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Hodgkin's Lymphoma and Late Morbidity |
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Introduction
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It is estimated that over 75% of Hodgkin's lymphoma patients should expect a long-term survival. Originally, fifty years ago, radiation therapy was the primary treatment. At the ASCO June, 2007 meeting, Yoachim Yahalom proposed concepts to reduce the late morbidity and mortality risks of patients treated for Hodgkin's lymphoma. The complications primarily occur late, often up to thirty years later (many related to radiation therapy and alkylating-agent chemotherapy) to young patients who need to be followed for possible development of a second tumor and/or cardiac disease. Screening is an ongoing process for 20/30+ years for second tumor discovery (breast cancer, lung cancer) and premature heart and coronary artery disease. Treatments are necessary to cure Hodgkin's disease. The newer and more sophisticated radiation therapy techniques (3-dimensional CAT scans for radiation planning) and newer and safer chemotherapy regimes are the current safer approach. With the event of the linear accelerator, more exact and safer treatments were developed. With time, the chemotherapy programs have been shown not only to be effective but also have been changed to safer programs that are more efficacious. More recently, the price of success has shown late toxic and sometimes lethal side effects from treatment. Second malignancies and premature heart disease are the major consequences of therapy. The new goal is to minimize long-term morbidity and at the same time increase the disease-free survival and cure rate. To assess the prognostic factors includes both disease control and risk of late side effects. Most of the problems are from patients treated between twenty to forty years ago. Less radical radiation therapy in combination with newer chemotherapy programs have helped reduce potential toxicities. Studies are now in progress, and thus in upcoming years, better answers will be available. Also, for those who have failure in disease control, improved salvage programs have become available.
Improved Ways of Reducing Toxicity
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1. Safer radiotherapy programs have a more regulated dose and radiation field size, and also the fields of treatment better encompass the disease.
2. To reduce the risk of breast cancer, improved axillary and more localized breast protection radiation fields (reduced field size, using careful computerized tomography - Cat Scan-based planning) reduces the mediastinal volume, especially after chemotherapy. Reduced breast, heart and lung exposure are also a goal.
3. Programs using chemotherapy alone without radiation have been advocated and are under study.
4. Reduction of chemotherapy programs using newer drug innovations are being studied, especially alkylating agent-based combinations and anthracycline-based combination (ABVD). Second tumors, primarily lung cancer, could be dose-related. - The ABVD program (Adriamycin, Bleomycin, Vinblastine, and Procarbazine and the newer Stanford V program {Adriamycin, Vinblastine, Prednisone, Vincristine, Bleomycin, and Etoposide}) allows a shorter chemotherapy course of twelve weeks, which helps maintain fertility, and decreases the incidence of secondary leukemia. Bulky Hodgkin's sites were often treated with local radiation therapy.
- 5. CAT scan imaging has helped in staging and assessment for improved treatments.
6. Screening programs: A long-term follow up - greater than twenty to thirty years - is necessary. -
Careful breast cancer follow up for women is vital with physical examination, mammography, and MRI as indicated.
Patient education on self-examination and healthy lifestyles is helpful and recommended.
Smokers require careful evaluations for potential lung cancer, especially if they received alkylating agents. Do not smoke!
Early menopause secondary to chemotherapy along with radiation-induced breast cancer are problems. Using hormonal replacement therapy to reduce menopausal side effects or replacement therapy is discouraged in women at potential risk for breast cancer post-radiation therapy. There was an increase in synchronous or matachronous breast cancer, and some women have had prophylactic mastectomies.
The risk of coronary heart disease in those who've had mediastinal radiation merits attention to help reduce the risk of myocardial ischemia and heart damage. Cardiac stents and coronary bypass for symptomatic patients post-radiation therapy (mean dose 43 Gy) merit a stress electrocardiogram, radionuclide profusion imaging, and sometimes coronary angiography as indicated. Coronary stenosis was noted in 50-55% of patients, often requiring bypass surgery. An increase in ischemic heart disease has been noted, and a heart risk reduction program is merited, including tests such as C-reactive protein and homocysteine tests. Healthy lifestyles, smoking cessation, control of hypertension and hypercholesterolemia may help reduce the risk of coronary heart disease in Hodgkin's lymphoma patients.
A study of 1,474, five-year survivors in the Netherlands showed a three- to five-times increased incidence of coronary vascular disease versus the general population. It is believed that 80% of the problem was related to therapy. In a Stanford report, 2,498 patients showed a 16% risk of death from coronary CVD (coronary vascular disease). Thus, the consequences of radiation therapy, including the heart structures, and anthracycline chemotherapy can cause irreversible and fatal cardiac damage. Altering lifestyle may help reduce the risk of heart damage, as well as with early recognition and treatment, survival and quality of life can be improved. Myocardial biopsies showed damage to cardiac myocytes (cells) with cell hypertrophy and interstitial fibrosis noted in children treated with Adriamycin. Late cardiac failure can be a consequence. Fatal congestive heart failure is another potential problem. Electrocardiographic changes, left ventricular dysfunction, decreased exercise capability, and heart failure may develop. Cardiomyopathy (enlarged heart), left heart ventricular function, contractibility decreases, and increased coronary artery disease are other risks. Pericarditis (inflammation of the sac lining outside the heart) is less common with current radiation therapy techniques. About 20% of those who have pericarditis develop a chronic condition that may require an operation - pericardiectomy -, opening up the constricting fibrotic sac surrounding the heart.
Cardiac valve abnormalities have been noted with either restriction/stenosis or insufficiency of the heart valves. This can affect both the aortic and mitral valves (with narrowing stenosis), and in one report by Adams, 42% of patients had at least one significant valve abnormality. Symptoms of aortic stenosis and mitral valve regurgitation with cardiac dysfunction have been reported.
