Disclosures: Blaes, Berrington, Goldfarb, Jacobs and Turcotte report no relevant financial disclosures.
February 25, 2021
7 min read

Second cancer in survivors a complex, multifaceted concern

Disclosures: Blaes, Berrington, Goldfarb, Jacobs and Turcotte report no relevant financial disclosures.
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Although many cancer survivors go on to live healthy, cancer-free lives, the prospect of facing cancer again is an ongoing concern.

Much of the discussion around this possibility relates to recurrence of the original cancer, but cancer survivors also appear to be at increased risk for developing a second, entirely different type of malignancy. This risk can be related to treatment for the primary cancer, particularly radiotherapy directed at an area close to another organ.

Genetic factors also may influence risk for certain types of second cancers, according to Amy Berrington, DPhil, senior investigator and chief of the radiation epidemiology branch at the NCI.

“A well-known example is breast and ovarian cancer in BRCA mutation carriers,” Berrington said in an interview with Healio. “We are studying these sorts of pairs of cancers that occur more commonly together and have studies in progress to assess whether there are genes that increase the risk for developing a second cancer after radiotherapy.”

Amy Berrington, DPhil
Amy Berrington

Lifestyle factors such as obesity, smoking or lack of exercise also may elevate the risk for a second cancer. For this reason, clinicians recommend that cancer survivors maintain healthy habits and undergo regular cancer screenings.

When treatment causes harm

Among the causes of second cancers in cancer survivors are the specific modalities used to treat the original malignancy.

Radiation is the treatment most often associated with the onset of second cancers. This link is most frequently observed among survivors of pediatric cancers, who traditionally have been subjected to higher doses of radiation.

Lucie Turcotte, MD, MPH, MS
Lucie Turcotte

“We treat children with cancer more aggressively, because they’re better able to tolerate more aggressive treatment than adults,” Lucie Turcotte, MD, MPH, MS, assistant professor in the division of pediatric hematology-oncology at University of Minnesota Masonic Children’s Hospital, said in an interview with Healio. “We’ve learned from this that we can’t just pound them with treatment. They can tolerate radiation, aggressive chemotherapy and stem cell transplant, but all of these things put them at higher risk.”

When other organs are within the radiotherapy treatment field in a child with cancer, the risk for a second cancer developing in those organs increases, according to Berrington.

“An example is radiotherapy for Hodgkin lymphoma used to treat large areas of the abdomen and chest that expose many organs to high doses,” she said. “External beam radiotherapy results in higher second-cancer risks than brachytherapy or I-131 [radioactive iodine] treatment, because more organs tend to be exposed, and to higher doses.”

Radiotherapy for Hodgkin lymphoma is thought to be one of the major causes of subsequent breast cancer among survivors of that disease. However, radiation treatments have evolved over the years, according to Anne Blaes, MD, associate professor in the division of hematology and oncology at University of Minnesota and director of survivorship research for Masonic Cancer Center.

Anne Blaes, MD
Anne Blaes

“Some of these treatments are getting better with time; for example, the chest radiation we used for a long time back in the 1980s, 1990s and early 2000s for Hodgkin lymphoma used really big fields,” Blaes, who serves as a member of Healio’s Navigating Survivorship Peer Perspective Board, told Healio. “It covered most of the chest, whereas now, if someone needed that treatment, we would use a very small field, basically just directed to the lymph nodes that were involved.”

Other types of cancer, such as thyroid and breast cancer, seem to be bidirectionally linked without a clear cause.

“We don’t quite understand the breast-thyroid connection, but there is certainly an increase both ways, thyroid to breast and breast to thyroid,” Melanie Goldfarb, MD, MSc, associate professor of surgical oncology and director of the Center for Endocrine Tumors and Disorders at Saint John’s Cancer Institute, said in an interview with Healio. “We know that survivors of Hodgkin lymphoma have an increased risk for both thyroid and breast cancer after they receive neck and/or chest radiation for treatment of their disease.”

Linda A. Jacobs, PhD, CRNP
Linda A. Jacobs

Chemotherapy can also play a role in the development of second cancers, Linda A. Jacobs, PhD, CRNP, clinical professor of nursing and director of development of cancer survivorship clinical programs, research and educational initiatives at University of Pennsylvania’s Abramson Cancer Center, said in an interview with Healio. Although this is not as common as second cancers related to radiation, there are patients who develop leukemia or myelodysplastic syndrome as a result of their treatment with chemotherapy, she said.

Genetics and age

The potential role of genetics in development of second cancers is not as well understood. Although researchers agree that genetics appear to be involved in some second cancers, the mechanism of this association is not yet clear.

“There are genetic syndromes, some of which we know about and some of which we don’t yet know about, that make people more prone to certain kinds of cancers and therefore multiple cancers,” Goldfarb said. “My colleagues and I have published research showing that it probably isn’t just treatment-related; there’s something else that is causing people to have more than one cancer.”

