Secondary Malignancies: Who Is at Risk and Why?

Lucie M. Turcotte, MD, MPH

The words "You have cancer" have a devastating effect on patients and their families. The diagnosis throws them into a previously unknown world of tests, treatments, and more tests. Once patients have gone into remission and are hopefully cured, they try to go back to their lives and put their cancer experience behind them. Given all they have been through, however, imagine how difficult it must be to hear those words again when a secondary malignancy is diagnosed.

As the population of cancer survivors has grown, so has the risk that patients will develop— and succumb to—a second cancer. An estimated 19% of cancers diagnosed in 2005 to 2009 were found among patients with a prior history of cancer, compared with 9% of diagnoses from 1975 to 1979.¹ Among those are secondary malignancies, defined as cancers that are not recurrences of the first malignancy or related to it. The role that the therapy used to treat the first cancer might play in the development of a secondary cancer continues to be a source of clinical investigation.

At-Risk Groups

Anyone who has been treated for cancer is at risk of developing a secondary cancer, but as with most conditions, the possibility is higher in certain groups. The largest at-risk group comprises childhood cancer survivors, who may go on to develop another cancer in adolescence or adulthood. For adults, there is a complex interplay of factors including the type of first and second cancer, patient age, and risk factors including primary cancer treatment, environmental and lifestyle hazards, and genetic susceptibility.¹Many secondary cancers among childhood cancer survivors are known to be related to treatment. However, some also occur because the children may have an underlying genetic predisposition that puts them at higher risk for developing cancer in the first place, Lucie M. Turcotte, MD, MPH, a pediatric hematologist/oncologist and assistant professor in the Division of Pediatric Hematology and Oncology at the University of Minnesota in Minneapolis, said in an interview with OncologyLive^®.“We know there are specific genetic syndromes in which children are at higher risk for multiple types of cancers.”

In addition, the cells of growing children tend to be especially susceptible to the effects of radiation, in particular and, to a lesser extent, to the chemotherapy used to treat cancer, Ari VanderWalde, MD, MPH, director of clinical research, West Cancer Center, and associate vice chancellor of research at the University of Tennessee Health Science Center in Memphis, explained in an interview. “It’s one of the reasons that cancer can be cured more often in younger patients, but at the same time because their cells are so susceptible to the effects of these cancer treatments, these cells can mutate more and ultimately develop more cancer.”

There is also the obvious reason why child- hood survivors have a higher incidence of second cancers: their age. “Generally, survivors of childhood malignancy have a lot more years of life left, during which they can develop cancer,” VanderWalde said.

Children are not the only patients at risk, however. Adults who have specific types of primary cancer may also go on to develop secondary malignancies, regardless of their age. A systematic review and meta-analysis of 21 studies published in the BMJ in 2016 found that although the absolute rates of developing another cancer were low, patients with prostate cancer who were treated with radiotherapy had a higher risk of developing second malignancies of the bladder, colon, and rectum compared with patients who did not undergo radiation therapy.² “The odds of a second cancer varied depending on type of radiotherapy: treatment with external beam radiotherapy was consistently associated with increased odds while brachytherapy was not,” Wallis et al wrote.

The location of the original cancer also is important. With prostate cancer, the most common areas for second cancers are in the lower body, but a study of 1257 patients who had squamous cell carcinoma of the head and neck that found the most common secondary malignancy among this group to be cancer of the larynx.³ Patients who had oral cancer also were more likely to develop a secondary cancer in the head and neck or esophagus.³

More specifically, survivors of head and neck cancer had up to a 27% higher risk of having a secondary cancer compared with the general population.⁴ The most common secondary cancers for this group were lung cancer and esophageal cancer. The most common cancers are of the upper respiratory tract or digestive tract (40% to 59%), lung (31% to 37.5%), and esophagus (9% to 44%).

Hodgkin disease (HD), among both children and adults, is another type of cancer that has long been associated with the risk of secondary malignancies. The results of a study of 1261 patients treated for HD before age 41 years between 1965 and 1987 showed patients with HD had an average of 6 times the risk of developing another cancer, compared with the general population.⁵ Another study found that survivors aged 16 years or younger with HD diagnosed between 1955 and 1986 found that the survivors had a 10% higher chance of developing a secondary cancer 20 years after completion of treatment, compared with the general population; this risk rose to 26.3% at 30 years.⁶

Causes of Secondary Cancers

Overall, 5-year survivors of childhood cancer were found to have a 20.5% cumulative incidence of second cancers, including a 7.9% cumulative incidence of invasive cancers, at 30 years from primary cancer diagnosis, according to results from a retrospective study of 14,359 survivors published in 2010.¹Chemotherapy and radiation therapy can play a role in the development of secondary cancers. “Within our childhood cancer survivors, we think about children who’ve been treated with radiation therapy as being the most vulnerable to second cancers,” Turcotte said.

