impact on the staging and treatment of patients with Hodgkin lymphoma of PET is currently being actively assessed. It is already clear that PET is more sensitive and specific than CT for staging and for assessment of residual masses after treatment. However, with the usual incorporation of chemotherapy into the management of all patients regardless of stage of disease it is not clear that the addition of PET to standard tests for Hodgkin lymphoma actually improves the outcome of treatment. It appears more likely that the greatest usefulness of PET will be in the assessment of disease response during or after planned treatment to identify the minority who need the plan to be changed.[18]
Specialists determine the stage of Hodgkin lymphoma with a standard set of tests including blood tests to check how well new blood cells are being made in the body and to determine if the liver and kidneys are working properly. Most important in determining the extent of the lymphoma, however, are a physical examination, chest X-Ray (Figure 3) and a computerized tomographic (CT) scanning of the neck, chest, abdomen and pelvis. Staging is so important to treatment that before CT scanners were invented many patients had to have exploratory surgery to take biopsies throughout the abdomen to determine if any lymphoma was hiding there. Fortunately, such staging laparotomies are no longer needed. Finally, if patients have lower than normal blood counts or if they are experiencing B symptoms, it is necessary to use a thin coring needle to take a specimen from the bone marrow, usually from the posterior portion of the pelvic bones, in a simple out-patient procedure. When the physical examination, blood tests, CT scans and, if necessary, bone marrow biopsy are complete the specialist has a very clear picture of the full extent of the lymphoma and can plan treatment. In doing so both the extent and the size of the enlarged lymph nodes are considered. Thus, stage II with a very large mass of enlarged lymph nodes is treated differently from stage II with only modestly swollen nodes. Usually the largest diameter of the biggest mass is used to characterize the bulk of the lymphoma and many experts consider any mass greater than 10 cm in any diameter to be bulky, although differing measurement criteria are sometimes used.
Armed with the stage and a measurement of the most bulky tumor mass the specialist can decide if the Hodgkin lymphoma is limited or advanced in extent, the two groups most commonly distinguished for treatment planning. Those with stages I or II, without any bulky tumors (larger than 10 cm in greatest diameter) and free of B symptoms are considered to have limited stage disease. Those with stage III or IV or bulky disease or with B symptoms have advanced disease. Using these definitions approximately 40 % of patients have limited and 60 % advanced disease.
Recently a new way of detecting cancer has been developed called positron emission tomography (PET), which performs a scan of the entire body looking for areas of abnormal uptake of glucose (sugar) labeled with a radioactive tracer to detect malignant cells. (http://en.wikipedia.org/wiki/Positron_emission_tomography) The impact on the staging and treatment of patients with Hodgkin lymphoma of PET is currently being actively assessed. It is already clear that PET is more sensitive and specific than CT for staging and for assessment of residual masses after treatment. However, with the usual incorporation of chemotherapy into the management of all patients regardless of stage of disease it is not clear that the addition of PET to standard tests for Hodgkin lymphoma actually improves the outcome of treatment. It appears more likely that the greatest usefulness of PET will be in the assessment of disease response during or after planned treatment to identify the minority who need the plan to be changed.[18]
Prognostic factors: estimating the likelihood of cure
Before
finally deciding how a patient with Hodgkin lymphoma should be treated,
sometimes doctors consider special aspects of the patient or the
disease that help to predict how likely the treatment is to be
successful called prognostic factors. Stage is one of those factors but
there are others, such as age. In fact those two factors dominate the
prognosis for patients with Hodgkin lymphoma. Elderly patients, those
over the age of 65 to 70 years, only constitute about 5 % of all
patients with Hodgkin lymphoma but they have a likelihood of being cured
that is only about one-half that of younger patients. This appears to
reflect both difficulty in delivering full dose treatment due to other
coincident serious medical conditions and loss of organ reserve with
aging, plus a greater intrinsic disease resistance to therapy.
