Certain oncology treatments can raise the risk of developing yet another cancer.
In mid-2013, Betty Strommer experienced a few strange and concerning health episodes, which she initially brushed off as minor or one-time issues. One morning in June, when the weather had finally warmed up in her hometown of Clara City, Minnesota, she decided to ride her motorcycle to work instead of driving her car. Strommer got up early to put on all her protective gear and was about to take off when an extremely painful wave of acid reflux hit her hard. Her esophagus burned so badly, she had to go back inside and lie down.
During the months that followed, she noticed that she grew short of breath more easily. Going up and down stairs left her winded, and her usual training for the Susan G. Komen 3-Day, a 60-mile fundraising walk — an event she had successfully completed five times in the past — felt like a herculean task. But as a breast cancer survivor, Strommer felt especially determined to go through with it.
“I would be going on my walks, and it was such a struggle to walk any amount of distance,” says Strommer, now 62. “I would sweat so bad, and I’m really not a sweater. I just don’t sweat very often, and during that summer, it dripped off my face.”
After Strommer completed the fundraiser in August, her right leg developed bothersome swelling that wouldn’t go away. Finally, she made a doctor’s appointment for September, assuring her partner and children that it wouldn’t result in anything serious. Two days later, she received a diagnosis of a second cancer, acute myeloid leukemia (AML).
“I remember wishing that my doctor would leave the room so I could just cry. It was not what I was expecting,” she says. “I knew that sometimes when you have breast cancer, you might get another type of cancer, but I was thinking maybe uterine cancer or something in my thyroid. I didn’t think it would cause me to get leukemia.”
RECURRENCE VERSUS SECOND CANCER
A growing number of survivors like Strommer are finding themselves with a second cancer, which can be unrelated or random but becoming increasingly common as more people are living longer and surviving their first cancer. But the two diseases can also be somewhat related, sharing the same risk factors — for example, lung and bladder cancer are more common in people who use tobacco — or caused by the treatment for one of the cancers.
It’s different from disease recurrence, which happens when the cancer comes back. Second cancers are associated with many risk factors, such as inherited genes, cancer cells that remain in the body after treatment, smoking, diet, weight, heavy drinking and environmental toxins.
Another risk factor involves treatments, such as certain chemotherapies and radiation, given to treat the first cancer. Strommer’s doctors told her that having chemotherapy and radiation in 2006 for breast cancer likely led her to develop AML.
Survivors have a small increased risk of developing a second cancer, according to the American Cancer Society. Ongoing research is looking to prevent second cancers by delivering chemotherapy and radiation with more precision and identifying those individuals most at risk. However, it’s crucial that survivors understand that cancer can recur and a new cancer can arise.
“The biggest thing to understand from a patient perspective is that just because one bad thing has happened to you, it doesn’t mean that more bad things will not happen,” says Dr. Aaron Seth Rosenberg, an assistant professor of hematology and oncology at the University of California, Davis Comprehensive Cancer Center in Sacramento. “It’s a small but real number of patients who go on to develop second malignancies. So the risk is there, but you can’t affect that risk by worrying about it, and all that we can do is monitor our patients closely.”
Over the past 30 years, the number of cancer survivors has increased fourfold. Today, roughly 17 million Americans live with a history of cancer, according to a report from the American Cancer Society. By 2030, that number is anticipated to rise to more than 22 million.
These individuals must live with a new normal that may include long-term side effects, financial hardships, possibility of recurrence or a second cancer. Survivors can work with their health care team to create a survivorship care plan — a record of a person’s cancer and treatment history, as well as any checkups or follow-up tests that may be needed in the future.
The likelihood of facing a second cancer varies depending on factors such as the type of cancer first diagnosed, treatment received, age at diagnosis and lifestyle choices. For instance, children and young adults have a higher risk of second cancers related to treatment with radiation and chemotherapy compared with older adults.
“With the increasing number of cancer diagnoses, as well as the improved prognosis for many patients, second cancers are more common today than in the past,” says Dr. Lindsay Morton, who holds a doctorate in epidemiology and is senior investigator in the Division of Cancer Epidemiology & Genetics at the National Cancer Institute (NCI). “In fact, about one in five cancers diagnosed today is diagnosed in a cancer survivor.”
THE RESEARCH SAYS
Researchers from Texas conducted a study, which was published in JAMA Oncology, that analyzed data from NCI’s Surveillance, Epidemiology and End Results (SEER) Program to see the prevalence of prior cancer among individuals newly diagnosed with cancer. Based on 740,990 cases from 2009 to 2013, 18.4% of all newly diagnosed cancers represented a second or subsequent cancer. A quarter of adults ages 65 and older and 11% ages 20 to 64 had a history of cancer when given their diagnosis.
Additional findings show a link between certain types of chemotherapy and blood cancers, most commonly AML, acute lymphocytic leukemia (ALL) and myelodysplastic syndrome (MDS). In particular, various alkylating agents, platinum compounds and topoisomerase 2 inhibitors have been associated with a fivefold increased risk of therapy-related MDS or AML. Alkylating agents such as mechlorethamine and cyclophosphamide affect the cancer’s ability to multiply and are most effective for leukemia and solid tumors. Platinum-based drugs like cisplatin and carboplatin inhibit DNA repair and/or synthesis in cancer cells. Topoisomerase 2 inhibitors stop cells from repairing DNA and have been used to treat breast, lung, testicular and other types of cancer. For Strommer’s breast cancer, her doctors administered the AC-T chemotherapy regimen, which consists of Adriamycin (doxorubicin) and cyclophosphamide, followed by Taxol (paclitaxel). Her doctors told her that it likely contributed to her development of AML.