According to the results of a study that looked at women who had HD as children, those treated with mantle radiotherapy and chemotherapy were at higher risk of developing breast cancer than women who did not receive such treatments.⁷ The researchers also noted that the type of breast cancer in this population differs than from that developed by other young women with breast cancer. Women who had HD tended to develop bilateral breast cancer and the tumors were generally located near the midline of the body.

Table. 15-Year Follow-up of Patients Previously Diagnosed and Treated for Cancer⁸

Turcotte led a study on subsequent neoplasms among 5-year survivors of childhood cancers, which was published in March 2017 in JAMA. This study found that, while survivors of child- hood cancers in the 1990s are still at higher risk of developing a second cancer, the number is lower than it was for children who were treated for cancer in the 1970s (Table).⁸Researchers looked at 23,603 childhood cancer survivors who were a mean age of 7.7 years at time of initial primary cancer diagnosis. The most common primary cancer diagnoses were acute lymphoblastic leukemia (ALL), HD, and astrocytoma, a brain tumor. The mean follow-up ranged from 15.7 years for survivors who were diagnosed in the 1990s to 27.5 years for survivors diagnosed in the 1970s. The findings showed that children treated in the 1990s had a significantly lower 15-year cumulative incidence of subsequent malignancies compared with those treated in the 1970s and 1980s.

Along with advances in chemotherapeutic agents that result in better treatments and fewer adverse events (AEs), clinicians have been trying to decrease radiation doses when treating all patients, especially children. “As we’ve shown with this study, this has been associated with decreased risk for a second cancer over the last decades, and these efforts have continued even beyond the time frame of the cohort,” Turcotte said.

Although radiation therapy does play a significant role in the development of some secondary cancers, certain chemotherapies also put patients at higher risk, as has been previously noted. “We know that a class of chemotherapy called epipodophyllotoxins (like etoposide) and alkylating agents put patients at higher risk for secondary leukemia,” Turcotte said. Alkylating agents that are known to cause myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) include cyclophosphamide, melphalan, and lomustine.⁹ Platinum-based agents also increase the risk of AML in particular, but not as much as alkylating agents.

Secondary Cancers Versus Second Cancers

Turcotte explained that one of the next steps within the childhood cancer survivor study is to more thoroughly investigate multiple chemo- therapy agents to better understand whether they may play a greater role than has been previously understood in second cancers. “I think that will be easier to tease out now that we are using less radiation. There are going to be more children who are only exposed to chemotherapy in the cohort,” she said.Having cancer twice does not necessarily mean that the second cancer is a secondary malignancy. For example, woman with deleterious germline BRCA mutations are at higher risk for breast cancer and ovarian cancer. If a woman develops and survives breast cancer related to BRCA, and years later develops ovarian cancer, they are not directly related. “The development of that rst cancer isn’t what increases the risk,” VanderWalde said. “It’s the genetic syndrome itself.”

Developing a second cancer can also be related a risk factor shared by the first and second cancers. “For example, a person with colon cancer is more likely to develop a new second colon cancer,” VanderWalde said. “Some of those are because of genetic syndrome, some of them are just because of shared lifestyle that causes the same risk factor. We suspect, for example, that obesity, certain types of diets, and lack of exercise can predispose somebody to developing colon cancer. After they’re cured from that colon cancer, those risk factors stay the same. Whether they’re due to genetic risk factors or environmental risk factors, we really don’t know.”

Immune-Modifying Therapies

Smoking is another lifestyle risk factor for second cancers unrelated to the first cancer. “That tends not to be described as much because, at least until relatively recently, people with advanced lung cancer often didn’t become cancer survivors for long periods of time,” VanderWalde pointed out. “As a result, we didn’t see long-term survival that could have allowed for a second cancer to develop.”Immunotherapy, particularly PD-1/PD-L1 pathways inhibitors, are having a significant impact on cancer survival among patients with some advanced cancers. However, whether immunotherapy can decrease the risk of secondary malignancies is unknown.

At first glance, this may be the case. VanderWalde pointed out that patients treated with immunotherapy could be spared the harsh effects of chemotherapy and radiotherapy. However, immunotherapy also may be given in conjunction with either therapy, thereby increasing the risk, particularly if a combination regimen makes radiation therapy more potent. “This is all very hypothetical,” VanderWalde said. “We don’t know that it does any of these things, but if it magnifies the effect of radiation, it actually might make the second cancer risk worse, almost paradoxically.”

