Cardiotoxic Effects of Radiation Therapy

Heart damage is a potential consequence of radiation therapy (RT) for breast cancer and lung cancer. As Katie Livingston et al in their 2020 review article state, radiation therapy to the chest can adversely affect heart function in a dose-dependent manner. Even though imaging and radiotherapy techniques have improved, exposure to the heart is often unavoidable. The review authors say that underlying mechanisms that lead to cardiac damage are still not fully understood but radiation is known to cause changes in mitochondrial structures and produce dysfunction. It also causes endothelial cell damage and increases inflammation. By understanding the mechanisms underlying radiation-induced cardiac injury, the authors hope that new therapies can be developed that decrease the known cardiovascular risks.

A 2021 study, led by Lauren E. Carlson, MPH, used data from the Women’s Environmental Cancer and Radiation Epidemiology Study (WECARE Study) to assess coronary artery disease (CAD) risk in women diagnosed before age 55. The participants were diagnosed with stage I or II invasive breast cancer between 1985 and 2008. Epidemiological risk factors, treatment details, tumor characteristics, and which breast was treated with radiation therapy were collected via structured questionnaires used in phone interviews or sent by mail and by medical records. This 2021 follow-up study looked at the incidence of nonfatal CAD events (cardiomyopathy, myocardial infarction, coronary heart disease, angina requiring medication, arrhythmia, stiff or leaking heart valves or heart surgery) among 972 women who lived in the US, Canada, or Denmark. Median follow-up time was 14 years (range 1-29 years). Women who did not receive radiation therapy (RT) or who had a history of CAD before their breast cancer diagnosis were not included. The researchers compared women treated with left-sided radiation (exposing the heart to more radiation) to those treated on the right, using multivariable Cox proportional hazards models.

The incidence of CAD was nearly twice as great in the group receiving RT to the left breast compared to the right: 10.5% vs. 5.8% (p=0.010). In actual numbers, 14 of 466 women with cancer in the right breast and 32 women of 506 women with cancer in the left breast reported a cardiac event. The researchers say that 91% of the CAD events occurred more than five years after radiation treatment.

CAD incidents in women who received right-sided RT between ages 25-39 was 0%, compared to 5.9% for those treated on the left side. For comparison, coronary heart disease among US women in the general population, according to 2015-2018 data, is 0.9%. For women diagnosed between 40-54 years, CAD events occurred in 6.8% of those treated on the right side and 18.7% of those treated on the left. The risk is 6.6% in the general population of US women, according to 2015-2018 data. In the WECARE follow-up, chemotherapy treatment seemed to exacerbate the difference between right- and left-sided RT treatment.

The authors point out that ≥250 mg/m² of anthracyclines (chemotherapy) was not used as adjuvant cancer treatment during 1985-2008, when WECARE participants were treated. In a 2020 study, Allison Padegimas, MD, and colleagues report that anthracyclines, particularly when given in bolus dosing, are known to be cardiotoxic. The WECARE authors say, “Further research is needed to identify the types and doses of breast cancer chemotherapy that may increase the risk of RT-associated CAD.” Although new techniques to reduce cardiac damage during radiation therapy are now in use, the WECARE authors recommend monitoring younger women treated with RT on the left-side for cardiovascular disease. As Padegimas et al note, “Overall survival outcomes are significantly worse in patients who develop [cardiovascular disease], and in certain breast cancer populations, cardiovascular death exceeds the risk of cancer death in the long-term.” Finding ways to mitigate RT cardiac damage is ongoing.

Carlson LE, et al. Coronary Artery Disease in Young Women After Radiation Therapy for Breast Cancer. JACC Cardiooncology. September 2021.

Livingston K, et al. The Role of Mitochondrial Dysfunction in Radiation-Induced Heart Disease: From Bench to Bedside. Frontiers in Cardiovascular Medicine. February 21, 2020.

Padegimas A, Clasen S, Ky B. Cardioprotective Strategies to Prevent Breast Cancer Therapy-Induced Cardiotoxicity. Trends Cardiovasc Med. January 2020;30(1):22-28.

FDA and the Doctor-Patient Relationship

On June 2, 2022, three physicians filed a lawsuit against the Department of Health and Human Services (DHHS), the Food and Drug Administration (FDA), the Secretary of Health and Human Services, and the FDA commissioner in a US federal district court (Southern District of Texas Galveston Division). The physicians—Robert L. Apter, MD, FACEP; Mary Talley Bowden, MD; and Paul E. Marik, MBBCh, M. MED, FCCM, FCCP—are represented by Trent McCotter, a partner with Boyden Gray & Associates. That law firm, based in Washington DC, focuses on constitutional and regulatory issues. McCotter, a former US Deputy Associate Attorney General and Assistant US Attorney, has taken part in many federal appeal cases. This case challenges the legality of FDA’s campaign against off-label use of an approved drug—ivermectin—to treat covid-19.

According to the Food, Drug, and Cosmetic Act (FDCA), FDA has the authority to approve drugs for consumer use if they are safe and have an expected effect when used according to the manufacturer label. FDA can also monitor a product’s safety after its approval, require changes in labeling, and withdraw approval in some cases. The agency has no authority to interfere with a doctor’s off-label use of an approved drug or device:

…the FDCA further provides in 21 U.S.C § 396 that nothing in the statute “shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device for any condition or disease within a legitimate health care practitioner-patient relationship.”