Patients with limited stage disease have a 90 % to 95 % likelihood of cure while those with advanced disease have approximately a 65 % to 80 % chance of cure with the initial course of treatment. However, for all stages of disease and in all age groups the prognosis of patients with Hodgkin lymphoma has steadily improved over the past half-century. Figure 4 shows actuarial estimates of the likelihood of being alive plotted against the number of years after treatment for Hodgkin lymphoma for 2170 patients from British Columbia treated since 1961 grouped by decade of diagnosis. This type of graph, called a Kaplan-Meier survival estimate, is based on the actual experience of many patients aggregated together to yield a best estimate of outcome. It can be read by simply following the curve out to a specific time (shown in years across the bottom). The level of the curve (shown to the left as a proportion of individuals still alive out of the entire group started on treatment) is the likelihood of a patient surviving to that point in time. The dramatic shifts upward in the curves shown by era of treatment demonstrate the marked improvement in prognosis for patients with Hodgkin lymphoma in the past half century, reflecting the combined impact of better diagnosis, improved staging and most importantly, more effective treatment.
Attempts to identify additional prognostic factors other than stage and age have been variously successful. In patients with limited stage Hodgkin lymphoma the likelihood of cure is greater than 90 %, so such factors are of limited usefulness. On the other hand, a set of prognostic factors has been identified for patients with advanced disease that has clear utility. The International Prognostic Factors Project on Advanced Hodgkin's Disease identified seven factors with approximately equal impact on probability of cure and survival for patients with advanced Hodgkin lymphoma (Table 3).
Patients with limited stage disease have a 90 % to 95 % likelihood of cure while those with advanced disease have approximately a 65 % to 80 % chance of cure with the initial course of treatment. However, for all stages of disease and in all age groups the prognosis of patients with Hodgkin lymphoma has steadily improved over the past half-century. Figure 4 shows actuarial estimates of the likelihood of being alive plotted against the number of years after treatment for Hodgkin lymphoma for 2170 patients from British Columbia treated since 1961 grouped by decade of diagnosis. This type of graph, called a Kaplan-Meier survival estimate, is based on the actual experience of many patients aggregated together to yield a best estimate of outcome. It can be read by simply following the curve out to a specific time (shown in years across the bottom). The level of the curve (shown to the left as a proportion of individuals still alive out of the entire group started on treatment) is the likelihood of a patient surviving to that point in time. The dramatic shifts upward in the curves shown by era of treatment demonstrate the marked improvement in prognosis for patients with Hodgkin lymphoma in the past half century, reflecting the combined impact of better diagnosis, improved staging and most importantly, more effective treatment.
Attempts to identify additional prognostic factors other than stage and age have been variously successful. In patients with limited stage Hodgkin lymphoma the likelihood of cure is greater than 90 %, so such factors are of limited usefulness. On the other hand, a set of prognostic factors has been identified for patients with advanced disease that has clear utility. The International Prognostic Factors Project on Advanced Hodgkin's Disease identified seven factors with approximately equal impact on probability of cure and survival for patients with advanced Hodgkin lymphoma (Table 3).
|
Table 3. Prognostic factors of importance in advanced Hodgkin lymphoma identified by the International Prognostic Factors Project on Advanced Hodgkin's Disease [19]
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Gender male
|
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Age > 45 years
|
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Stage IV
|
|
Hemoglobin < 105 g/L
|
|
White blood cell count > 15 x 109/L
|
|
Lymphocyte count < 0.6 x 10 9/L or < 8 % of the white cell differential
|
|
Serum albumin < 40 g/L
|
The
first three are the patient’s age, gender and stage of disease. The
last four are specific blood tests that measure how a patient’s body is
responding to the lymphoma, that is, how ill the lymphoma is making the
patient. The more adverse factors present the lower the likelihood that
the lymphoma will be cured. This prognostic factor score helps medical
scientists compare results from different clinical trials and make the
best choice of treatment.
How is Hodgkin lymphoma treated?
Today, since most patients with Hodgkin lymphoma are cured, attention is shifting to minimizing the long-term consequences of treatment. This is because even though the likelihood of curing Hodgkin lymphoma is high, overall survival expectation is not normal. Patients cured of Hodgkin lymphoma continue to die at excess rates several decades after being cured because of late complications of treatment. Currently when doctors choose the initial treatment approach they pay equal attention to curing the disease and to keeping the risk of later serious complications to a minimum. A straightforward plan of initial evaluation and treatment for Hodgkin lymphoma can be developed on the basis of clinical stage, presence of B symptoms, and bulkiness of the largest tumor mass. Figure 5 shows an overall approach based on this simple categorization.Treatment of limited stage Hodgkin lymphoma: Minimizing toxicity, maximizing cure
Most
patients with limited stage disease can be cured and the challenge
today is to optimize treatment so this is accomplished with the least
toxicity, lowest cost, and greatest efficiency. Doctors consider several
crucial historical observations as they plan treatment to accomplish
these desirable goals.
