Long-term cardiorespiratory effects occur in survivors of all types of cancer. Because a large number of patients with breast cancer, testicular cancer, Hodgkin disease, and non-Hodgkin lymphoma survive the disease, these types of cancer tend to be associated with most cases of long-term cardiorespiratory toxicity. The prevalence of long-term toxicity to the adult cardiac and pulmonary systems is not known, because studies in adult patients with cancer have not looked specifically at this issue. However, studies have looked at the pediatric population. Children who received anthracycline chemotherapy have developed cardiac abnormalities from four to as many as 20 years after treatment. 1, 2
Patients who received anthracycline-based chemotherapy regimens, with or without mediastinal radiation, have developed clinical and subclinical abnormalities of ventricular function years after treatment. 3–8 Pneumonitis, pulmonary fibrosis, and hypersensitivity toxicities have occurred after radiation treatment and after chemotherapy. 9–17 Vascular complications, such as myocardial infarction, Raynaud disease, and coronary artery disease, have also occurred after cancer treatment. 18–20
Many studies showing cardiopulmonary toxicities were performed more than 10 years ago and had small sample sizes. 3, 13 Although the research suggests the risk of major cardiopulmonary effects after chemotherapy and radiation, the benefits of treatment outweigh the possible longterm sequelae. 1, 2, 13, 19, 21 To detect these sequelae, survivors at risk for long-term cardiac and pulmonary damage (see Table 1, page 56) require lifelong monitoring.
Effects on the heart and lungs can occur weeks, months, or years after the last chemotherapy or radiation treatment.
Cardiac effects range from non-significant changes in the left ventricular ejection fraction and electrocardiogram (ECG) to irreversible congestive heart failure. 1–6 Cardiac toxicity is most commonly associated with the use of anthracyclines, such as doxorubicin (Adriamycin), daunorubicin (Cerubidine), or epirubicin (Ellence). Anthracyclines directly damage the cardiac myocyte cells, resulting in loss of myocardial fibrils, mitochondrial changes, and cellular destruction within the cardiac tissue. 22 Changes ranging from subclinical abnormalities to congestive cardiomyopathy have been related to total cumulative doses of anthracyclines. 22 Other drugs that can damage cardiac myocytes include high-dose cyclophosphamide (Cytoxan), 5-fluorouracil (Adrucil), paclitaxel (Taxol), ifosfamide (Ifex), and trastuzumab (Herceptin). 23
Cardiac toxicities frequently occur in patients treated with radiation therapy for non-Hodgkin lymphoma, Hodgkin disease, and left-sided breast cancer, where large portals include the heart. 3, 5, 19 Complex derangement of cardiac tissue from radiation can continue to evolve for months and even years after treatment. 10 The most common toxicity is radiation-associated pericarditis. 24 Vascular injury can also result from radiation, with thickening of the arterial wall leading to long-term development of coronary artery disease. 5
The initial site of pulmonary damage from chemotherapy seems to be the endothelial cells. An inflammatory-type reaction results in drug-induced pneumonitis. 14 An immunologic mechanism such as an allergic reaction also can damage the pulmonary system. 25 Chemotherapy can cause an extensive alteration of the pulmonary parenchyma, with changes in the connective tissue, obliteration of alveoli, and dilation of air spaces. 15, 17 Pulmonary toxicity is associated with high doses (greater than 450 mg/m 2) of bleomycin (Blenoxane). 26 Other drugs that can exert a direct toxic effect on the pneumocytes include cytarabine (Cytosar-U), high-dose cyclophosphamide, carmustine (BiCNU), mitomycin-C (Mutamycin), busulfan (Busulfex), methotrexate (Rheumatrex), procarbazine (Matulane), docetaxel (Taxotere), and gem-citabine (Gemzar). 25
Chest irradiation can produce pulmonary toxicities such as pneumonitis and fibrosis. The effects depend on the volume of lung irradiated, the total radiation dose, and the daily fractionated dose. 15 Radiation destroys the cells lining the alveoli, and the alveoli become inflamed with accumulated exudative fluid. This process inhibits the diffusion of oxygen and carbon dioxide within the alveoli. 26
Multimodal therapy with a combination of chemotherapy and thoracic radiation increases the risk of cardiopulmonary toxicities. 1, 5, 9, 15 Each cancer treatment targets different types of normal cells and, in combination, multiple treatments can result in substantial cardiopulmonary damage. Radiation recall (redness, blistering, and breakdown of skin in the radiation field) is a concern when thoracic radiation is given before or with an anthracycline. 3, 4, 9
Aggressive multimodal regimens have resulted in much progress in cancer treatment. However, long-term toxicities should be anticipated with the use of such regimens.