Turcotte noted that in a subgroup of cancer survivors there may be an underlying genetic factor that places them at increased risk for developing multiple cancers. She cited Li-Fraumeni syndrome, which is an inherited predisposition to a wide range of cancers. This syndrome is related to a mutation in TP53, a tumor suppressor gene.

“Except for patients with a strong family history suggestive of a known inherited tumor syndrome, we often don’t know at the time of cancer diagnosis that a patient has this propensity for making cancers,” Goldfarb said. “However, as we continue to follow them through survivorship, we might see differences in the way they respond to therapy, or we might see them develop certain kinds of cancers at certain ages. As we learn more, we hopefully will be able to identify people who are more likely to develop multiple cancers during their survivorship.”

Mutations in the tumor suppressor genes BRCA1 and BRCA2 also have been linked to higher risk for multiple cancers. According to Jacobs, cancer survivors who have been treated with radiation for Hodgkin lymphoma have approximately the same risk for developing a second cancer as a survivor with a BRCA mutation. In some cases, this prompts the survivor to preventively address the possibility of a second cancer with more aggressive cancer screening.

“We have several patients who had chest radiation when they were young for Hodgkin lymphoma, and over the years they have repeated biopsies because they keep finding lumps,” she said. “Then they finally opt for bilateral prophylactic mastectomy.”

Younger patients have an increased risk for developing a secondary cancer, perhaps in part due to the longer duration of these patients’ survivorship.

“Age is important, because they have a long life expectancy ahead of them,” Blaes said. “Back in the 1970s and 1980s, we never even thought about survivorship. The whole goal was to make the cancer go away. So, it’s a good problem to have even though we have room to go in terms of understanding these changes.”

However, age at the time of a second cancer diagnosis also appeared to be linked to worse outcomes.

According to a 2017 study by Keegan, Goldfarb and colleagues, younger patients had significantly worse outcomes than older patients with the following second primary malignancies: thyroid cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, soft-tissue sarcoma and central nervous system cancer.

“We have found that some of these second cancers do tend to have a worse outcome, although some of that may depend on whether we are looking at overall survival or disease-specific survival,” Goldfarb said. “If we’re looking at overall survival, they certainly have a worse outcome, with some of that related to the first cancer; it’s a double whammy on their bodies. Even from a disease-specific survival standpoint, a number of second cancers had decreased survival in adolescent and young adult survivors.”

Ongoing survivorship

For some cancer survivors, long-term follow-up care to prevent second cancers is essential to healthy survivorship. ASCO recommends that cancer survivors have treatment summaries and survivorship care plans and offers several disease-specific templates for such plans at its website. These documents furnish follow-up providers with information about the survivor’s treatment and potential risks they might face. A clinician can glean information about different medications a patient is taking and their attendant risks.

“It basically outlines the kind of surveillance they are going to need,” Blaes said. “The follow-up clinician might counsel patients on what they need to do to stay healthy, and that is going to depend on a lot of factors that can be found in the care plan.”

Challenges in geographic access to qualified providers have driven a shift toward risk-based follow-up for cancer survivors.

“We recommend that people who are at high risk for serious problems stay in their oncology practice, with the team that treated them,” Jacobs said. “Patients with more moderate risk can be seen in advanced practice provider (nurse practitioner or physician assistant)-led follow-up clinics, and many of the low-risk patients can be referred to their primary care physician for follow-up.”

Blaes agreed: “If a colon cancer survivor is 5 years out from their treatment and didn’t need any chemotherapy, they could easily be followed by a primary care doctor,” she said.

In some cases, however, the primary care physician might not be able to meet the survivors’ surveillance needs.

“Primary care providers have to see patients of all ages with a wide array of medical issues,” Jacobs said. “They don’t necessarily have the knowledge or confidence to provide the appropriate surveillance for patients with every type of cancer.”

This presents a challenge, Jacobs said, because oncologists often lack the time to provide effective long-term surveillance. This is why the use of advanced practice providers may provide a solution. At her institution, they provide follow-up care for many cancers and work to educate colleagues at community hospitals on cancer surveillance.

“We have a network of [community hospital] affiliates, and we advocate for institutions to set up follow-up clinics for lower-risk patients,” she said. “We presented our model as an example of best practices at National Comprehensive Cancer Network and Commission on Cancer national meetings.”

Making cancer follow-up guidelines more consistent internationally also has become a priority, Turcotte said.

“We’ve recognized that in some situations, our guidelines in North America are discrepant from guidelines in some European countries, so there’s really been an effort over the last several years to harmonize these guidelines internationally,” she said. “This way, surveillance is more uniform, and we aren’t all doing slightly different things.”


For more information:

Anne Blaes, MD, can be reached at blaes004@umn.edu.

Amy Berrington, DPhil, can be reached at berringtona@mail.nih.gov.

Melanie Goldfarb, MD, MsC, can be reached at goldfarbm@jwci.org.

Linda A. Jacobs, PhD, CRNP, can be reached at linda.jacobs@pennmedicine.upenn.edu.

Lucie Turcotte, MD, MPH, MS, can be reached at turc0023@umn.edu.