Big Blow To Radiation Therapy For Breast Cancer - Part II

History of a Controversy

The fact that breast irradiation increases the risk of heart disease is not a new finding. Starting in the late 1960s, it became known that, after receiving adjuvant radiation to prevent breast cancer recurrence, more women than expected were dying of heart disease, sometimes decades after their initial surgery.

It took brilliant medical detective work to prove that this apparently successful use of radiation therapy was also the cause of many cardiac deaths (Fajardo 2001). So many women were dying of the long-term adverse effects, in fact, that it more or less counterbalanced any survival benefit from the treatment itself.

There was great resistance to this discovery. Reports of heart damage from radiation began emerging as early as 1927, but even so, for the first 60 years of the 20th century, the heart was routinely described a “radioresistant” organ (i.e., resistant to the negative effects of radiation) and cardiac complications of radiation therapy were often described as rare and insignificant (Desjardins 1932 and Leach 1943).

It took systematic studies, over several decades, by Prof. Luis Fajardo of Stanford University to dispel this tenacious misperception (Cohn 1967 and Fajardo 1968). The sensitivity of the heart to radiation therapy was only really acknowledged in the early seventies (Bouyer-Dalloz 2003). Even then, a long time elapsed before the complete picture of radiation-induced heart disease finally became accepted in medical thinking (Hancock 1993).

Further evidence began to emerge in the 1970s. A Swedish team conducted a randomized, controlled clinical trial (RCT) involving 960 breast cancer patients over the period 1971 to 1976. These patients received either surgery alone or surgery preceded or followed by radiation. A total of 58 patients had heart attacks during the follow-up period, which averaged 20 years. Patients who received high doses of radiation had twice the risk of those who did not. There was also a 2.5-fold increased risk of ischemic heart disease (i.e., the kind caused by a decrease in the blood supply to the heart).

The difference between the two groups began to appear after 4 to 5 years and the heart attack incidence rates continued to increase in the irradiated group for 10 to 12 years. There was some evidence that most of the deaths were due to radiation-induced damage to the small blood vessels of the heart (Gyenes 1998).

In another study, the strength of the heart was measured 15 to 20 years after treatment for breast cancer. It was found that 25 percent of patients treated with radiation to the left breast had heart-related problems on standard stress tests, compared to none in the control group. The authors’ main conclusion was that left-sided chest irradiation (which more frequently affects the heart) may represent a risk factor for ischemic heart disease (Gyenes 1994).

Because of these studies, modifications were made in the 1980s to the way that radiation was delivered after surgery for breast cancer. Radiation oncologists have often claimed that with more precise equipment and techniques, heart damage was no longer a clinically relevant problem. This seemed plausible. However, the latest study shows that such complacency was ill-founded.

The range of cardiovascular problems that can follow intense irradiation of the heart is in fact very broad. It includes six major categories and various subcategories:

• Pericardial disease

Acute pericarditis during irradiation
Delayed acute pericarditis
Pericardial effusion (delayed)
Constrictive pericarditis

• Myocardial dysfunction

• Diffuse myocardial fibrosis (with or without pericardial disease)

• Coronary artery disease (CAD)

• Electrical conduction abnormalities

• Valvular heart disease

What complicates the issue is that radiation affects the heart and cardiovascular system unevenly: different parts of the system are affected in different ways, and individuals differ in their responses. For the sake of simplicity, I will not discuss the complicated mechanisms by which radiation damages the heart and circulatory system. What is most relevant is the experimental and clinical evidence of such damage.

Laboratory Data

There is a considerable body of laboratory data demonstrating the harmful effects of radiation on the heart. Most of these experiments have been carried out on the New Zealand white rabbit, because it has reactions to heart irradiation that are similar to those of humans.

In one such study, after a single 20 Gy dose of radiation, fully 94 percent of the rabbits developed some form of heart disease (Fajardo 1970). First there was an acute reaction, which disappeared within 48 hours. But starting at the 50th day, a delayed reaction set in, and this reached its full development by 90 days. By 150 days, half the experimental animals had died. What is particularly striking about these experiments is the degree to which radiation was shown to cause myocardial fibrosis (a thickening of the heart muscle).

Similarly, in the human clinical situation, the heart’s response to radiation is also divided into an acute and a long-term response. As in the test animals, the initial response vanishes rather quickly. But then, some months or even years later, the patient may experience heart pain (angina), difficulty breathing, or even a full-scale myocardial infarction (heart attack). The problem is that since they occur a considerable time after treatment, these radiation-induced effects are indistinguishable from ‘ordinary’ (i.e., randomly occurring) heart problems. There is nothing about such events that screams out “radiation-induced heart disease.” The cardiologist therefore may not make a connection to the patient’s prior exposure to radiation.

The latest findings should caution us against hubris in the medical field. It took tremendous investigative work by Prof. Fajardo and others to prove that radiation damages the heart. As a result of their work, some changes were indeed made - and radiation oncologists hailed these changes as proof that radiation treatment was now safe.

Although the accuracy of radiation delivery and targeting has improved considerably, other problems, such as the cumulative cardiotoxic effect of chemotherapy and radiation, remain largely unaddressed. This is especially relevant now that Adriamycin-based chemotherapy has become the standard of care for breast cancer.

Radiation is a classic two-edged sword. It does substantially reduce the risk of recurrences of breast cancer in the irradiated field. But this comes at the price of an increased risk of damage to the heart, especially when the internal mammary lymph node chains are irradiated, and among smokers. Patients and their physicians need to carefully weigh benefits and risks before agreeing to this or any other potentially toxic treatment.

–Ralph W. Moss, Ph.D.

References:

Breastcancer.org quote available at:
http://www.breastcancer.org/research_radiation_042805.html

Bouyer-Dalloz F, Maingon P, Benderitter M, et al. Effect of in vivo heart irradiation on coronary reactivity in the rat. Cell Mol Biol (Noisy-le-grand). 2003;49 Online Pub:OL435-442.

Cohn KE, et al. Heart disease following radiation. Medicine 1967;46:281-298.

Desjardins AU. Action of Röntgen rays and radium on the heart and lungs. Am J Röntgenol 1932;27:153,303,447.

Fajardo LR, et al. Morphology of radiation-induced heart disease. Arch Pathol 1968;86:512-519.

Fajardo LR and Stewart JR. Experimental radiation-induced heart disease. I. Light microscopic studies. Am J Pathol 1970;59:299-316.

Fajardo LR, et al. Radiation Pathology. Oxford: Oxford University Press, 2001.

Food and Drug Administration (FDA). Package Insert, Herceptin (Trastuzumab), Genetech, Sept. 2003. Available at:
http://www.fda.gov/cder/foi/label/2000/trasgen020900LB.htm

Giordano SH, Hortobagyi GN. Local recurrence or cardiovascular disease: pay now or later. J Natl Cancer Inst. 2007 Mar 7;99(5):340-341.

Gyenes G, et al. Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol 1998;48:185-190.

Gyenes G, et al. Morbidity of ischemic heart disease in early breast cancer 15-20 years after adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 1994;28:1235-1241.

Henschke C, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006 Oct 26;355(17):1763-71.

Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst. 2007;99:365-375.

Jensen BV. Cardiotoxic consequences of anthracycline-containing therapy in patients with breast cancer. Semin Oncol. 2006 Jun;33(3 Suppl 8):S15-21. Review.

Leach JEL. Effect of Röntgen therapy on the heart: Clinical study. Arch Intern Med 1943;72:715-745.

Lenhard RE, et al. Clinical Oncology. Atlanta: American Cancer Society, 2001.