In the past decade, numerous attempts have been made to develop strategies to prevent or minimize cardiorespiratory effects of cancer treatment. The frequency and severity of radiation-induced cardiopulmonary effects have decreased with refinement of radiation techniques. 5, 24, 27 One such technique is to shield as much of the healthy heart and lung tissue as possible. Techniques that have decreased the incidence of cardiotoxicity from anthracyclines include the use of cardioprotectants such as dexrazoxane (Zinecard), development of liposomal anthracyclines, reduced cumulative dosages of anthracycline, and development of anthracycline analogs that are incorporated into chemotherapy regimens. 24 Various techniques to administer ablative therapy with stem cell transplantation also have been used to decrease the occurrence of cardiorespiratory toxicities. Studies on the effectiveness of this strategy have not yet been completed.
The lifelong cardiopulmonary toxic effects of anthracycline therapy and thoracic irradiation require continual monitoring for cardiac and pulmonary dysfunction. However, no guidelines have been developed on the optimal interval of cardiac and pulmonary testing after treatment for cancer. Nor are the best tests to detect cardiopulmonary effects in cancer survivors known.
Methods to evaluate cardiac function include noninvasive monitoring with ECG, echocardiography, and radionuclide cardiography. An ejection fraction less than 45% or a decrease of 5% or more from the resting value is considered abnormal. 1, 2
Follow-up evaluation with an echocardiogram or radionuclide angiography three months after completion of therapy allows detection of late-developing toxicity. 1, 2 Long-term follow-up recommendations include a minimum of one echocardiogram each year and a cardiac scan every five years if the survivor remains asymptomatic. 3, 4, 16, 18 Some studies have recommended following survivors with an echocardiogram every three years—except for those at high risk, who should have a yearly echocardiogram. 4 These recommendations are based on studies that mostly followed patients only two years after treatment completion. Only pediatric studies have followed survivors longer. 1, 2
Methods to evaluate pulmonary function include chest X-ray, computed tomography (CT) scan of the chest, and pulmonary function tests. A pattern of diffuse interstitial markings on a chest X-ray indicates pulmonary toxicity, but a CT scan may be more precise in detecting damage. Pulmonary function tests measure the carbon monoxide diffusion capacity, which is sensitive in detecting abnormalities and restrictive patterns. 16 As with cardiac tests, the optimal interval for tests of pulmonary function for cancer survivors has not been determined.
The absence of guidelines for follow-up surveillance for cardiopulmonary toxicities raises important questions. How will survivors be monitored? Who will order appropriate cardiac and pulmonary tests? Will the survivor have to assume some responsibility, such as reporting symptoms and requesting surveillance tests?
Cardiac and pulmonary injury may limit daily activities. Few survivors are prepared for this debilitating effect. Patients must be taught the importance of close cardiac and pulmonary follow-up, once treatment for cancer is completed, to monitor for late toxicities. Nurses need to teach patients about signs of potential long-term cardiorespiratory effects from cancer treatment (see Table 2, page 58). Survivors should be encouraged to seek medical advice when symptoms occur and to request noninvasive tests (for example, chest X-ray, echocardiogram) to evaluate these symptoms.
Long-term survivors are usually followed in the community setting by internists or family practitioners rather than by oncologists. Health care providers may not be aware of cardiopulmonary toxicities of cancer treatment and may mistake the symptoms for another disease. Therefore, education of health care providers, including primary care physicians and nurses, also is important.
Comprehensive care of the cancer survivor must include health promotion and disease prevention strategies for cardiopulmonary toxicities. Nurses always should encourage smoking cessation. (See “Tobacco Cessation at Greenwich Hospital” in the December 2004 AJN.)