Secondary to radiation fibrosis, there can be abnormalities in the electrical conduction pathway, leading to life-threatening arrhythmias post therapy. These are not common.
Risk Factors
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1. Drugs - anthracyclines - cumulative dose relationship.
2. Age. Children under four and older adults are at higher risk (breast cancer, small-cell lung cancer, and congestive heart failure).
3. Sex. Girls are more vulnerable than boys.
4. Radiation therapy techniques (now improved).
5. Known coronary artery disease, hypertension, obesity, older age, family history of cardiac disease, abnormal lipoproteins (cholesterol), and lifestyle habits (smoking).
Screening for Cardiac Abnormalities - For valvular and ischemic heart disease, using echocardiograms, radionuclide angiography, cardiac MRI, PET scans, cardiac profusion, and other imaging techniques for assessment. Tests for every one to three years are justified. Premature arteriosclerotic valvular disease assessments are important.
Late Effects of Long-Term Survivors of Hodgkin's Disease
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Late effects can include fatal infections, especially for those who've undergone laparotomy and splenectomy - need for a complete vaccination program - with prompt antibiotic treatment for fevers in asplenic (post-splenectomy) patients. Subsequent abnormalities in pulmonary function, hypothyroidism, fatigue, infertility, and psychosocial distress are common. Most are not life-threatening but affect quality of life.
The occurrence of second malignancies has been described over the last thirty-five years, including acute leukemia secondary to alkylating agents (poor prognosis) and development of non-Hodgkin's lymphoma, with an inferior prognosis.
After a latency of over ten years, secondary solid tumors are noted. The most common are breast and lung cancers. Breast cancer second malignancies usually occur ten to fifteen plus years post initial treatment, and the risk has ranged in various studies from 12-42%. This was more prominent with older techniques of radiation therapy to the left chest and mediastinum, usually after a dose of 28 Gy or higher.
Lung cancer, with a relative risk of 3- to 7-times that of the general population following Hodgkin's disease therapy, has a poor prognosis with a median survival of usually less than a year. Radiation therapy is usually not an option, as it has already been done as part of the Hodgkins mantle therapy field. Smokers of greater than ten-pack years had a six-fold increased risk of lung cancer than those with a one-pack year history of smoking.
There's a wide variety of cardiac complications as described above, including non-coronary vascular disease (aortic and mitral valves), non-coronary arteriosclerotic disease, including strokes and transient ischemic attacks (TIAs), carotid artery stenosis, and subclavian artery stenosis, where low-neck radiation therapy was included in the field.
Pulmonary dysfunction and physiologic decline post therapy often relate to Bleomycin and chest irradiation. Bleomycin toxicity ranges between 18 and 40% and can be fatal and radiation pneumonitis has about a 3% risk. There is a risk alert on the use of oxygen post Bleomycin therapy.
Other problems include the risk of infections, especially in those who've had a splenectomy and have fever and the need for Haemophilus influenza B vaccine, zoster vaccine, pneumococcal polysaccharide vaccine, and meningococcal polysaccharide vaccine are important.
Hypothyroidism occurs in about 30% of patients after mantle irradiation. Most cases occur two to three years after treatment, and assessment of an elevated thyroid stimulating hormone (TSH) can usually make a diagnosis. Replacement therapy is successful.
Sterility. Changes in the chemotherapy program, using ABVD (Adriamycin, Bleomycin, Vinblastine, and Decarbazine {Procarbazine}) as replacement for nitrogen mustard (Mechlorethamine), Oncovin, and Prednisone and, also by use of the Stanford V, (Bleomycin, Etoposide, Doxorubicin (Adriamycin), cyclophosphamide, Vincristine, Procarbazine and Prednisone), has reduced the risk of sterility. Those receiving ovarian transposition diaphragmatic Hodgkin's disease radiation therapy sometimes have the ovaries removed laterally, (oophoroplexy), and men receiving 4-6 Gy of fractionated radiation therapy to the testes will result in permanent azoospermia in most men. 8-10 Gy of ovarian radiation therapy can result in ovarian failure; although, children may still maintain ovarian function. Sperm banking for men and oophoroexy for women wishing to preserve fertility can be helpful.
Fatigue is a major problem in survivors, and if anemia, hypothyroidism, cardiac and immune dysfunction, and muscular atrophy due to deconditioning are not problems, depression and psychological distress are found to be contributory. Psychosocial support, exercise, and good nutrition may help relieve symptoms.
Psychological distress for any form of cancer is common, as it's estimated that up to 30% of cancer patients have distress/depression. Psychological support and sometimes medication can be of help.
In summary, there are many types of complications, side effects and late recurrences of toxicities and second cancers noted in patients treated for Hodgkin's disease, and supportive care, knowledge about how to handle these problems and treatments, as well as improving lifestyle habits with diet, exercise and good preventive and diagnostic knowledge and techniques can help reduce some of the risks that can occur.
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References:
This information was gleaned from the educational book from the 2007 ASCO meeting in Chicago in June. Reviews of articles by: - Andrea K. Ng, MD, MPH, "Late Effects in Long-Term Survivors of Hodgkin's Disease," pg. 567-570.
Lewis S. Constine and Stephen Lipshultz, "How Cytotoxic Therapy for Hodgkin's Lymphoma Affects Heart Health," pg. 571-577.
Yoachim Yahalom, "Strategies for Reduction of Late Morbidity in Patients with Hodgkin's Lymphoma," pg. 578-583.
First appeared August 19, 2007; updated October 13, 2008