The first demonstration that Hodgkin lymphoma could be reliably cured came with the application of external beam radiation treatments pioneered in the middle of the twentieth century. By directing a shaped beam of gamma radiation through the body, aimed at the diseased tissue and avoiding sensitive organs as much as possible – and by exposing patients to modest daily doses that could be summed up to a high level of exposure over several weeks – radiation oncologists found that they could treat not only the area of known lymph node disease, but also the nearby surrounding lymph nodes, markedly reducing relapse rates. Using this technique the majority of patients with limited stage lymphoma were regularly cured and radiation became the mainstay of treatment. Its effectiveness, however, was crucially dependent on accurate staging. Disease missed by the beam of radiation was unaffected and eventually grew back. High cure rates with radiation alone depended on meticulously accurate staging, even requiring abdominal exploratory surgery for some patients, to rule out any spread of the lymphoma to that area of the body.
By the late 1970s it had become clear that curing Hodgkin lymphoma with radiation came at a potentially high price. Organs in the path of the radiation were sometimes irreversibly damaged. For example, because of its common presentation in the neck and chest, Hodgkin lymphoma was frequently treated and cured with radiation to the neck, central chest, and beneath the shoulders (armpits), a so-called mantle radiation field. After such treatment, patients often developed failure of salivary glands resulting in dental disease; failure of the thyroid gland necessitating life-long medication to replace the missing thyroid hormone, and; injury to the heart and lungs leading to breathing problems and accelerated heart disease. With even longer follow-up, however, the most serious problem linked to radiation treatment became clear: induction of other cancers. Fortunately, such secondary cancers are uncommon, but it is clear today that patients cured of their Hodgkin lymphoma with radiation are at risk of developing breast, lung, thyroid, and other cancers as a complication of their originally life-saving treatment.
Even as it was becoming apparent that localized Hodgkin lymphoma could be cured by radiation, other researchers were demonstrating that lymphoma that had spread too widely to be safely treated with radiation could respond to chemotherapy. Combining several chemotherapy drugs that were independently able to cause temporary regression of Hodgkin lymphoma into multi-drug combinations led to the remarkable observation that a metastatic cancer could be cured in humans. Recognition of the benefits of chemotherapy was, however, tempered by observation of many undesirable side effects including hair loss, severe nausea and vomiting, injury to nerves impairing sensation, sterility in men, infertility and premature menopause in women and, most threatening, temporary but dramatic fall in blood cell counts such that resistance to common infections was reduced and serious infection could develop.
With the realization that multi-agent chemotherapy could cure Hodgkin lymphoma and that wide fields and high doses of radiation, while curative, can cause major late complications, it became logical to combine the two approaches, building on their individual strengths (radiation almost always cures Hodgkin lymphoma within the field of treatment; chemotherapy reaches throughout the body to eliminate the lymphoma wherever it may be hiding) while minimizing their toxicity (reducing the field of treatment and total dose of radiation lowers the risks of late organ damage and second cancers; shortening the overall course of chemotherapy minimizes its toxicity). Today, the most common approach to curing limited stage Hodgkin lymphoma follows those principles.
First, a short course of chemotherapy, perhaps two to four cycles, establishes control over both the known local tumors and the possible metastatic lymphoma hiding elsewhere in the body. Then radiation is delivered to the primary site where the lymphoma was discovered. Such an approach cures more than 90% of patients with limited stage Hodgkin lymphoma while minimizing late complications of treatment.
The first demonstration that Hodgkin lymphoma could be reliably cured came with the application of external beam radiation treatments pioneered in the middle of the twentieth century. By directing a shaped beam of gamma radiation through the body, aimed at the diseased tissue and avoiding sensitive organs as much as possible – and by exposing patients to modest daily doses that could be summed up to a high level of exposure over several weeks – radiation oncologists found that they could treat not only the area of known lymph node disease, but also the nearby surrounding lymph nodes, markedly reducing relapse rates. Using this technique the majority of patients with limited stage lymphoma were regularly cured and radiation became the mainstay of treatment. Its effectiveness, however, was crucially dependent on accurate staging. Disease missed by the beam of radiation was unaffected and eventually grew back. High cure rates with radiation alone depended on meticulously accurate staging, even requiring abdominal exploratory surgery for some patients, to rule out any spread of the lymphoma to that area of the body.
