Journal of the National Cancer Institute Advance Access originally published online on June 17, 2009
JNCI Journal of the National Cancer Institute 2009 101(13):904-905; doi:10.1093/jnci/djp164
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Published by Oxford University Press 2009.
EDITORIALS |
Late Effects From Radiation Therapy: The Hits Just Keep on Coming
Affiliation of author: National Institute on Aging, Baltimore, MD
Correspondence to: Dan L. Longo, MD, National Institute on Aging, 251 Bayview Blvd, Ste 100, Rm 04C224, Baltimore, MD 21224-6825 (e-mail: longod{at}grc.nia.nih.gov).
There can be little doubt by now that if radiation therapy use in Hodgkin's disease were a drug regulated by the US Food and Drug Administration (FDA), it would have been taken off the market. Can you imagine the response to a drug company's argument? "Even though we don't have any long-term follow-up data, we are pretty sure that reducing the dose of the drug by one third is going to eliminate the late fatal and life-threatening side effects. We are giving the drug completely differently these days. Trust us on this." It seems highly unlikely that such an argument would influence the FDA's decision making, doesn't it?
However, precisely that argument seems to be influencing the persistent use of radiation therapy plus chemotherapy in Hodgkin's disease when equally effective treatment that omits radiation therapy altogether, namely chemotherapy alone, is available. The practice defies logical explanation. Like Samuel Johnson's comment on second marriages, it seems to reflect a triumph of hope over experience.
To add to the already overwhelming evidence that the use of radiation therapy in Hodgkin's disease is shortsighted, De Bruin et al. (1), reporting for Flora van Leeuwen's group at the Netherlands Cancer Institute, have quantified yet another late side effect from the use of radiation therapy. They examined the incidence of strokes and transient ischemic attacks (TIAs) among 2201 patients who had been treated with radiation therapy, combined modality therapy, or chemotherapy for Hodgkin's disease, and who had survived at least 5 years. The subjects had a median follow-up of 17 years, a long time by usual standards but still not long enough that one can be sure that all events that are likely to occur have occurred. Patients remain at risk. The median time to first stroke was 17.4 years and the median age at first stroke was 52 years. Forty-five percent of the cerebrovascular events occurred in patients younger than 50 years of age.
In the entire group, about 20% of the strokes were fatal, and 7% of the population is projected to die from stroke at 30 years of follow-up. That projection is actually a bit of an underestimate of the risk because only one person among the 187 who received chemotherapy alone had a stroke (three strokes would have been expected in an age-matched population not treated for Hodgkin's disease), that stroke was not fatal, and none had TIAs. Thus, 87 of the 88 documented ischemic events and all the fatal events were in Hodgkin's disease survivors who had received radiation therapy. Among those who received radiation to the neck and/or mediastinum, the risk of a cerebrovascular event was increased 2.5-fold compared with an age-matched control group that had received no radiation therapy.
A remarkable feature of the study is the detailed medical documentation and nearly complete follow-up of the patients. Most of the cerebrovascular events were embolic, and the emboli originated in the heart in one in four cases. This result implies that coronary artery disease was an important predisposing factor in addition to carotid artery disease. Hull et al. (2) have also noted that radiation therapy can damage the aortic valve, which can then become a nidus for clotting.
The study has a weakness. The relationship of stroke to radiation doses and fractions was not examined. Thus, it was not possible to evaluate the assumption that lower doses produce less risk.
However, other data suggest that dose of radiation may influence time to first stroke. Bowers et al. (3) found that children with Hodgkin's disease whose treatment included radiation therapy had a relative risk of 4.3 for developing a stroke compared with a sibling control group, and the median time after treatment for strokes to occur was 17.5 years. These results are similar to those of De Bruin et al. in adults. By contrast, when the Netherlands Cancer Institute group measured stroke risk among head and neck cancer patients who generally received 60–70 Gy of radiation, rather than the 36–40 Gy used in patients with Hodgkin's disease, the relative risk was about 5.6 but the time to first stroke was only 10.9 years (4). It was proposed that the time to develop a cerebrovascular complication is affected both by dose of radiation and by age at the time of exposure (1). Patients with preexisting atherosclerotic vessels may develop embolic complications in a shorter time.
The results of the study by De Bruin et al. (1) emphasize that physicians following patients who received mantle-field radiation therapy that included the cervical region should aggressively manage modifiable risk factors for atherosclerosis including hypercholesterolemia, hypertension, and smoking. Agents that influence vascular stiffness are in development (5); therefore, stroke prevention in patients who have received cervical radiation therapy may be a useful measure for the role of vascular stiffness in subsequent embolic events.