Treatment of cardiopulmonary toxicities is mainly supportive. Who will provide this supportive care, that is, oxygen and medications? Who will provide monitoring? In certain circumstances, organ transplant can be performed. Who will determine the cancer survivor’s eligibility for an organ transplant?
GAPS IN SCIENCE
Cancer therapies and their administration have changed and modifications continue. The current and future incidences of cardiorespiratory toxicities may differ from incidence rates over the past three decades because of changes in chemotherapy regimens and radiation techniques. Previous long-term follow-up studies may have limited relevance to patients currently undergoing treatment.
Among the many questions remaining about cardiorespiratory toxicities in cancer survivors are the following:
- Will dose intensity and dose-dense chemotherapy regimens affect the prevalence of cardiopulmonary toxicities?
- Will the overall occurrence of long-term cardiopulmonary toxicities in cancer survivors change with the addition of preventive strategies?
- How often should survivors have follow-up examinations for cardiac and pulmonary toxicity?
- What tests should be done in survivors at risk for cardiopulmonary toxicity?
- Do preexisting cardiopulmonary comorbidities affect the occurrence of cardiopulmonary toxicities in cancer survivors?
- Can findings from pediatric long-term follow-up studies be extrapolated to adult cancer survivors?
What to Ask Survivors at Risk for Long-Term Cardiorespiratory Effects
- Have you had any shortness of breath, pain or heaviness in your chest, or the feeling that your heart is racing?
- Have you had any other symptoms that could be signs of cardiorespiratory problems, such as swelling, tiredness, or low fever?
- When did you last have a chest X-ray, electrocardiogram, or echocardiogram?
1. Steinherz LJ, et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA
2. Steinherz LJ, et al. Cardiac failure and dysrhythmias 6–19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol
3. Haddy TB, et al. Late effects in long-term survivors of high-grade non-Hodgkin’s lymphomas. J Clin Oncol
4. de Graaf H, et al. Cardiotoxicity from intensive chemotherapy combined with radiotherapy in breast cancer. Br J Cancer
5. Kreuser ED, et al. Evaluation of late cardiotoxicity with pulsed Doppler echocardiography in patients treated for Hodgkin’s disease. Br J Haematol
6. Mattioli R, et al. Long-survival in responding patients with metastatic breast cancer treated with doxorubicin-docetaxel combination. A multicentre phase II trial. Anticancer Res
7. Ryberg M, et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol
8. Sorensen K, et al. Cardiac function in Wilms’ tumor survivors. J Clin Oncol
9. Aisner J, et al. Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study. J Clin Oncol
10. Anscher MS, et al. Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy. Int J Radiat Oncol Biol Phys
11. van Besien K, et al. Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. Bone Marrow Transplant
12. Blayney DW, et al. High-risk germ cell tumors in men. High response rate and severe toxicity with cisplatin, vinblastine, bleomycin, and etoposide. Cancer
13. Kojima A, et al. Analysis of three-year survivors among patients with advanced inoperable non-small cell lung cancer. Jpn J Clin Oncol
14. Read WL, et al. Severe interstitial pneumonitis associated with docetaxel administration. Cancer
15. Villani F, et al. Late pulmonary toxicity after treatment for Hodgkin’s disease. Anticancer Res
16. Wilczynski SW, et al. Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med
17. Chap L, et al. Pulmonary toxicity of high-dose chemotherapy for breast cancer: a non-invasive approach to diagnosis and treatment. Bone Marrow Transplant
18. Berger CC, et al. Secondary Raynaud’s phenomenon and other late vascular complications following chemotherapy for testicular cancer. Eur J Cancer
19. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet
20. Paszat LF, et al. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol
21. Zambetti M, et al. Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol
22. Fischer DS, et al. The cancer chemotherapy handbook
. 6th ed. Philadelphia: Mosby; 2003.
23. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf
24. Theodoulou M, Seidman AD. Cardiac effects of adjuvant therapy for early breast cancer. Semin Oncol
25. Sleijfer S. Bleomycin-induced pneumonitis. Chest
26. Abid SH, et al. Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol
27. Stewart JR, et al. Radiation injury to the heart. Int J Radiat Oncol Biol Phys