War on Cancerby Ralph W. Moss, PhDwww.cancerdecisions.com

Big Blow to Radiation Therapyfor Breast Cancer

Radiation is widely used as an adjuvant treatment aftersurgery for breast cancer. It is primarily administered toprevent recurrences and is quite effective at doing so.But a study published in the March 7, 2007 Journal of theNational Cancer Institute (JNCI) has shown that radiationalso increases the risk of heart disease in women whoreceive it following surgery for breast cancer. Usingmodern radiation delivery techniques shifts the patternof harm, but does not remove it.

It has long been acknowledged that the type ofradiation used in the 1960s and 1970s elevated women'srisk of subsequent cardiovascular disease. However,techniques have changed since then, and radiationoncologists have often stated that newer radiationdelivery procedures have been deliberately designedto minimize this sort of heart damage. The dangers ofradiation to the heart have therefore frequently beendismissed as a thing of the past, and countless womenhave been told that the procedures performed on themwere safe.

For example, in Clinical Oncology, a textbookpublished in 2001 by the American Cancer Society, theproblem is downplayed. In the course of two paragraphs,its seriousness is minimized half-a-dozen times:

Cardiac toxicity due to irradiation is rare... Effects on theendocardium are rare...Below a total dose of 4500 cGy,radiation-induced damage is uncommon...Tamponade[a life-threatening compression of the heart resultingfrom a collection of fluid in the pericardium (the sacsurrounding the heart), ed.] occurs infrequently.In general, pericarditis is self-limited... Chronicpericarditis is uncommon. Acute myocardial infarction[is] rare... (Lenhard 2001: 243-244).

Many websites similarly claim that modern radiationtherapy is entirely safe. Here is an example of such astatement from breastcancer.org;

Radiation therapy techniques have changeddramatically since then (the 1970s, ed.]. Newtechnology ailows doctors to use the lowest dose ofradiation possible. They can also more precisely targetthe radiation to the breast and away from the heart - sothe heart receives a minimal amount or none at alt.

This is what the orthodox medical profession believed- and wanted us to believe. However, the facts now speakotherwise. The JNCI study is unquestionably a majorblow to the orthodox medical profession's insistentclaims that radiation has evolved into a safe modality forthe post-operative treatment of breast cancer.

In the JNCI study, researchers at the NetherlandsCancer Institute in Amsterdam evaluated 4,414 breastcancer patients who survived for at least ten years afterreceiving radiotherapy between the years 1970 and 1986.The patients were followed for a median of 18 years.These patients' rates of cardiovascular disease werethen compared with those seen in the general population(Hooning 2007). In other words, this was a very large andprolonged study.

There were a total of 942 "cardiovascular events"during the follow-up period. The good news was thatradiation therapy limited to the breast itself did notincrease the risk of cardiovascular disease. However,when either the left or right internal mammary chainof lymph nodes was included in the radiation field,as is common in post-operative radiotherapy, it didsignificantly increase that risk.

Internal mammary chain irradiation performedduring the 1970s increased the risk of a heart attack(myocardial infarction) by 2.55 times compared to noradiation. It also raised the risk of congestive heartfaiiure 1.72-fold. Radiotherapy given in the 1980s wasalso associated with an increased risk of heart disease:a 2.66-foId greater risk of heart failure and a 3.17-foldgreater risk of dysfunctional heart valves. (This was one

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of the first studies to investigate radiation-related heartvalve failure.)

In the 1980s, it became common to add adjuvantchemotherapy to radiotherapy. The standardchemotherapy regimen used during the 1980s wasCMF (which stands for the three drug combination ofcyclophosphamide. methotrexate, and 5-fluorouraciI).However, this study found that the addition of CMFchemotherapy to radiation conferred a 1.85-fold increasedrisk of congestive heart failure. This finding has caused agreat deal of surprise since this combination was neverthought to be particularly cardiotoxic.

It is chilling to realize that nowadays CMFchemotherapy has been replaced by regimens basedaround so-called anthracycline drugs, the mostprominent of which is Adriamycin (doxorubicin). Thisclass of drugs is already well-icnown to carry serious risksof cardiotoxicity, including life-threatening congestiveheart failure. This risk increases exponentially thegreater the lifetime dose.

A recent review in Seminars of Oncology concludedthat "10 percent to 26 percent of patients administeredcumulative anthracycline doses above thoserecommended... develop congestive heart failure, andthat more than 50 percent of patients administered thesedoses will experience measurable functional impairmentmonths to years after the end of therapy." Also, thesusceptibility of patients to anthracycline-inducedcardiotoxicity varies widely, with a dramatic increasewith advancing age (Jensen 2006).

