Karen Blum

KAREN HANNA says it was interesting to be on a clinical trial testing a maintenance therapy she would later be prescribed. 

Karen Hanna was first diagnosed with ovarian cancer in April 2013. At the time, she underwent a debulking (tumor burden reduction) surgery and received chemotherapy. 

Then her oncologist asked if she would like to enter a clinical trial testing a new type of drug called a PARP inhibitor, which her doctor hoped would become maintenance treatment one day. Hanna gladly volunteered.

By the time Hanna’s cancer recurred in November 2018, her oncologist had good news: the maintenance therapy was now approved by the Food and Drug Administration (FDA) and she would be eligible for it following another round of surgery and chemotherapy. She started the treatment, called Lynparza (olaparib), in February 2020.

She first heard about the potential for maintenance treatment in 2013. 

“I didn’t think much about it because I was just in survival mode,” says Hanna, now 50 years old, of Oklahoma City. “It’s kind of interesting that you’re in a clinical trial for a PARP inhibitor in hopes (it) will show that maybe it will be of benefit one day as maintenance therapy. And seven years later, you’re using it as maintenance therapy.”

Maintenance therapy is given after a patient completes chemotherapy to decrease the chance that the cancer will come back or to delay it from recurring, explains Dr. Kathryn P. Pennington, an assistant professor of obstetrics and gynecology at the University of Washington in Seattle.

“It’s given to continue or maintain the good results of a prior treatment,” Pennington says. “The idea behind it is that it is often better tolerated than traditional chemotherapy, so it’s something that someone could be on for a long time and feeling well, while hopefully delaying the cancer coming back.”

Maintenance therapy is an option for women with stage 2, 3 and 4 cancers that respond well or very well to surgery and platinum-based chemotherapy, according to the National Comprehensive Cancer Network (NCCN). 

Options for therapy depend on whether a person has a germline (inherited) mutation in the BRCA1 or BRCA2 gene or if their tumor is considered homologous recombination deficiency (HRD) positive, meaning the tumor is unable to repair double-strand breaks in DNA and is determined by gene sequencing characteristics. Options also depend on whether a person’s primary chemotherapy regimen included Avastin (bevacizumab).

Two types of targeted therapies are used in this setting. Avastin works by inhibiting vascular endothelial growth factor (VEGF), a protein that helps cancer grow blood vessels for food and oxygen. And PARP inhibitors that stop cancer cell DNA from being repaired by a protein called PARP, so that damaged DNA stays at a level that causes cells to trigger their own death, constraining tumor growth. Three PARP inhibitors are approved by the FDA for ovarian cancer: Lynparza, Rubraca (rucaparib) and Zejula (niraparib).

Depending on the drug, patients should receive maintenance therapy for 15 months to three years. The goal is to stop, says Dr. Kathleen Moore, the Virginia Kerley Cade Endowed Chair in Cancer Development and a professor of gynecologic oncology at the University of Oklahoma College of Medicine in Oklahoma City.

“Patients who have evidence of disease, and (for whom) you’re holding things stable, … need to continue for as long as they’re receiving benefit,” she says. “But for patients who are in a complete response, I do think it’s important to stop, because some of those patients may not recur ever, or for many years.” 

Additionally, there is a sense that continuing on a PARP inhibitor could lead to a less robust response to subsequent chemotherapy if cancer recurs, Moore notes.

The rationale behind maintenance therapy is based on two principles, according to Dr. Robert L. Coleman, chief scientific officer at US Oncology Research, in Woodlands, Texas. One is that as many as 20% to 30% of patients will have a recurrence of their cancer in a short period of time following treatment, even if it doesn’t initially show up on biomarker tests or imaging studies, he notes.

“Many years ago, we used to assess the quality of the initial response by operating,” says Coleman, who is also a gynecologic oncologist at Texas Oncology. The procedure is called second-look surgery. “When we looked for cancer in patients who didn’t have any other overt evidence of disease, we would ultimately find residual disease in about half the patients. So we knew this strategy probably wasn’t very sensitive or specific with respect to the disease being gone.”

