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Double Trouble

December 6, 2021

December 2021

Dual primary malignancies are more common than previously thought, but management is complex and research is limited.

When Rouslan Kotchetkov, MD, PhD, a hematologist/oncologist at Simcoe Muskoka Regional Cancer Centre in Ontario, Canada, started practicing independently eight years ago, he found a second malignancy during the workup of one of the first patients he saw. “I thought, maybe it was just a coincidence,” he told ASH Clinical News. Then, it happened again in another patient not long after. “I thought then that I needed to start looking into it.”

As he scoured medical journals, though, he could not find any research about patients with multiple, seemingly unrelated cancers, except for a few case studies. “There really is not much practical guidance for physicians on how to manage these patients,” said Dr. Kotchetkov, who is also an assistant professor of medicine at the University of Toronto.

Jane Churpek, MD, assistant professor in the Division of Hematology, Medical Oncology, and Palliative Care at the University of Wisconsin School of Medicine and Public Health, had a similar experience, and noted that “it is exciting that people are now asking questions about it.”

As cancer treatments improve, patients are living longer and more are presenting with multiple malignancies – second cancers that are not caused by metastasis. However, whether the increase is related solely to longer survival or to other inherent risk factors is unclear. With limited research on the topic, treatment decisions are often more art than science, experts said.

ASH Clinical News spoke with Drs. Kotchetkov, Churpek, and other hematologists/oncologists about what is known – and unknown – regarding the risk factors, diagnosis, and treatment of multiple primary malignancies.

Seeing Double

“As an oncologist who works in hereditary cancer types, and specifically testing for situations where people have multiple cancers in themselves or in the family, I see it all the time,” said Dr. Churpek. At the University of Wisconsin, she specializes in the diagnosis and management of patients and their families with hereditary cancer predisposition syndromes such as familial leukemia syndromes, Li-Fraumeni syndrome, Cowden syndrome, and BAP1 syndrome.

The prevalence of dual primary malignancies in the overall population is less well understood. In 2007, the National Cancer Institute’s (NCI’s) Surveillance, Epidemiology, and End Results (SEER) program, which provides information on statistics about solid tumors as well as blood cancers, found that the prevalence of a second primary malignancy ranged from 1 to 16%, depending on the type of initial cancer diagnosis.1

More recently, Dr. Kotchetkov and his team set out to determine how often patients diagnosed with a single hematologic malignancy are unexpectedly diagnosed with a synchronous dual hematologic malignancy, hoping to classify patients based on characteristics and timing. In 2018, he and his team published a paper suggesting that 1.5% of patients with hematologic malignancies presented with a second malignancy (46 of the 3,036 patients included).2 They also found several heterogeneous combinations of synchronous dual hematologic malignancies comprised of myeloid or lymphoid lineages. These conditions are underreported, the study authors noted, and, with more sophisticated statistics, Dr. Kotchetkov said he would expect to find an even greater prevalence.

Scientists classify cases of multiple primary malignancies in several ways. First, they determine whether the malignancies are synchronous or asynchronous. A synchronous second malignancy is one that is found shortly after the first is diagnosed. An asynchronous one is found later in the initial disease course. The cutoff between the two categories is not exact, though in some studies, researchers suggest about six months.

Dr. Kotchetkov noted that the next step to understanding the incidence of dual malignancies is clarifying these terms. “We need to define the proper diagnostic algorithms and methods of diagnosis, as well as develop a clear definition of what actually are synchronous or asynchronous hematologic malignancies,” he said.

Currently, differentiating between the two is difficult. For example, a second hematologic malignancy that appears four to five months after the first may have been there longer (making it synchronous), or it could have been triggered by the treatment of the initial cancer (making it asynchronous).

As Dr. Kotchetkov and his co-authors described in the paper, there are three main categories of double hematologic malignancies: myeloid plus lymphoid, myeloid plus myeloid, and lymphoid plus lymphoid.

The combination of myeloid plus myeloid lineage malignancies was rare, the authors noted, while most cases were myeloid plus lymphoid malignancies, most often a combination of myeloproliferative neoplasm (MPN) plus monoclonal gammopathy of undetermined significance (MGUS) or myelodysplastic syndromes (MDS) plus another malignancy. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was the most common concomitant lymphoid cancer.

For patients with two primary lymphoid malignancies, the combination of lymphoma with plasma cell dyscrasia (MGUS/myeloma/amyloidosis) was the most common (20%). Notably, this group also had the highest frequency of concomitant nonhematologic cancers (64%).

In patients with lymphoid malignancies, “it makes pathophysiological sense that they would develop a second malignancy because of the immune deficiency,” said Dr. Kotchetkov. MPNs and CLL come from two different stem cells, but some other combinations are “a bit trickier,” he said. In the case of both lymphoid and myeloid neoplasia, a single primordial stem cell lesion can cause both malignancies simultaneously, potentially complicating treatment decisions.