The lawsuit lists several cases in which court decisions have upheld the physician’s right to use approved drugs off-label: e.g., “’A physician may prescribe a legal drug to serve any purpose that he or she seems appropriate, regardless of whether the drug has been approved for that use by the FDA’” (Wash. Legal Found v. Henney, DC Cir. 2000).

The plaintiffs claim that FDA, which is a branch of DHHS, interfered with the doctor-patient relationship and exceeded its authority when it campaigned against the use of the approved drug ivermectin as a treatment for covid-19. The agency produced a publication on March 5, 2021, called “Why You Should Not Use Ivermectin to Treat or Prevent COVID-19,” which failed to highlight its medical uses in humans or acknowledge the legality of off-label use. Beginning in April 2021, FDA publicized the drug’s veterinary use while ignoring its long-time (since late 1970s), widespread and safe use in humans. Several countries permit its sale over the counter. The agency started the Twitter campaign “You are not a horse. You are not a cow Seriously, y’all. Stop it.”—which gained extensive media attention and was repeated by numerous outlets, including USA Today, The Guardian, and NPR. The agency sent letters warning against its use for covid (but not against other off-label uses) to the Federation of State Medical Boards and the National Association of Boards of Pharmacy.

“The FDA’s actions resulted in their foreseeable and intended effect of stopping doctors from using ivermectin to treat COVID-19,” according to the lawsuit. “Following the FDA’s lead, the AMA, American Pharmacists Association, and American Society of Health-System Pharmacists all issued a joint statement ‘strongly oppos[ing] the ordering, prescribing, or dispensing of ivermectin to prevent of treat COVID-19 outside of a clinical trial,’ and pointed to the FDA’s ‘Why You Should Not Use Ivermectin to Treat or Prevent COVID-19’ as part of their justification.” Hospitals, courts, and insurers also used the publication as support for prohibiting the drug’s use, even when prescribed by a patient’s personal physician.

The lawsuit alleges that FDA “did not provide adequate justification for taking official positions on the use of ivermectin to treat COVID-19, failing to address or respond to any of the scientific evidence showing that ivermectin is an effective prophylactic or acute treatment for COVID-19.” In addition, “[b]y directing against the use of ivermectin to treat COVID-19, the FDA has deliberately interfered with the practice of medicine and the authority of health care practitioners to prescribe approved drugs in bona fide practitioner-patient relationships, in violation of the FDCA.”

Each of the plaintiffs say FDA’s actions interfered with their ability to take care of their patients. Robert L. Apter, MD, is licensed in Arizona and Washington; he has over 40 years of experience in emergency medicine. He prescribed ivermectin during over 6,000 patient consultations (half for prophylaxis and half for treatment). Pharmacists’ refusal to fill the prescriptions delayed treatment—“when early intervention is paramount.” Dr. Apter is facing disciplinary proceedings by the Washington Medical Commission and Arizona Medical Board for prescribing ivermectin to treat covid.

Mary Talley Bowden, MD, who is licensed to practice in Texas, completed residency in otolaryngology-head and neck surgery at Stanford University Medical Center in 2003. She has also found that pharmacists have refused to fill ivermectin prescriptions for covid patients, which she began recommending in early 2020. In addition, Houston Methodist Hospital suspended her and forced her to resign her hospital privileges because of her early treatment recommendations. Dr. Bowden is a clinical advisor for Front Line COVID-19 Critical Care Alliance and owner of BreatheMD. Dr. Bowden has treated over 3,900 patients for covid with a success rate over 99.97%. She reports, however, that many patients were reluctant to take ivermectin because of the FDA campaign: “…health professionals, regulatory boards, and patients feel compelled to follow any directives or recommendations from the FDA, which presents itself as the authoritative source on the appropriate use of drugs.”

Dr. Paul E. Marik, a critical care specialist who has practiced medicine for over 40 years, is the third plaintiff. Dr. Marik, who “is among the top scientists across all scientific fields according to John P. A. Ioannidis et al,” was professor of medicine and chief of pulmonary and critical care medicine at Eastern Virginia Medical School (EVMS) from 2009-2021; he was also a director of the intensive care unit at Sentara Norfolk General Hospital. After the FDA tweet about animals and ivermectin, EVMS ordered Dr. Marik to remove the drug from the hospital’s protocol for covid, a protocol that he had developed. Sentara also forbade ivermectin’s use. Both EVMS and Sentara forced him to resign.

The plaintiffs are asking the Court to declare FDA’s actions unlawful and to declare “FDA cannot interfere with the practice of medicine, that the FDA cannot issue statements or directives about how or whether health professionals should use ivermectin off-label to treat patients, and that such FDA actions have no legal effect and do not bind health professionals or patients.” They also ask for an award of “reasonable attorney fees and allowable costs.”

This case has major ramifications for the practice of medicine, the doctor-patient relationship, and—in my opinion—the future of integrative and alternative medicine, which often uses approved devices and drugs off-label. As McCotter states in his brief:

If the FDA is not limited to its statutory lane, its unlawful actions will no doubt persist and repeat themselves.

Moreover, if the FDA is allowed to interfere with the practice of medicine now under cover of a pandemic, this interference will metastasize to other circumstances, destroying the carefully constructed statutory wall between federal and state regulatory powers, and between the FDA and the professional judgment of health professionals.

R. Trent McCotter. In the United States District Court Sothern District of Texas Galveston Division. Case 3:22-cv-00184. Robert L. Apter, MD, FACEP et al v. Department of Health and Human Services. https://www.courthousenews.com/wp-content/uploads/2022/06/apter-fda-complaint-usdc-texas.pdf