, Leslie Ballas2 and Kristin Simar1
(1)
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
(2)
Valley Radiotherapy Associates, Los Angeles, CA, USA
Chapter Overview
Lymphoid malignancies are a family of diverse cancers arising in the cells of the immune system. Lymphoid leukemia, lymphoma, and myeloma belong to this category of cancers. This chapter will focus on lymphomas and the late effects of treatment. Lymphomas are broadly categorized into Hodgkin lymphomas, which are uncommon, and non-Hodgkin lymphomas, which are the sixth most common malignancy in men and women. Incidence of non-Hodgkin lymphoma appears to be rising, although the reasons for this are unclear. Treatment for lymphoma has improved substantially over the past 50 years, resulting in a large population of long-term lymphoma survivors. Patients with lymphoma are treated principally with chemotherapy, immunotherapy, radiation, or stem cell transplantation. Surgery generally does not have a role in the treatment of these disorders except in rare cases. Different treatment modalities have different late side effects. In this chapter, we will summarize the most commonly known potential late effects of chemotherapeutic agents and radiation, the few situations in which surgery is used and its long-term effects, and recommended practice for surveillance of recurrence and late effects.
Introduction
Incidence of lymphoma has increased dramatically over the past 60 years, as reported by US and international registries. Approximately 66,000 new cases of non-Hodgkin lymphoma were diagnosed in the United States in 2011. It is the sixth most common cancer in both men and women, with a slight predominance in men compared with women (1.5:1). In the United States, the incidence is higher in whites compared with other racial or ethnic groups. The two most common subtypes of non-Hodgkin lymphoma are follicular lymphoma and diffuse large B-cell lymphoma. Hodgkin lymphoma constitutes less than 5% of all lymphomas. The overall 5-year survival rate for all lymphomas is 70% (Howlader et al. 2012). However, survival rates differ for each lymphoma subtype, depending on stage of the lymphoma, age of the patient, and inherent biologic risk factors of the lymphoma itself. In general, Hodgkin lymphoma is highly curable in early stages, as is diffuse large B-cell lymphoma, whereas other lymphoma subtypes, such as peripheral T-cell lymphoma, have a poor prognosis. Patients with other lymphomas, such as follicular lymphoma, may survive for many years but require intermittent treatment for repeated recurrences.
Treatment for most lymphomas has improved substantially over the past century. Radiation therapy was recognized early in the twentieth century as a potentially curative treatment for Hodgkin lymphoma, particularly for early-stage, localized disease. After World War I, nitrogen mustard, a neurotoxic agent used during the war as a chemical weapon, was also observed to be an active anticancer agent. This observation signaled the birth of a new therapeutic field: cancer chemotherapy. Lymphoid malignancies were the first type of cancer to be effectively treated with chemicals. Hodgkin lymphoma was the first type of cancer to be cured with a treatment regimen that combined four chemotherapy drugs, known as the MOPP regimen (nitrogen mustard, vincristine, procarbazine, and prednisone). Today many drugs can effectively treat lymphoma, and frontline treatment with some drugs may be curative for several subtypes of primary or relapsed lymphoma. The MOPP regimen is no longer used today; it has been superseded by the less toxic and equally efficacious ABVD drug combination (doxorubicin, bleomycin, vinblastine, and dacarbazine).
Over the past decade, several effective new immunotherapy agents have been introduced into the array of treatment options for patients with lymphoma (see Table 12.1). The population of lymphoma survivors today includes both patients who have been treated up front and those who have been treated in repeated episodes for recurrences, using a wide variety of approaches: chemotherapy, immunotherapy, combinations of chemotherapy and immunotherapy, radiation, and combinations of all of these modalities (The University of Texas MD Anderson Cancer Center 2012). In addition, patients who have experienced a relapse of the disease likely have also received intensive salvage chemotherapy and immunotherapy, often including stem cell transplantation. As treatments for lymphoma continue to improve and survival rates remain high, it is important to understand the potential late effects of the various therapies. The risk of secondary effects and complications of treatment depend on the type of treatment(s), as well as the age and health of the patient. The survivorship care plan must therefore be tailored to each patient’s disease, treatment, and health history. We will review the late effects of the most commonly used chemotherapeutic and immunotherapeutic agents, as well as late effects of radiation. Survivorship concerns after stem cell transplantation are reviewed in a separate chapter.