Late last year, Morton and her colleagues reported in JAMA Oncology about a substantial expansion in the number of patients who are at risk of therapy-related leukemia in the modern treatment era. From 2000 to 2014, patients in the SEER registry database treated with chemotherapy for solid tumors (except for colon cancer) experienced an increased risk of therapy-related MDS or AML. The researchers also noted a rise in the proportion of patients treated with a known leukemogenic agent (alkylating agent, platinum compound or topoisomerase 2 inhibitor), from 10% during 2000 to 2001 to 81% in 2012 to 2013.
Morton emphasizes that developing MDS or AML after chemotherapy remains rare: “In most of the patient populations we studied, the risk of developing therapy-related leukemia was less than 1% at 10 years,” she says.
“The benefits of cancer treatment typically far outweigh the risk of developing a new cancer due to that treatment.”
Although chemotherapy is a greater-known risk factor, radiation therapy can also cause leukemia, MDS and solid tumor cancers. The amount of risk depends on the dose of radiation, the specific region of the body that is treated and the age of the patient at the time of therapy.
Radiation therapy-associated leukemia and MDS most often occur within several years of treatment, generally five to nine years later. It usually takes at least 10 years — sometimes more than 15 years — for radiotherapy-related solid tumors to develop.
“Therapy-related malignancies are part of why we emphasize regular follow-up and survivorship in patients. But one of the things I stress upon my patients is that we have to deal with the cancer in front of us,” Rosenberg says. “If we don’t treat you with the best therapies avail- able because there’s a risk five to 10 years down the line, we’re ignoring the short-term dangers of the cancer that’s currently in front of us.”
An active area of research in the field of second cancers is finding a way to identify which survivors are most at risk, so they can be monitored more closely for new disease. One promising method is a peripheral blood test for a recently identified disease entity called clonal hematopoiesis of indeterminate potential, or CHIP. It is defined as the presence of preleukemic mutations — those that pave the way to developing leukemia — in an otherwise healthy person who does not have cancer.
“Doctors and scientists are starting to understand that there may be a small subset of patients who have an increased risk of therapy-related leukemias that may be genetically based,” says Dr. Guillermo Garcia-Manero, a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “The tests are currently in clinical trials, but one day, they could allow us to come up with effective identification and preventive strategies for patients.”
Garcia-Manero specializes in therapy-related myeloid neoplasm (t-MN), a term proposed by the World Health Organization to cover the spectrum of malignant disorders previously described as therapy-related MDS or AML. In 2017, he and colleagues published a study in Lancet Oncology in which they compared the prevalence of CHIP between patients who developed t-MNs and those who did not. More than 70% of the t-MN group had CHIP at the time of their initial cancer diagnosis, before ever having t-MN, compared with 31% of the control group. “Until not too long ago, we thought that this process of developing t-MN was totally random. We didn’t know why some patients with breast cancer never get this kind of therapy-related leukemia, (whereas) others do,” Garcia-Manero says. “CHIP has really transformed this field. Now, for a significant percentage of patients, you can predict who has a higher risk of therapy-related disease.”
CHIP is rare, especially at a young age, but the prevalence rises to roughly 10% among individuals ages 70 to 80. Liquid biopsies, which are becoming more common at cancer centers, could also be used to identify patients with CHIP and assess their risk of t-MN.
AVOIDING A NEW DIAGNOSIS
Cancer survivors can lower their overall cancer risk by living a healthy lifestyle, which includes getting regular exercise, eating a healthy diet, avoiding tobacco and limiting alcohol use. Individuals should also keep follow-up appointments and let their doctors know if any symptoms or problems arise. Signs of a second cancer include fatigue, loss of appetite, bleeding, feeling like bones ache and vision changes.
Thinking back to that fateful summer, Strommer realizes that she should have seen a doctor sooner, right after she noticed something off about her health. But after six grueling months of treatment for AML, which involved chemotherapy, a bone marrow transplant on her birthday and multiple near-death experiences — two fungal infections and fluid in her heart — she made what doctors call a miraculous recovery and was well enough to go home in April 2014. She still takes Nexavar (sorafenib), a kinase inhibitor originally used for kidney cancer and showing promise for some patients with AML — depending on the results of her next bone marrow biopsy, her oncologist may take her off it after six years. Strommer realizes that not everyone beats the odds as she did — she often encounters those patients at her new job at the local hospital’s cancer center. She switched departments after her recovery, driven by a desire to help others going through what she once did. She credits a positive attitude, her seven grand- children and the grace of God for helping her survive the hardest time in her life.
“When the doctors said I only had a 1% chance to make it, it’s hard to understand why God chose me to win the battle, yet others who had someone to live for lost their battle,” Strommer says. “There were so many times I’d sit in my room in the hospital and didn’t know whether I would live or die, but I was really at peace with it. All I can say is, I’m a firm believer in miracles.”