The risk is further augmented by the addition ofHerceptin (trastuzumab), another cardiotoxic drugthat is increasingly used in the treatment of breastcancer. Herceptin can cause heart damage ranging frommild and transient to life-threatening congestive heartfailure. To quote the package insert warning, mandatedby the Food and Drug Administration, Herceptin "hasbeen associated with disabling cardiac failure, death,and mural thrombosis leading to stroke" (FDA 2003).(Mural thrombosis is the formation of a fibrinous cloton the endocardial lining of the heart or on the wail of alarge blood vessel). In view of these ominous warnings,studies focusing on the cumulative cardiac risk ofradiation therapy in patients who have also been givenAdriamycin and/or Herceptin-containing chemotherapyregimens are urgently needed.

The JNCI study also found a disturbing threefoldincrease in the risk of heart attacks among radiotherapy-treated patients who also smoked tobacco. The authorsproperly caution that "irradiated breast cancer patientsshould be advised to refrain from smoking to reduce theirrisk for cardiovascular disease." Easier said than done!The more logical solution would surely be to refrainfrom giving adjuvant radiation to patients who insist onsmoking.

Medical Detective WorkThe fact that breast irradiation increases the risk of

heart disease is not a new finding. Starting in the late1960s, it became known that, after receiving adjuvantradiation to prevent breast cancer recurrence, morewomen than expected were dying of heart disease,sometimes decades after their initial surgery. It tookbrilliant medical detective work to prove that thisapparently successful use of radiation therapy was alsothe cause of many cardiac deaths (Fajardo 2001). Somany women were dying of the long-term adverse effects,in fact, that it more or less counterbalanced any survivalbenefit from the treatment itself.

There was great resistance to this discovery. Reportsof heart damage from radiation began emerging asearly as 1927, but even so, for the first 60 years of thetwentieth century, the heart was routinely describeda "radioreslstant" organ (i.e., resistant to the negativeeffects of radiation), and cardiac complications ofradiation therapy were often described as rare andinsignificant (Desjardins 1932 and Leach 1943).

It took systematic studies, over several decades, byProf. Luis Fajardo of Stanford University to dispel thistenacious misperception (Cohn 1967 and Fajardo 1968).The sensitivity of the heart to radiation therapy was onlyreally acknowledged in the early 1970s (Bouyer-Dalloz2003). Even then, a long time elapsed before the completepicture of radiation-induced heart disease finally becameaccepted in medical thinking (Hancock 1993).

Further evidence began to emerge in the 1970s. ASwedish team conducted a randomized, controlledclinical trial (RCT) involving 960 breast cancer patientsover the period 1971 to 1976. These patients receivedeither surgery alone or surgery preceded or followed byradiation. A total of 58 patients had heart attacks duringthe follow-up period, which averaged 20 years. Patientswho received high doses of radiation had twice the riskof those who did not. There was also a 2.5-foId increasedrisk of ischemic heart disease (i.e., the kind caused by adecrease in the blood supply to the heart). The differencebetween the two groups began to appear after four to fiveyears, and the heart attack incidence rates continued toincrease in the irradiated group for ten to 12 years. Therewas some evidence that most of the deaths were due toradiation-induced damage to the small blood vessels ofthe heart (Gyenes 1998).

In another study, the strength of the heart wasmeasured 15 to 20 years after treatment for breastcancer. It was found that 25% of patients treated withradiation to the left breast had heart-related problems onstandard stress tests, compared to none in the controlgroup. The authors' main conclusion was that left-sidedchest irradiation (which more frequently affects theheart) might represent a risk factor for ischemic heartdisease (Gyenes 1994).

Because of these studies, modifications were made inthe 1980s to the way that radiation was delivered aftersurgery for breast cancer. Radiation oncologists have

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War on Cancer

often claimed that witii more precise equipment andtechniques, heart damage was no longer a ciinicaliyrelevant problem. This seemed plausible. However,the latest study shows that such complacency was ill-founded. The range of cardiovascular problems thatcan follow intense irradiation of the heart is in factvery broad. It includes six major categories and varioussubcategories:

1. Pericardia! disease• Acute pericarditis during irradiation• Delayed acute pericarditis• Pericardial effusion (delayed)• Constrlctive pericarditis

2. Myocardiai dysfunction3. Diffuse myocardiai fibrosis

(with or without pericardial disease)4. Coronary artery disease (CAD)5. Electrical conduction abnormalities6. Valvular heart disease

What complicates the issue is that radiation affectsthe heart and cardiovascular system unevenly; differentparts of the system are affected in different ways, andindividuals differ in their responses. For the sake ofsimplicity, I will not discuss the complicated mechanismsby which radiation damages the heart and circulatorysystem. What is most relevant is the experimental andclinical evidence of such damage.