By the late 1970s it had become clear that curing Hodgkin lymphoma with radiation came at a potentially high price. Organs in the path of the radiation were sometimes irreversibly damaged. For example, because of its common presentation in the neck and chest, Hodgkin lymphoma was frequently treated and cured with radiation to the neck, central chest, and beneath the shoulders (armpits), a so-called mantle radiation field. After such treatment, patients often developed failure of salivary glands resulting in dental disease; failure of the thyroid gland necessitating life-long medication to replace the missing thyroid hormone, and; injury to the heart and lungs leading to breathing problems and accelerated heart disease. With even longer follow-up, however, the most serious problem linked to radiation treatment became clear: induction of other cancers. Fortunately, such secondary cancers are uncommon, but it is clear today that patients cured of their Hodgkin lymphoma with radiation are at risk of developing breast, lung, thyroid, and other cancers as a complication of their originally life-saving treatment.
Even as it was becoming apparent that localized Hodgkin lymphoma could be cured by radiation, other researchers were demonstrating that lymphoma that had spread too widely to be safely treated with radiation could respond to chemotherapy. Combining several chemotherapy drugs that were independently able to cause temporary regression of Hodgkin lymphoma into multi-drug combinations led to the remarkable observation that a metastatic cancer could be cured in humans. Recognition of the benefits of chemotherapy was, however, tempered by observation of many undesirable side effects including hair loss, severe nausea and vomiting, injury to nerves impairing sensation, sterility in men, infertility and premature menopause in women and, most threatening, temporary but dramatic fall in blood cell counts such that resistance to common infections was reduced and serious infection could develop.
With the realization that multi-agent chemotherapy could cure Hodgkin lymphoma and that wide fields and high doses of radiation, while curative, can cause major late complications, it became logical to combine the two approaches, building on their individual strengths (radiation almost always cures Hodgkin lymphoma within the field of treatment; chemotherapy reaches throughout the body to eliminate the lymphoma wherever it may be hiding) while minimizing their toxicity (reducing the field of treatment and total dose of radiation lowers the risks of late organ damage and second cancers; shortening the overall course of chemotherapy minimizes its toxicity). Today, the most common approach to curing limited stage Hodgkin lymphoma follows those principles.
First, a short course of chemotherapy, perhaps two to four cycles, establishes control over both the known local tumors and the possible metastatic lymphoma hiding elsewhere in the body. Then radiation is delivered to the primary site where the lymphoma was discovered. Such an approach cures more than 90% of patients with limited stage Hodgkin lymphoma while minimizing late complications of treatment.
Treatment of advanced stage Hodgkin lymphoma: Major challenges
Advanced
Hodgkin lymphoma was almost always fatal until the development of
combination chemotherapy. The first widely used multi-agent programs
cured up to 50% of patients, even those presenting with disease spread
into their liver or bone marrow.[10] In the 1970s and ‘80s more drugs
were discovered in fungi (doxorubicin {Adriamycin ®}), bacteria
(bleomycin), and chemical research (dacarbazine) that were effective
against several cancers, including Hodgkin lymphoma. New combinations,
usually referred to by their initials (for example ABVD for Adriamycin
®, bleomycin, vinblastine and dacarbazine) were tested and found to be
even more effective than earlier regimens. One of the chemotherapy
programs used most commonly around the world today, ABVD, was developed
by researchers in Milan in the early 1970s.[20] It is sufficiently
potent that it can sometimes cure the lymphoma, even when earlier four
drug regimens did not. Clinical trials showed that ABVD is more capable
than older regimens of curing Hodgkin lymphoma when it is used as the
first line of treatment. As a bonus it is much less likely to cause
infertility or premature menopause and, because it is less injurious to
the blood making cells in the bone marrow, it causes secondary leukemia
less frequently.
Such effectiveness does not come without a price, however. The doxorubicin (Adriamycin ®) in ABVD can cause injury to the muscle cells of the heart. This damage is directly related to the cumulative dose of the doxorubicin so it can be minimized by keeping the total dose below a certain limit. Bleomycin causes a unique type of scarring or fibrosis in the lungs that leads to a loss of the natural elasticity of lung tissue. The risk of such damage can also be minimized by carefully limiting the total dose. With attention to these dose limits the large majority of patients treated with ABVD escape major late toxicities.