A second principle is that maintenance therapy, when used to prevent cancer recurrence, also can shrink tumors if it’s active against cancer or has anti-cancer activity, Coleman adds. “Patients are getting even deeper responses while they’re taking the therapy, so in that context, maintenance is actually a form of additional treatment,” he says.

Hanna says her experience on Lynparza since February 2020 has been positive, and she has tolerated the therapy well.

“I might have had a little fatigue up front,” she says, but she remembers telling her doctor at the four-month mark that it didn’t feel as though she was taking anything. “I try and take very good care of myself,” she adds. “I exercise six days a week, I eat very healthy (foods). I’m very mindful about living a healthy lifestyle.” 

She also has a busy career in pharmaceutical sales and serves on boards of directors for different organizations. “I’m going and going and going all of the time. So if I am experiencing fatigue from this pill, I don’t know it.”

February 2022 marked her two-year check-in being on maintenance therapy. Her scans and blood markers looked good enough that her oncologist wanted her to remain on the treatment for one more year. If she continues to do well, she’ll then stop therapy.

Hanna is one of thousands of women who have done well on maintenance therapy. For such patients who have a mutation in either the BRCA1 or BRCA2 gene, maintenance therapy medications are “extremely effective,” says Pennington.

For example, investigators of a clinical trial called SOLO-1, which evaluated Lynparza after primary treatment for patients with BRCA1 and BRCA2 mutations, found that the drug delayed cancer recurrence by more than 40 months at the median. It also lowered the risk of cancer progression or death by 70% compared with a placebo, she says.

Other trials also have demonstrated benefits of the therapies. Results from the PRIMA study, which examined Zejula in patients who had responded to platinum-based chemotherapy, showed that the drug delayed disease progression for people with BRCA1 and BRCA2 mutations by 11 months compared with placebo. 

The drug delayed cancer progression by a similar length of time among patients who did not have a mutation but whose tumors had HRD. In contrast, the drug delayed cancer progression among people who had tumors without BRCA1/2 mutations or HRD by just three months.

KIM BELL says that the severe fatigue caused by her maintenance therapy has forced her to cut back on her business.

Kim Bell, 58, of College Station, Texas, started maintenance therapy with Lynparza and Avastin in February 2022. Bell was treated for stage 3 ovarian cancer in 2021 and had surgery followed by six chemotherapy treatments. She had an Avastin infusion in early February, with repeat infusions every three weeks, and takes Lynparza pills twice a day. 

®, she was scheduled for imaging tests to see how well the treatment was working.

Her experience has been a little different from Hanna’s.

Lynparza “causes severe fatigue for me since I’m taking 600 (milligrams) a day,” says Bell, who has had to cut back a bit on her floral design business due to her lack of energy. 

“After periods of rest or sitting, it takes me a few steps to move normally since it is affecting my joints and muscles a great deal, as well as my back. My doctor and specialty pharmacist indicated that many patients see side effects subsiding after a couple of months, and I’m only two months in to taking the drug. I generally don’t have any side effects from my (Avastin) infusions.”

Although she says she doesn’t want to quit the therapy because of the potential benefits, she notes she plans to ask her doctor about reducing the dose to see if that helps. That option had been presented to her during discussions before starting the therapy.

Fatigue, nausea, vomiting and low blood cell counts are among the most common symptoms with Lynparza, according to the NCCN. Anemia or myelodysplastic syndrome, a cancer in which the bone marrow does not make enough healthy blood cells, are rarer.

Patients “feel like a wet noodle,” Moore says. “They’ll say over time they accommodate to it and they’re able to do everything they want to do, but they do feel this level of fatigue that is real and needs to be acknowledged.” 

Despite that, “their quality of life, even though they may have more side effects, does not appear to be diminished,” Coleman notes, “so it seems to be what we could call a tolerable regimen.”

As the science continues to evolve, oncologists are looking forward to additional or refined treatments including combination therapies. HR proficient tumors is one area ripe for improvement, Pennington says. 

