Many held their breath on November 8, 2018, when they learned that Supreme Court Justice Ruth Bader Ginsburg, 85, had been hospitalized after a fall in her office left her with three broken ribs. But Ginsburg, the oldest of the justices on the Court, and one of four remaining liberal-wing judges, isn’t one to lay about. She was discharged two days later and worked from home for a few days. A week after the fall, she attended a Medal of Freedom ceremony at the White House for her late friend and fellow Justice Antonin Scalia. She returned to the bench on November 26.
But what we didn’t know at the time was that doctors found something suspicious in her lung on the CT scans taken when she had fractured her ribs. On December 21, two malignant lesions were removed by a lobectomy which took place at Memorial Sloan Kettering Cancer Center in New York City.
Justice Ginsburg’s surgeon, Dr. Valerie W. Rusch, reported that “there was no evidence of any remaining disease” and “scans performed before surgery indicated no evidence of disease elsewhere in the body.” No further treatment is planned, and Ginsburg planned to be back on the bench when the new session began this week, although she was not.
This isn’t Ginsburg’s first brush with cancer. In September 1999, she was diagnosed with colon cancer. It was found incidentally when she had gone to the doctor for an abdominal infection. She underwent a sigmoid colectomy followed by “precautionary” chemotherapy and radiation treatments which began in October and finished in June 2000. According to Ginsburg, “Following the treatments, it is anticipated that I will require only routine examinations to assure my continuing good health.”
It was during one of those routine examinations, 10 years later, when her screening CT scan found a single lesion, measuring about 1 centimeter across, in the center of Ginsburg’s pancreas. She underwent surgery to remove the body and tail of the pancreas along with her spleen.
It has not been disclosed what kind of pancreatic cancer Ginsburg had — the more common but typically devastating adenocarcinoma, or the slower growing neuroendocrine type (the kind that eventually killed Steve Jobs). Neither has the pathology of Justice Ginsburg’s lung tumors been made public. Therefore, we don’t know if it was a third primary cancer or, possibly, metastatic recurrences of the pancreatic or colon cancer. The latter seems unlikely though because there was no evidence of disease elsewhere in her body and no further treatment planned.
According to the National Cancer Institute, in 2016, there were an estimated 15.5 million cancer survivors in the U.S. The number of cancer survivors is expected to increase to 20.3 million by 2026.
Nearly one in five cancers diagnosed today occurs in an individual with a previous diagnosis of cancer, and these “second cancers” are a leading cause of morbidity and mortality among cancer survivors. These are not recurrences of a previous form of cancer, but the development of a second, unrelated cancer occurring in someone who has had cancer sometime in their past. Research into the causes, prevention, and treatment of second cancers has the potential to improve public health, guide clinical management of survivors, and provide further insight into the mechanisms of carcinogenesis.
According to the NCI’s Division of Cancer Epidemiology and Genetics, second primary cancers appear to be associated with three important factors:
- Lifestyle, environmental, and medical history factors
- Genetic susceptibility
- Treatment-related second cancers
Shared Lifestyle, Environmental, and Medical History Factors
Some cancers are caused by known cancer-producing agents, such as smoking, alcohol, and HPV (human papillomavirus) infection. For example, smokers can get cancer of the larynx but are also at risk of getting lung or esophageal cancer. HPV infection can cause cervical as well as head and neck cancer.
Tobacco smoke contains several different carcinogens and prolonged exposure can result in a phenomenon called “field cancerization.” Field cancerization, as defined by Braakhuis et al., is “the growth of a mutant clone to produce a field of cells predisposed to subsequent tumor growth.” This mutant field is preneoplastic and may appear either histologically normal, hypoplastic, or dysplastic.
Alcohol is another environmental agent associated with increased risk of a variety of cancers, including oral cavity and pharynx, esophagus, liver, colon, larynx, and female breast.