The search for more effective, less toxic chemotherapy for Hodgkin lymphoma goes on. Newer combinations are regularly being tested incorporating new drugs or using older drugs on new schedules or at higher doses. This process of testing new treatment regimens against previously proven ones is known as clinical research and this orderly development of clinical trials, which fundamentally underpins progress in cancer treatment, has been widely emulated throughout medicine to identify new, more effective, less toxic therapies.
Such effectiveness does not come without a price, however. The doxorubicin (Adriamycin ®) in ABVD can cause injury to the muscle cells of the heart. This damage is directly related to the cumulative dose of the doxorubicin so it can be minimized by keeping the total dose below a certain limit. Bleomycin causes a unique type of scarring or fibrosis in the lungs that leads to a loss of the natural elasticity of lung tissue. The risk of such damage can also be minimized by carefully limiting the total dose. With attention to these dose limits the large majority of patients treated with ABVD escape major late toxicities.
The search for more effective, less toxic chemotherapy for Hodgkin lymphoma goes on. Newer combinations are regularly being tested incorporating new drugs or using older drugs on new schedules or at higher doses. This process of testing new treatment regimens against previously proven ones is known as clinical research and this orderly development of clinical trials, which fundamentally underpins progress in cancer treatment, has been widely emulated throughout medicine to identify new, more effective, less toxic therapies.
What if the primary treatment fails to cure the Hodgkin lymphoma?
Even
with all the improvements of the last 50 years the best combinations of
chemotherapy and radiation do not always cure Hodgkin lymphoma.
Fortunately, with Hodgkin lymphoma there is often a second chance, even
if the lymphoma comes back widely throughout the body. The technique
most frequently used when this happens is often called bone marrow
transplantation, even though the transplantation is only part of the
overall treatment and today the source of the transplanted cells is
usually the blood, not the bone marrow. A more accurate name is
autologous hematopoietic stem cell transplantation; “autologous” because
the cells are the patient’s own, “hematopoietic” because the
transplanted cells grow into new blood cells, and “stem cells” because
only a few million of these cells can grow into the many billions of
mature blood cells an adult needs.
The principle behind treatment with autologous stem cell transplantation is simple. First, a substantial number of stem cells are gathered from the blood using a special machine that can process blood drawn out of a vein, removing the desired stem cells and returning the rest of the blood to the patient. These stem cells are carefully stored. Then the patient is given a very high dose of several chemotherapy drugs, often more than ten times the standard dose, spread out over several days. The purpose of giving such high doses of chemotherapy is to eliminate any malignant cells that are resistant to standard doses chemotherapy. This also wipes out the normal blood cells; thus, to restore the immune system, the stem cells are given back to the patient through an intravenous into the blood. These stem cells find their way to the bone marrow, grow rapidly, and produce the mature circulating blood cells needed by a normal adult. This ability of the transplanted stem cells to replenish the blood cell precursors in the bone marrow that were wiped out by the high dose chemotherapy allows the patient to recover from what would otherwise be a lethal loss of blood cells. There are many variations on the basic technique, for example addition of whole body radiation to augment the chemotherapy or use of blood cell stimulating medications to speed up the regrowth of the stem cells, but the principle remains the same: exposure to an enormous dose of chemotherapy followed by restoration of normal blood cells by infusion of stored stem cells.
Before the development of high dose chemotherapy and autologous stem cell transplantation, Hodgkin lymphoma that came back after multi-drug chemotherapy could seldom be cured, especially if it recurred quickly. Although this technique is not always successful it can eliminate the lymphoma in many patients who are otherwise incurable. Around the world today thousands of patients are alive who could not have been cured before this technique was developed. Once again, however, just as with wide field radiation and multi-agent chemotherapy, this progress comes at a price. Late complications do occur, including frequent sterility and premature menopause as well as infrequent leukemia and bone marrow failure. Active research programs are seeking ways to diminish these risks. For the 20% to 30% of patients who are not cured by their initial treatment, high dose chemotherapy and autologous stem cell transplantation offers a genuine second chance and succeeds in curing at least 50% of those who undergo it.[21, 22]
The principle behind treatment with autologous stem cell transplantation is simple. First, a substantial number of stem cells are gathered from the blood using a special machine that can process blood drawn out of a vein, removing the desired stem cells and returning the rest of the blood to the patient. These stem cells are carefully stored. Then the patient is given a very high dose of several chemotherapy drugs, often more than ten times the standard dose, spread out over several days. The purpose of giving such high doses of chemotherapy is to eliminate any malignant cells that are resistant to standard doses chemotherapy. This also wipes out the normal blood cells; thus, to restore the immune system, the stem cells are given back to the patient through an intravenous into the blood. These stem cells find their way to the bone marrow, grow rapidly, and produce the mature circulating blood cells needed by a normal adult. This ability of the transplanted stem cells to replenish the blood cell precursors in the bone marrow that were wiped out by the high dose chemotherapy allows the patient to recover from what would otherwise be a lethal loss of blood cells. There are many variations on the basic technique, for example addition of whole body radiation to augment the chemotherapy or use of blood cell stimulating medications to speed up the regrowth of the stem cells, but the principle remains the same: exposure to an enormous dose of chemotherapy followed by restoration of normal blood cells by infusion of stored stem cells.