Risk Factors for Dual Primary Malignancies

With the expansion of cancer treatment options in recent decades, many patients with cancer are living much longer than they would have previously. This could be one reason why clinicians are seeing an uptick in people presenting with multiple malignancies, according to the authors of a 2015 registry analysis of second malignancy rates in patients with myeloma, but it is not the only reason.3

The analysis followed 744 patients for 25 years. During that time, additional malignancies were found in 118 patients, 63% of which were considered prior or synchronous and 37% of which were considered subsequent or asynchronous.

Second malignancies, which the authors considered long-term complications of a myeloma diagnosis, may evolve as a necessary consequence of several factors, including “life-saving treatment, patients aging with cancer, multi-agent drugs being used, prolonged treatment exposure, better surveillance programs, our greater awareness of [second primary malignancies], and improved diagnostic measures to detect them,” the authors wrote.

Just like cancer in general, there is a wide range of risk factors that might predispose someone to developing multiple malignancies, like genetic mutations and environmental exposures.

“If somebody has been a smoker, their whole lungs feel the effect from that exposure,” offered Dr. Churpek as an example. “Those patients are enriched for getting other cancers in the tissues that are exposed to the same smoking toxins, such as the mouth and throat.”

Other lifestyle risks, such as a lack of exercise, can have more widespread and less obvious impacts. “Few of our analyses have been able to identify [lifestyle risk factors] because we are either not getting accurate self-reported data or the effects are being overshadowed by other treatment-related risk factors,” said Lucie Turcotte, MD, MPH, assistant professor of pediatrics in the Division of Hematology/Oncology at the University of Minnesota.

In addition, the treatment of one cancer, like radiation therapy, can heighten a patient’s risk of developing a subsequent cancer. “We see a lot of secondary breast cancers in our patients who have had Hodgkin lymphoma and been previously treated with mantle field or chest radiation,” said Dr. Turcotte. “That is probably one of the biggest drivers of secondary cancers that we see in survivors of childhood cancer.”

Other treatments such as chemotherapy and alkylating agents can also increase risk. “We know that there are secondary hematologic malignancies, particularly cases of treatment-related MDS or acute myeloid leukemia (AML) that can be associated with previous chemotherapy exposures, like alkylating agents or topoisomerase inhibitors,” she added.

A gene that is found to be implicated in one type of cancer can also be implicated in others, leading to a heightened risk of multiple malignancies. One of the best understood examples is patients with Li-Fraumeni syndrome, which is caused by a mutation in the TP53 gene. The mutation puts patients at much higher risk of developing cancer by the time they are 30 or 40 years old, “and those patients also are at risk for getting another cancer after that,” said Dr. Churpek.

Some other genes, she added, “put you at risk for a future blood cancer, and some of these genes predispose people to both sides of the spectrum: lymphoid or myeloid. Some mutations can be in the middle, where it’s hard for us to tell which lineage it is.”

Subsets of certain cancers, such as diffuse large B-cell lymphoma and marginal zone lymphoma also seem to put patients at higher risk of subsequent cancers, specifically those cancers that are related to infections such as hepatitis, HIV, and H. pylori, according to a 2019 study.4

“No clear recommendations exist for long-term second cancer surveillance among non-Hodgkin lymphoma survivors with certain infections,” said study author Lindsay M. Morton, PhD, senior investigator in the NCI’s Radiation Epidemiology Branch. “Our findings emphasize the importance of screening for infections, since recent data suggest that an unexpected number of patients with newly diagnosed cancer are unaware that they may have certain infections, such as hepatitis B or C virus.”

Diagnosis and Screening

Usually, the diagnosis of a second primary malignancy occurs when a clinician sees a symptom or lab reading that did not seem to fit with the first cancer diagnosis. “Most cancers have a particular kind of pattern of spread or kind of behavior that we recognize,” said Dr. Churpek. “If you see something that doesn’t fit the pattern that you expect, it might lead you to go looking for another cancer.”

For patients with blood cancer, hematologist/oncologists expect that some of a patient’s blood counts will lower, she explained, but “sometimes people’s blood counts don’t recover like they’re supposed to, raising suspicion that they have another bone marrow cancer on top of the cancer that we thought we were dealing with.”

Still, if a patient is found to have another cancer, that does not mean that it is clinically important. Occasionally, “defining a second malignancy will not actually be beneficial for the patient,” said Dr. Kotchetkov. “We need to address the question, ‘What type of patient really needs an in-depth workup to search for secondary malignancies?’”

Double Duty Treatment?

Even if physicians could reliably diagnose multiple malignancies, the question becomes how – and when – to treat them. All the hematologist/oncologists who spoke with ASH Clinical News agreed that, if one of the malignancies is far more aggressive than the other, the plan is simple: focus on the aggressive cancer first and deal with the other one later. Still, clinicians must monitor the patient carefully, looking for any effect of the first treatment on the second malignancy.