Hormonal factors may play a role in multiple cancers, especially those in breast, ovary, and uterine cancers.
Immune deficiency syndromes, either inherited or acquired, also play a role in increasing the risk of secondary primary tumors. Fraumeni and colleagues found that patients receiving immunosuppressive therapy after kidney transplant had increased risks of non-Hodgkin lymphoma, Kaposi sarcoma, and squamous cell cancer.
Infection with HPV and HIV are also associated with increased risk of multiple primary cancers.
About 1-2% of all cancers are associated with hereditary cancer syndromes. They are caused by mutations in certain genes passed from parents to children. In an inherited cancer syndrome, certain patterns of cancer may be seen within families. These patterns include having several close family members (such as a mother, daughter, and sister) with the same type of cancer, developing cancer at an early age, or having two or more types of cancer develop in the same person. Examples of inherited cancer syndromes are hereditary breast and ovarian cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome, and Lynch syndrome. Hereditary cancer patients need to be evaluated by cancer genetic counselors who can assess the risks of other family members.
Treatment-Related Second Cancers
With increasing numbers of cancer survivors come increasing risk of second primary cancers caused by the very treatment they needed to treat their first cancer. Fortunately, the benefit of primary treatment is much higher than the risk of secondary cancer. A monograph from SEER “found that cancer survivors had a 14% higher risk of developing a new malignancy than would have been expected in the general SEER population.” Risks of developing a new malignancy were substantially higher among children (relative risk of 6-fold) than among adults. Use of aggressive cancer treatments, particularly combined modality radiotherapy and chemotherapy, likely contributed to the increased incidence of second malignancies.
Many kinds of blood cancers can be linked to previous radiation therapy. Acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) can all be caused by previous radiation exposure. The increase in risk is dependent on the amount of radiation the bone marrow received during treatment. These cancers tend to occur within a few years after radiation therapy, typically within 5-9 years.
Solid tumors caused by radiation therapy tend to occur much later, perhaps 10-15 years or more after exposure. The risk is dependent on the dose of radiation, the patient’s age at the time of treatment (higher in younger patients), and the area where the radiation was given. Some organs, such as breast and thyroid, are more sensitive to the effects than others.
Chemotherapy has also been linked to second cancers. The most common malignancies linked to chemotherapy are myelodysplastic syndrome (MDS) and AML. Some patients develop MDS, which later turns into AML. The risk of these cancers is higher with chemotherapy than with radiation therapy.
Alkylating agents, such as mechlorethamine, chlorambucil, cyclophosphamide (Cytoxan), melphalan, lomustine (CCNU), carmustine (BCNU), and busulfan are all known to cause leukemia and MDS. Higher drug dose and dose intensity, as well as longer therapy duration, increase the risk of leukemia. The risk is greatest beginning two years after treatment and reaches its peak 5 to 10 years after exposure.
Other chemotherapeutic drugs known to cause leukemia include cisplatin and carboplatin, as well as a class of drugs called topoisomerase II inhibitors. They work by stopping cancer cells from being able to repair DNA. One subset of topoisomerase II inhibitors called anthracyclines are less likely to cause leukemia.
Stem Cell Transplant
According to the American Cancer Society, any type of stem cell transplant puts a patient at increased risk of second cancer because of the chemo- and radiation therapy involved. In addition, patients who receive stem cells from an allogeneic donor need to be on immunosuppressive drugs to prevent rejection of the donor’s stem cells. As some cells of the immune system recognize cancer cells as abnormal and kill them, immunosuppressive drugs can decrease this ability, increasing the risk of a second cancer.
Michele R. Berman, MD, and Mark S. Boguski, MD, PhD, are a wife and husband team of physicians who have trained and taught at some of the top medical schools in the country including Harvard, Johns Hopkins, and Washington University in St. Louis. Their mission is both a journalistic and educational one: to report on common diseases affecting uncommon people and summarize the evidence-based medicine behind the headlines.