Table 12.1
Chemotherapeutic agents commonly used to treat lymphoma
Regimen | Drugs included | Indication |
|---|---|---|
Monoclonal antibodies targeted to specific cell surface antigens (given as single agents) | Rituximab; ofatumumab | Indolent B-cell lymphoma, frontline or relapse |
Brentuximab | Hodgkin lymphoma and CD30+ lymphoma, approved for relapsed disease (also effective when added to frontline chemotherapy; studies ongoing) | |
RCOP | R = rituximab, C = cyclophosphamide, O = vincristine, P = prednisone | Indolent B-cell lymphoma, frontline or relapse |
BR, FR, FND, or FCR | B = bendamustine, R = rituximab, F = fludarabine, N = mitoxantrone, D = dexamethasone, C = cyclophosphamide | Indolent B-cell lymphoma, frontline or relapse |
RCHOP, REPOCH, or RHCVAD/RMA | In RCHOP and REPOCH: | Aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma, mantle cell lymphoma, or Burkitt lymphoma; peripheral T-cell lymphoma, with rituximab excluded; usually frontline |
R = rituximab, C = cyclophosphamide, H = doxorubicin, O = vincristine, P = prednisone, E = etoposide | ||
In RHCVAD/RMA: | ||
R = rituximab, H = “high-dose”, C = cyclophosphamide, V = vincristine, A = doxorubicin (RHCVAD) or cytarabine (RMA), D = dexamethasone, M = methotrexate | ||
ABVD | A = doxorubicin, B = bleomycin, V = vinblastine, D = dacarbazine | Hodgkin lymphoma, frontline (approval for addition of brentuximab pending) |
ICE, RICE | I = ifosfamide, C = carboplatin, E = etoposide, R = rituximab | ICE: relapsed Hodgkin lymphoma or T-cell lymphoma; RICE: relapsed aggressive B-cell lymphoma; usually precedes autologous stem cell transplantation |
DHAP (±R), ESHAP (±R) | D = dexamethasone, HA = high-dose cytarabine, P = platinum, E = etoposide, S = methylprednisolone, R = rituximab | −R: Relapsed Hodgkin lymphoma or T-cell lymphoma; +R: relapsed B-cell lymphoma; usually precedes autologous stem cell transplantation |
Surgery
Laparotomy with lymph node sampling and splenectomy used to be an important procedure for staging Hodgkin lymphoma in the era preceding computed tomographic (CT) scanning technology. CT body imaging techniques, which became common in the late 1970s and early 1980s, now allow excellent visualization of internal nodal sites, including the spleen, for staging purposes. Hence, surgical staging procedures have become obsolete for lymphoma. Splenectomy is still considered appropriate, however, as a therapeutic and diagnostic modality for patients who present with splenic lesions or enlargement of the spleen indicating selectively localized disease, with no evidence of nodal or marrow disease. This is a classic presentation of a particular subtype of lymphoma called primary splenic marginal zone lymphoma. Splenectomy may also be indicated for patients with autoimmune thrombocytopenia or anemia syndromes that are related to the lymphoma but do not respond to medical therapy. The principal concern for long-term survivors after splenectomy is the risk of life-threatening infections by encapsulated bacteria, such as meningococcus or pneumococcus. Vaccination is recommended prior to the splenectomy, with continual booster vaccines every other year for life, according to the Centers for Disease Control and Prevention (http://www.immunize.org/acip/).
Gastric surgery for resection of lymphoma is not generally indicated, unless the patient has a tumor-related ulcer that is actively bleeding, or if imminent perforation is a concern. Most gastric lymphomas will respond to medical management with chemotherapy or radiation, precluding resection. Preserving the gastrointestinal tract anatomy intact is the preferred option. In the event that a resection is required, long-term malabsorption of some nutrients may manifest as anemia. For example, patients with lesions in the terminal ileum and cecum may need to undergo resection of a portion of the distal bowel, which can lead to malabsorption of nutrients, such as vitamin B12, over the long term. Adhesions may also occur years later, presenting as bowel obstruction.
Late Effects of Chemotherapy
General Symptoms
Fatigue is the most common general complaint in lymphoma survivors, and it may persist for a long period of time after completion of treatment. The etiology of fatigue is complex, and many factors play into the equation. More information about fatigue is available in Chap. 22.
Patients also complain of a syndrome referred to as “chemobrain,” which is described in various ways by the patients but in general indicates awareness that cognitive processes are slower than usual and short-term memory is somewhat impaired. This syndrome and its management are discussed in greater detail in Chap. 20.
Heart Problems
Cardiac adverse effects are the most common complication of the anthracycline family of chemotherapeutic agents. Doxorubicin is the most common anthracycline drug used in chemotherapeutic regimens for lymphoma (see Table 12.1). The classic injury caused by anthracyclines is myocardial muscle weakness, leading to congestive heart failure. Anthracyclines have a lifetime maximum dose threshold; therefore, if patients require additional treatment with anthracyclines for relapsing disease or secondary malignancies, cardiac evaluation and close monitoring for signs of congestive heart failure is imperative.