Considerable Laboratory DataThere is a considerable body of laboratory data

demonstrating the harmful effects of radiation on theheart. Most of these experiments have been carriedout on the New Zealand white rabbit, because it hasreactions to heart irradiation that are similar to thoseof humans. In one such study, after a single 20 Gy doseof radiation, fully 94% of the rabbits developed someform of heart disease (Fajardo 1970). First, there was anacute reaction, which disappeared within 48 hours. Butstarting at the 50th day, a delayed reaction set in, and thisreached its full development by 90 days. By 150 days, halfthe experimental animals had died. What is particularlystriking about these experiments is the degree to whichradiation was shown to cause myocardiai fibrosis (atliickening of the heart muscle).

Similarly, in the human clinical situation, the heart'sresponse to radiation is also divided into an acute anda long-term response. As in the test animals, the initialresponse vanishes rather quickly. But then, some monthsor even years later, the patient may experience heartpain (angina), difficulty breathing, or even a full-scalemyocardiai infarction (heart attack). The problem is thatsince they occur a considerable time after treatment,these radiation-induced effects are indistinguishablefrom "ordinary" (i.e., randomly occurring) heart

problems. There is nothing about such events thatscreams out "radiation-induced heart disease." Thecardiologist therefore may not make a connection to thepatient's prior exposure to radiation.

The latest findings should caution us against hubris inthe medical field. It took tremendous investigative workby Professor Fajardo and others to prove that radiationdamages the heart. As a result of their work, somechanges were indeed made - and radiation oncologistshailed these changes as proof that radiation treatmentwas now safe. Although the accuracy of radiationdelivery and targeting has improved considerably, otherproblems, such as the cumulative cardiotoxic effect ofchemotherapy and radiation, remain largely unaddressed.This is especially relevant now that Adriamycin-basedchemotherapy has become the standard of care forbreast cancer.

Radiation is a classic two-edged sword. It doessubstantially reduce the risk of recurrences of breastcancer in the irradiated field. But this comes at the priceof an increased risk of damage to the heart, especiallywhen the internal mammary lymph node chains areirradiated or when the patient is a smoker. Patients andtheir physicians need to carefully weigh benefits andrisks before agreeing to this or any other potentiallytoxic treatment.

ReferencesBreastcancer.org quote available at: http://www.breastcancer.org/researcli

radiation_042805.1itml.Bouyer-Dalloz F. Maingon P, BenderUter M, et al. Effect of in vivo heart

irradiation on coronary reactivity in the rat. Cell Mol Biol (Notsy-le-grand). 2003;49 (Online Pub:OL): 435-442.

Cohn KE, et al. Heart disease following radiation Medicine. 1967;46:281-298,Desjardins AU. Action of Rontgen rays and radium on the heart and lungs Am

JRontgenoi 1932;27;I53,303,447.Fa)ardo LR, et al. Morphology of radiation-induced heart disease. Arch Pathol

1968;86:512 .̂'il9.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, 2001Food and Drug Administration (FDA). Package Insert, Herceptin

(Trastuzumab). Genetech. Sept. 2003. Available at: http://www.fda.gov/cder/(oi/label/2000/trasgen020900LB.htni. Accessed April 26. 2007.

Giordano SH, Hortobagyi GN. Local recurrence or cardiovascular disease:pay now or later. J NatI Cancer Insi 2007 Mar 7;99(.S):340-34l.

Gyenes G. et al. Long-term cardiac morbidity and mortality in a randomizedtrial of pre- and postoperative radiation therapy versus surgery alone Inprimary breast cancer. Radiother Oncol. 1998:48:18.S-I9O.

Gyenes G. et al. Morbidity of ischemic heart disease in early breast caticer15-20 years after adjuvant radiotherapy. Inr J Radiat Oncol Biol P/iys1994:28:1235-1241.

Henschke C, Yankelevitz DF, Libby DM. et al. Survival of patients withstage I lung cancer detected on CT screening. N Enffl J Med 2006 Oct26:355(17):l7fi3-7l.

Hooning MJ, Botma A, Aleman BM. et al. Long-term risk of cardiovasculardisease In lO-year survivors ol breast cancer. J Nail Cancer Inst2007;99:365-375.

Jensen BV. Cardiotoxic consequences of anthracycline-containing therapy inpatients with breast cancer. Semin Oncol, 2006 .lun:33(3 SuppI 8):SI5-21.Review,

Leach JEL. Effect of Rontgen therapy on the heart: clinical study. Arch InternMed. 1943:72:715-745.

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

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