In some situations, treatments with molecular targets may be able to address two cancers simultaneously. “It has gotten easier over time, because some of the targeted treatments are not totally dependent on the tumor’s origin,” said Dr. Churpek. “It’s more about the molecular basis, so there are more drugs that cross tumor types.”

According to Dr. Kotchetkov, there are anecdotal and observational findings about drugs for certain cancers that can help treat others simultaneously. The hypomethylating agent azacitidine, used to treat MDS, may also treat patients with T-cell large granulocyte lymphocytic leukemia, for example. He’s also seen that “some medications used for chronic myelomonocytic leukemia also work for lymphoma, or vice versa.”

He recalled once working with a patient who had aggressive lymphoma and aggressive myeloma, both of which needed treatment right away. His care team began myeloma treatment and, when they retested the patient, both cancers were in remission. “Years after, he was still in remission from lymphoma, but he had never received lymphoma-directed treatment,” he said.

Dr. Kotchetkov emphasized that these are only anecdotal observations and larger studies are needed to understand fully which treatments might truly be able to perform double duty.

Of course, not every patient gets so lucky. Dr. Kotchetkov had another patient with leukemia who became profoundly anemic after a course of chemoimmunotherapy.

The most challenging patients may be those who require treatment for two cancers at once, but even those who develop multiple malignancies years apart require special treatment considerations.

Typically, if a patient has localized breast cancer, the options are a mastectomy or a lumpectomy with radiation. If that patient has Li-Fraumeni syndrome, placing her at higher risk for developing subsequent cancers, Dr. Churpek said, “we elect to go down the mastectomy route because we do not want them to get the radiation that could cause a second cancer, when they could survive their breast cancer with either approach.”

“[Patients who have already been through cancer treatment] often have strong feelings about how they want to be treated and what they do or do not want to receive for their next time through therapy.”

—Lucie Turcotte, MD, MPH

Treatment becomes even more complicated for patients who develop secondary MDS or AML. “Those patients are only curable with a hematopoietic stem cell transplant,” said Dr. Turcotte. But if they have previously received cancer therapies, they may not be healthy enough to undergo transplantation.

While the risk analysis of performing a hematopoietic stem cell transplant may be particularly acute, Dr. Turcotte emphasized that a similar cost-benefit calculation is required for all patients with second primary cancers. “You have to consider what they have received for their initial cancer in terms of cumulative dosing and organ function, and what their body can withstand for another cancer therapy,” she explained.

The Patient Perspective

In addition to managing the physiological effects of multiple treatments, experts said that patients often feel differently about their cancer the second time around.

When a patient survives a first cancer only to hear a diagnosis of a second malignancy, he or she may feel like, “all of a sudden, they’re back at square one, starting on a totally new cancer journey. It is so disheartening,” Dr. Churpek said. “That is one of the hardest things about taking care of the patients with hereditary disorders whom I care for.”

Mental health is an important aspect of care for her patients, she noted.

Dr. Turcotte agreed. “Maintaining quality of life, in the emotional sense, is very challenging.” Plus, she added, patients who have already been through cancer treatment “often have strong feelings about how they want to be treated and what they do or do not want to receive for their next time through therapy.”

When a patient is experiencing multiple malignancies, care can get complicated quickly. “These patients are complex,” said Dr. Kotchetkov. “They certainly require more time, more effort, and more attention.”

Hematologist/oncologists must work with other oncology specialists to determine the best course of care. Clinicians must think through the treatment options for the cancer they specialize in and discuss the possible risks and benefits of each one with a provider who is an expert in the other malignancy. As part of those discussions, “they might ask if any of these options overlap so they could produce some efficacy for both cancer types,” said Dr. Churpek.

Dr. Kotchetkov described two of his current patients going through a combination of lymphoma and gastrointestinal cancer. The care team must balance a plethora of treatment risks when considering the management of these patients. For Dr. Kotchetkov, that means closely coordinating with an oncologist, nursing professionals, and other hospital staff. These patients may “require more support in terms of blood transfusions, human growth factors, and supportive therapy with immunoglobulins if they are immunodeficient,” he explained.

Clear communication between patients and their care team is essential, not just for the appropriate management of dual malignancies, but also for the earlier detection of these underreported conditions. —By Emma Yasinski

References

  1. Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist. 2007;12(1):20-37.
  2. Kotchetkov R, Ellison E, McLean J, et al. Synchronous dual hematological malignancies: New or underreported entity? Hematology. 2018;23(9):596-599.
  3. Engelhardt M, Ihorst G, Landgren O, et al. Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years. Haematologica. 2015;100(10):1340-1349.
  4. Herr MM, Schonfeld SJ, Dores GM, et al. Risk for malignancies of infectious etiology among adult survivors of specific non-Hodgkin lymphoma subtypes. Blood Adv. 2019;3(13):1961-1969.

 

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