Lung Problems
Pulmonary adverse effects are not as common as cardiac adverse effects. Lung problems secondary to chemotherapy are most commonly caused by the drug bleomycin. This drug is one of the agents in the ABVD combination, which is the standard regimen used to treat Hodgkin lymphoma. Pulmonary adverse effects are also possible with fludarabine, cytarabine, and high-dose chemotherapy regimens used prior to stem cell transplantation. Patients most at risk for pulmonary adverse effects are those who smoke, are elderly, or have had other lung injury events, such as exposure to asbestos or other inhaled toxic chemicals.
Kidney Problems
A number of chemotherapy drugs, especially cis-platinum and ifosfamide, can cause renal adverse effects. Kidney damage caused by chemotherapy drugs may manifest as creatinine elevation or electrolyte disturbances, including profound loss of magnesium, which can persist for many years after treatment is completed. Susceptible patients are the elderly, those with diabetes, and those with hypertension or other renal disorders. Contrast material used for CT scans can worsen renal injury in patients with persistently elevated creatinine levels. Patients should also be counseled to avoid nonsteroidal anti-inflammatory drugs if they have renal damage.
Liver Problems
Many chemotherapeutic agents (e.g., methotrexate, cytarabine) can cause transient elevation of liver enzymes. High-dose regimens are also more likely to cause liver enzyme elevations than are low-dose regimens. However, lasting hepatic problems are rare unless they are associated with an underlying chronic infectious illness (e.g., hepatitis B or C) or toxic liver trauma (e.g., alcohol). Patients with chronic elevation of liver enzymes should be counseled to avoid acetaminophen-containing medications and to be aware of risks associated with medications that are known to cause liver enzyme abnormalities, such as statins. Patients should also avoid common substances that are toxic to the liver, such as alcohol. The monoclonal antibody rituximab may cause reactivation of a dormant hepatitis B virus in patients with a prior infection.
Neuropathy
Vinca alkaloids (i.e., vincristine and vinblastine) and proteasome inhibitors, such as bortezomib, can cause chronic neuropathy. Patients particularly at risk are the elderly and those with diabetes or peripheral vascular disease. Neuropathy may manifest in various ways, usually with sensory symptoms such as burning sensations or needle-like pains or with proprioceptive changes (e.g., loss of sensation of the location or position of one’s feet on the floor). The most severe symptom of neuropathy, foot drop (loss of motor control of the ankle), is unusual.
Myelodysplasia
High-dose chemotherapy (as used prior to blood or marrow stem cell transplantation) or chronic doses of alkylators, such as cyclophosphamide, can cause myelodysplasia (pre-leukemia), with eventual transformation to leukemia. This complication may manifest as chronic unexplained anemia or slowly progressing pancytopenia, and it may occur years after treatment is completed.
Immunodeficiency
Antibodies directed at lymphoid cells (e.g., alemtuzumab, rituximab) and some other drugs, such as fludarabine, can cause lasting suppression of immunity that can lead to chronic infections. Another immune abnormality, graft-versus-host disease, is a potential chronic long-term effect of transplanted allogeneic stem cells. Late effects of allogeneic stem cell transplantation are discussed in Chap. 10.
Late Effects of Radiation Therapy
Late effects of radiation therapy are adverse effects that become apparent several years after the completion of treatment. Because many of these effects take years to manifest, most of the accumulated data are from patients treated with old technology and out-of-date radiation doses. Treatment-related adverse effects vary according to the area of the body treated. Here, we discuss effects related to radiation to the head and neck, pelvis, and mediastinum, as well as the increased risk of second malignancies that can accompany radiation therapy.
Xerostomia
The risk of long-term xerostomia associated with radiation has been well documented in patients with head and neck cancer. However, the risk of xerostomia associated with radiation therapy is unknown in patients with lymphoma, which is treated with lower doses than those used to treat head and neck cancers. In the subacute setting (6 months after radiation therapy is completed), patients have a reduced risk of mouth dryness and sticky saliva if the mean dose to each of the parotid glands was less than 31 Gy and the mean dose to the minor salivary glands was less than 11 Gy (Rodrigues et al. 2009). This reduced risk is presumed to persist in the long term.
Thyroid Disorders
The most common late effect after radiation to the lower neck is hypothyroidism. The risk of thyroid disease 20 years after radiation therapy has been reported to be 52% (Hancock et al. 1991). In a childhood cancer survivorship study, survivors who had been treated with radiation had a 17 times higher risk of hypothyroidism than did siblings who did not receive radiation (Sklar et al. 2000). Thyroid disorders have also been closely linked to the doses of radiation received. In the pediatric population, 17% of children who received less than 26 Gy developed a thyroid disorder, whereas 78% of children who received more than 26 Gy developed thyroid problems (Constine et al. 1984). The median time to develop hypothyroidism after radiation therapy is approximately 6 years (Bhatia et al. 1989). Less common thyroid disorders that may develop after radiation therapy include Graves disease, thyroiditis, thyrotoxicosis, thyroid nodules, and thyroid malignancies.
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