These results also should make an impact on the physician's choice of primary treatment. What does the balance sheet look like? If you are treated with radiation therapy, you are accepting a risk of 1% per year of developing a second malignancy and that risk does not appear to decrease even 30 years after treatment (6). If you are a woman younger than 30 years old who is being treated with mantle-field radiation therapy, your risk of developing breast cancer within 25 years is more than one in three, comparable in fact with the risk associated with some genetic forms of the disease (7). You are also accepting a threefold increased risk of a fatal myocardial infarction as well as a risk for myocardial infarctions that are not immediately fatal (8). And now, it appears you are accepting a 2.5- to 3-fold increased risk of an ischemic cerebrovascular event, one in five of which will kill you (1). Those are the fatal risks. In addition, there are other nuisance risks like dental carries, dry mouth, dysgeusia, transverse myelitis, hypothyroidism, and others that are not necessarily fatal but require some compensatory action on the part of the patient that affects quality of life variably (9).
Now, what about the advantages? For head and neck cancer, the advantages to using radiation therapy as a component of treatment are well defined and clear. For breast-conserving approaches to breast cancer treatment, the advantages are well defined and clear. For Hodgkin's disease, the advantage of using radiation therapy is not clear at all. Indeed, it could be and has been argued that there are none (10).
With a risk to benefit ratio for the use of radiation therapy that is approaching infinity, it remains a puzzle that the vast majority of patients with Hodgkin's disease are treated with combined modality therapy today. Noncurative courses of chemotherapy are combined with noncurative courses of radiation therapy in most cases. Why? Certainly lower doses and shorter courses of chemotherapy produce less acute toxicity and that is good. No convincing data have defined more than anecdotal late fatal toxicities associated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy, so fewer cycles are unlikely to make any substantial impact there. It is hoped that lower doses of radiation therapy will reduce the risk of late fatal toxicities from radiation therapy, but long-term follow-up data documenting that hope do not yet exist. One should keep in mind the fundamental radiobiology research showing that the risk of inducing cancer has a bell-shaped relationship to dose in the laboratory (11). If we do not know where we are on that bell-shaped curve, it is not completely clear that moving to a lower dose will actually lower the risk. So it seems that the political pressure to keep using radiation therapy has allowed hope to triumph over experience in our exercise of clinical judgment.
Maybe lowering the dose of radiation therapy will actually reduce the incidence of late effects. We can certainly hope it is true, but until it is proven to be true, it cannot be assumed to be true. No therapy is effective until it has been proven effective, and no therapy is safe until it has been proven to be safe. Unfortunately, given the lifelong increased risks of late effects that have been documented from the use of radiation therapy, we simply cannot keep exposing patients to risk without clear benefit while we wait for safety data to be produced. With an alternative therapy at hand that is just as effective and has been proven to be safe with 25-year follow-up data (12), it is simply unjustified to keep using a toxic modality for the next 10–20 years while safety data are collected and analyzed.
NOTES
The author reports no conflicts of interest.
REFERENCES
1. De Bruin ML, Dorresteijn LDA, van't Veer MB, et al. Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst (2009) 100(13):928–937.
2. Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA (2003) 290(21):2831–2837.
3. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin's disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol (2005) 23(27):6508–6515.
4. Dorresteijn LD, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol (2002) 20(1):282–288.
5. Vaitkevicius PV, Lane M, Spurgeon H, et al. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci U S A (2001) 98(3):1171–1175.
6. van Leeuwen FE, Klokman WJ, van't Veer MB, et al. Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol (2000) 18(3):487–497.
7. Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst (2005) 97(19):1428–1437.
8. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA (1993) 270(16):1949–1955.
9. Bookman MA, Longo DL. Concomitant illness in patients treated for Hodgkin's disease. Cancer Treat Rev (1986) 13(2):77–111.[CrossRef][Web of Science][Medline]
10. Seam P, Janik JE, Longo DL, De Vita VT Jr. Role of chemotherapy in Hodgkin's lymphoma. Cancer J (2009) 15(2):150–154.[Web of Science][Medline]
11. Upton AC. The dose-response relation in radiation-induced cancer. Cancer Res (1961) 21(July):717–729.
12. Longo DL, Glatstein E, Duffey PL, et al. A prospective trial of radiation alone vs combination chemotherapy alone for early-stage Hodgkin's disease. Implications of 25-year follow-up to current combined modality therapy. Blood (2006) 108(11):33a. Abstract 98.
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