Before the development of high dose chemotherapy and autologous stem cell transplantation, Hodgkin lymphoma that came back after multi-drug chemotherapy could seldom be cured, especially if it recurred quickly. Although this technique is not always successful it can eliminate the lymphoma in many patients who are otherwise incurable. Around the world today thousands of patients are alive who could not have been cured before this technique was developed. Once again, however, just as with wide field radiation and multi-agent chemotherapy, this progress comes at a price. Late complications do occur, including frequent sterility and premature menopause as well as infrequent leukemia and bone marrow failure. Active research programs are seeking ways to diminish these risks. For the 20% to 30% of patients who are not cured by their initial treatment, high dose chemotherapy and autologous stem cell transplantation offers a genuine second chance and succeeds in curing at least 50% of those who undergo it.[21, 22]
What happens after the Hodgkin lymphoma is cured?
All
effective cancer treatments have at least some undesirable side
effects. Many of these, for example hair loss or low white blood cell
counts, are temporary and entirely reversible. Some toxicity, however,
may be permanent after chemotherapy or radiation and can prove
troublesome or life-threatening well after the primary neoplasm was
cured.
The effects of therapeutic irradiation on normal tissues are only partially reversible. In particular, certain organs such as the lungs, liver, testes, or ovaries have limited ability to recover from radiation exposure and cannot be included in treatment fields for Hodgkin lymphoma without anticipating loss of function. In addition, irradiation induces genetic damage that enhances the likelihood of later development of secondary cancers, the major cause of excess mortality in patients with Hodgkin lymphoma more than 10 to 15 years after successful treatment. Reducing the size of the radiation field and omission of radiation unless it is absolutely necessary helps to limit its long term side effects.
Most patients with Hodgkin lymphoma are cured and in most cases they are untroubled by late side effects. However, certain late effects of treatment for Hodgkin lymphoma should be remembered because relatively simple measures can be taken to minimize their effects. Table 4 lists the common late effects and responses to minimize their impact. Immunizations for pneumococcus, influenza (“flu” shot), diphtheria and tetanus should be updated regularly. Knowledge of the possible second cancers that can be caused by treatment for Hodgkin lymphoma can be used to guide screening and follow-up procedures. Patients should be strongly discouraged from smoking and encouraged to perform careful breast and skin examination on a regular basis. Annual pap smears should be performed in women and at age 40 years or ten years after completion of treatment for the Hodgkin lymphoma, whichever comes earlier; women who received radiation treatments for their Hodgkin lymphoma should begin annual screening mammography.
The effects of therapeutic irradiation on normal tissues are only partially reversible. In particular, certain organs such as the lungs, liver, testes, or ovaries have limited ability to recover from radiation exposure and cannot be included in treatment fields for Hodgkin lymphoma without anticipating loss of function. In addition, irradiation induces genetic damage that enhances the likelihood of later development of secondary cancers, the major cause of excess mortality in patients with Hodgkin lymphoma more than 10 to 15 years after successful treatment. Reducing the size of the radiation field and omission of radiation unless it is absolutely necessary helps to limit its long term side effects.