The overall long-term outcomes of immunotherapy are not yet known, especially with children. “I do wonder whether there will be some populations like the children with high-risk neuroblastoma, who experience more second malignancies as their treatment intensifies,” Turcotte said.

And, as VanderWalde noted, treatment with immunotherapy is still in its infancy. It has only been used for a relatively brief period, and it tends to be used in cancers that are otherwise very aggressive. “We don’t have a lot of long-term survivorship data on melanoma, lung cancer, kidney cancer or bladder cancer, which are the diseases that are right now being treated with immunotherapy,” he said. “We don’t know what cancers these patients would have developed had they survived a long time.”

Targeted Therapy

Meanwhile, clinical trial findings have shown an association between regimens that include lenalidomide (Revlimid), an immunomodulatory drug, and secondary primary malignancies.¹⁰ An increase in secondary cancers including AML and MDS has been reported among patients with newly diagnosed multiple myeloma treated with lenalidomide in combination with melphalan compared with melphalan alone. In patients who received lenalidomide maintenance therapy in 2 large clinical trials, the incidence of hematologic plus solid tumor secondary primary malignancies (excluding squamous cell and basal cell carcinomas) was 14.9% compared with 8.8% of participants who took placebo after a median follow-up of 91.5 months.¹⁰ Patients are advised to weigh the potential benefits and risks of lenalidomide therapy with respect to second cancers.Although targeted therapy has been in use for 20 years, investigations continue into whether there is a connection between these agents and secondary malignancies. The results of a study published in 2012 showed vemurafenib (Zelboraf), a BRAF inhibitor used to treat BRAF V600E-positive unresectable or metastatic melanoma, may trigger a response in patients who also carry RAS mutations, resulting in skin squamous cell cancers.¹¹

Treating Secondary Malignancies

A 2016 study found similar results among patients taking dabrafenib (Tafinlar), another BRAF inhibitor, for non—small-cell lung cancer.¹² Among 84 patients, 35 experienced serious AEs. According to the authors, cutaneous squamous cell carcinoma was among the most frequent grade 3 or worse AEs, affecting 10 patients (12%), followed by basal-cell carcinoma in 4 patients (5%).Determining optimal therapy for secondary malignancies may be more challenging than treating the first cancer, depending on the tumor type. The cancer generally considered most difficult to treat in general is leukemia, according to VanderWalde. “If a patient develops leukemia as a second cancer as a result of therapy, the risk of death from that leukemia goes up significantly. The cancer tends to be much more aggressive, much more difficult to treat, so those diseases can be much more deadly even than non-therapy— related leukemia.”

Screening for Secondary Malignancies

He pointed out that strategies for other cancers, such as the solid tumors in colon cancer, breast cancer, and lung cancer, tend to be about equal in terms of treatment, whether they are primary or secondary cancers. However, what could make secondary cancers easier to treat is early recognition. By knowing that patients are at risk for these cancers, screening programs may find the malignancies in their earlier stages.Knowing that the risk of a secondary malignancy is higher for cancer survivors, effective screening programs and adherence to screening is vital to catch any resulting cancers as quickly as possible, experts say. As a result, there should be a focus on appropriate secondary screening and clinicians should not depend on general population screening programs.

For example, regardless of age, a woman who has had breast cancer should be getting yearly mammograms on the opposite breast if she’s had a mastectomy and on the affected breast if she had a lumpectomy. Individuals who have had colon cancer should be undergo colonoscopies the year after their diagnosis, and then regularly thereafter, again regardless of their age.

Counseling Patients and Families

The recent American Society of Clinical Oncology guidelines for head and neck cancer survivors emphasize surveillance for secondary primary cancers.¹³ The recommendations suggest a risk stratification approach; for example, patients who are smokers should be followed more closely than those without that risk factor.Oncologists know about the increased risk of second cancers among their patients, so counseling is important, particularly encouraging patients to reduce their risks through lifestyle changes and adherence to screening recommendations. Despite that risk, however, oncologists do not want to undertreat the primary cancer for fear of what might happen years later.

“We really hope that we can have people survive long enough with some of these terrible diseases because of these new therapies, that we end up running into some of these problems,” VanderWalde said. “These are problems that are a result of success, not a result of failure, and hopefully we’ll find ways that we can limit them, and yet still give patients the best chance of survival when they have their first cancer.”

According to Turcotte, the most important message clinicians should take away from the research is that there has been good progress in reducing a second cancer risk. “We can mostly attribute that to the reduction in radiation therapy,” she said. “I think that’s a positive thing that we can share with our patients and their families as they’re going through their journeys.”

References

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