Most patients with Hodgkin lymphoma are cured and in most cases they are untroubled by late side effects. However, certain late effects of treatment for Hodgkin lymphoma should be remembered because relatively simple measures can be taken to minimize their effects. Table 4 lists the common late effects and responses to minimize their impact. Immunizations for pneumococcus, influenza (“flu” shot), diphtheria and tetanus should be updated regularly. Knowledge of the possible second cancers that can be caused by treatment for Hodgkin lymphoma can be used to guide screening and follow-up procedures. Patients should be strongly discouraged from smoking and encouraged to perform careful breast and skin examination on a regular basis. Annual pap smears should be performed in women and at age 40 years or ten years after completion of treatment for the Hodgkin lymphoma, whichever comes earlier; women who received radiation treatments for their Hodgkin lymphoma should begin annual screening mammography.
|
Table 4. Potential late complications of treatment of Hodgkin lymphoma and appropriate responses and preventive strategies
| |
|
Risk/Problem
|
Incidence/Response
|
|
Dental caries
|
Upper
neck irradiation may cause decreased salivation. Patients should have
careful dental care follow-up and should make their dentist aware of the
previous irradiation.
|
|
Hypothyroidism
|
After
irradiation that encompasses the thyroid with doses sufficient to cure
Hodgkin lymphoma, at least 50 % of patients will eventually become
hypothyroid. All patients should have an annual blood test to detect
hypothyroidism and if it is found they should be treated with life-long
thyroxine replacement.
|
|
Infertility
|
ABVD,
the most commonly used chemotherapy program for Hodgkin lymphoma, is
not known to cause any permanent infertility although very low sperm
counts persisting for one to two years after treatment are common.
Direct or scatter radiation from nearby tissue may cause infertility,
interruption of menstrual cycling or premature menopause but this seldom
occurs with the current fields of radiation currently used for the
treatment of Hodgkin lymphoma. Thus, with the current chemotherapy
regimens and radiation fields used, most patients will not
develop these problems. In general, after treatment, women who continue
menstruating are fertile, but men require semen analysis to provide a
specific answer. High dose chemo-radiotherapy and hematopoietic stem
cell transplantation usually cause permanent infertility in both genders
although some young women occasionally recover.
|
|
Impaired immunity to infections
|
Hodgkin
lymphoma and its treatment can lead to life-long impairment of full
immunity to infection. All patients should be given annual influenza
immunization and pneumococcal immunization once at diagnosis and a
repeat dose after five years. Patients whose spleen has been irradiated
or removed should also be immunized against meningococcal types A and C
and Hemophilus influenza type b. As for all adults diphtheria and tetanus immunizations should be kept up to date.
|
|
Secondary cancers
|
Although
uncommon, certain secondary neoplasms occur with increased frequency in
patients who have been treated for Hodgkin lymphoma. It is appropriate
to screen for these neoplasms for the rest of the patient's life because
they may have a lengthy induction period.
Cancer type Screening test
Thyroid cancer examination of the thyroid for nodules
Breast cancer annual screening mammography starting 10 years
after treatment for the Hodgkin lymphoma or
at age 40 years, whichever comes sooner
Melanoma regular inspection of skin for abnormal pigmented
lesions
Lung avoidance of smoking
Cervix Pap smear or HPV (human papilloma virus)
screening
|
Are there special conditions that can complicate Hodgkin lymphoma management?
Because
Hodgkin lymphoma tends to occur in young adults it is sometimes
discovered during pregnancy putting the welfare of two individuals at
stake, both the mother and the developing baby. Fortunately, it is
almost always possible to allow the pregnancy to proceed successfully to
full term and still provide ultimately curative treatment for the
mother.
If Hodgkin lymphoma is discovered during pregnancy a standard assessment can still be done except that imaging such as a chest x-ray or CT scanning, both of which require radiation, must be avoided. Abdominal ultrasonography, which uses only sound waves, can be very useful to identify enlargement of lymph nodes or the spleen.
Most pregnant patients with Hodgkin lymphoma do not require immediate treatment. Those with no or minimal symptoms can be watched through the pregnancy as long as it proceeds well. If symptoms develop often the best choice of treatment is mild chemotherapy with vinblastine, which does not appear to be harmful to the baby. Often just a few doses given several weeks apart are enough to allow the pregnancy to proceed to term and for the baby to be delivered normally. Patients who complete the pregnancy without treatment for the Hodgkin lymphoma can then have all of the standard staging tests and be treated appropriately. Patients who required vinblastine, however, can no longer be accurately staged and should be treated with multi-agent chemotherapy. The usual result is a cured mother and a happy baby.
Another condition that can complicate Hodgkin lymphoma is infection with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). The incidence of Hodgkin lymphoma in patients with HIV infection is as high as five- to ten-fold above expected rates.[23] Differently from patients without HIV infection, these patients often have early spread of the lymphoma to sites outside the lymph nodes; constitutional symptoms such as weight loss or heavy night sweating are common.
The treatment of coincident HIV infection and Hodgkin lymphoma is challenging. Patients have a reduced tolerance to chemotherapy and are prone to unusual infections. Fortunately, many patients can be cured of their Hodgkin lymphoma through coincident use of highly active anti-HIV therapy, appropriate use of antibiotics, and the use of growth factors to stimulate recovery of blood cell counts after chemotherapy. That said, the complexity of managing the coincident HIV infection substantially complicates overall treatment and, even after the lymphoma is gone, the HIV infection requires ongoing management.[24]
If Hodgkin lymphoma is discovered during pregnancy a standard assessment can still be done except that imaging such as a chest x-ray or CT scanning, both of which require radiation, must be avoided. Abdominal ultrasonography, which uses only sound waves, can be very useful to identify enlargement of lymph nodes or the spleen.
Most pregnant patients with Hodgkin lymphoma do not require immediate treatment. Those with no or minimal symptoms can be watched through the pregnancy as long as it proceeds well. If symptoms develop often the best choice of treatment is mild chemotherapy with vinblastine, which does not appear to be harmful to the baby. Often just a few doses given several weeks apart are enough to allow the pregnancy to proceed to term and for the baby to be delivered normally. Patients who complete the pregnancy without treatment for the Hodgkin lymphoma can then have all of the standard staging tests and be treated appropriately. Patients who required vinblastine, however, can no longer be accurately staged and should be treated with multi-agent chemotherapy. The usual result is a cured mother and a happy baby.
Another condition that can complicate Hodgkin lymphoma is infection with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). The incidence of Hodgkin lymphoma in patients with HIV infection is as high as five- to ten-fold above expected rates.[23] Differently from patients without HIV infection, these patients often have early spread of the lymphoma to sites outside the lymph nodes; constitutional symptoms such as weight loss or heavy night sweating are common.
The treatment of coincident HIV infection and Hodgkin lymphoma is challenging. Patients have a reduced tolerance to chemotherapy and are prone to unusual infections. Fortunately, many patients can be cured of their Hodgkin lymphoma through coincident use of highly active anti-HIV therapy, appropriate use of antibiotics, and the use of growth factors to stimulate recovery of blood cell counts after chemotherapy. That said, the complexity of managing the coincident HIV infection substantially complicates overall treatment and, even after the lymphoma is gone, the HIV infection requires ongoing management.[24]
What about the future?
The
history of Hodgkin lymphoma has been one of methodical progress. Fifty
years ago most patients succumbed to the disease. Today the large
majority is cured. Thirty years ago the treatments necessary to cure the
lymphoma caused more numerous and more severe side effects than the
programs used today. Twenty years ago most patients whose Hodgkin
lymphoma came back after chemotherapy eventually died, but today, with
the use of high dose chemotherapy and autologous stem cell
transplantation, the majority can be cured.
Despite this progress, however, much remains to be accomplished. Chemotherapy and radiation therapy are unpleasant at best and dangerous at worst. Late complications, although much less frequent, still affect some patients. Worse, a minority of patients still die from Hodgkin lymphoma despite the best and most intensive treatments. Because we do not know what causes the disease there is no way to prevent it. These problems can be solved. The same scientific approaches that have brought the progress made so far will continue to provide insights into the biology of Hodgkin lymphoma and lead to the discovery of better treatments. It is not unreasonable to hope that the next few decades will change Hodgkin lymphoma from a serious, sometimes fatal malignancy into a preventable illness or one that can be detected early and treated with brief, mild, highly effective medications with few side effects. Thomas Hodgkin would have been delighted to see the disease named after him finally eliminated.
Despite this progress, however, much remains to be accomplished. Chemotherapy and radiation therapy are unpleasant at best and dangerous at worst. Late complications, although much less frequent, still affect some patients. Worse, a minority of patients still die from Hodgkin lymphoma despite the best and most intensive treatments. Because we do not know what causes the disease there is no way to prevent it. These problems can be solved. The same scientific approaches that have brought the progress made so far will continue to provide insights into the biology of Hodgkin lymphoma and lead to the discovery of better treatments. It is not unreasonable to hope that the next few decades will change Hodgkin lymphoma from a serious, sometimes fatal malignancy into a preventable illness or one that can be detected early and treated with brief, mild, highly effective medications with few side effects. Thomas Hodgkin would have been delighted to see the disease named after him finally eliminated.
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