“It would be ideal to find a maintenance therapy where we could do better than that three months’ magnitude.”

Another concern is what to do with patients whose cancer recurs even after treatment with PARP inhibitors, she adds. Should they be prescribed PARP inhibitors again? Are there ways to restore PARP resistance? Could the inhibitors be combined with another chemotherapy or medication to make it sensitive to PARP inhibition again? 

This is an area of active study, says Pennington, investigating combinations of PARP inhibitors with other drugs, such as agents that inhibit the ATR protein or those that block the growth of blood vessels that support tumor growth. Analysis of tumors that recur after PARP inhibition may be able to reveal specific alterations that could inform new therapies.

“Even in patients who are really good candidates for a therapy, we find some who still have recurrence and progression,” Coleman says. “Better treatments are always going to be an unmet medical need for our patients.”

There are potential opportunities for additional maintenance therapies using a newer class of drugs called antibody-drug conjugates, he notes, especially among patients that don’t have BRCA 1/2 mutations. 

Some of these are in clinical trials launching now, Moore points out. “There’s probably going to be a lot of development in this space moving forward.”

For now, Hanna says she encourages patients to give maintenance therapy a try. 

“This is the biggest breakthrough for ovarian cancer in decades, and one that is showing very promising outcomes … and extending the lives of ovarian cancer patients, which is huge,” she says. “Embrace it, don’t be afraid of it. The odds of you being able to tolerate this are in your favor. … Go into it knowing that this is something that can hopefully get you to the next best option that is coming in the future.”

She also encourages patients to stay positive and to believe that “your mind is your greatest weapon.” Staying in a positive and grateful framework makes a difference, she says, “I truly believe that.”

Bell agrees. Hearing from her doctor that her body could adjust to the medications, making the side effects more tolerable, “gave me hope that at least there’s a light there and I can work toward that light, push through, and get there.”

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Articles

Although maintenance treatments have helped patients with ovarian cancer live longer, experts note there are still some unmet needs that must be addressed. 

Maintenance Therapy the 'Biggest Breakthrough in Decades' for Ovarian Cancer

Michael Kimbarow was 13 years old in 1966 when he received a diagnosis of Hodgkin lymphoma. Doctors surgically removed a tumor within the parotid (salivary) gland on the left side of his face and applied radiation treatments to the area. He was then considered cancer-free and went on to live his life.

Nearly 40 years later, Kimbarow was working as a professor of communicative disorders and sciences at San Jose State University in California when one day, the left side of his face started to droop and became paralyzed.

A series of tests revealed a secondary cancer — a parotid tumor, which doctors thought was a late effect of the radiation he had received decades before. In contrast to the lymphoma that originated from lymphocytes in the parotid gland area, the second cancer arose from the parotid gland cells, likely induced by radiation.

“I was really just devastated to hear that I had another cancer,” says Kimbarow, now 69, “and I didn’t know at that point what all of the implications were.” But he continued to work while undergoing treatment, and a year later underwent reconstructive surgery to restore some facial symmetry.

Kimbarow’s experience is not isolated. Nearly 1 in 5 cancers diagnosed today occurs in an individual with a previous diagnosis of cancer, according to the National Cancer Institute.

The term “secondary cancers” can be confusing, explained Dr. Stephanie Schaub, an assistant professor of radiation oncology at the University of Washington in Seattle. She usually describes them to patients as “new and different tumors caused by treatments,” such as radiation, chemotherapy or targeted therapy. “That helps just emphasize to patients that it’s not their (original) tumor coming back.”

Treatments such as radiation or radioactive iodine (for thyroid cancer) are one known cause of secondary cancers. Chemotherapy can later 

. The hormonal therapy tamoxifen, used to treat breast cancers, increases the risk of developing uterine cancer later on. Despite associations such as these, the benefits of cancer treatment far outweigh the risk of developing secondary cancers, according to experts.

However, not all secondary cancers are caused by earlier treatment. Other risk factors include 

family history, or genetic predisposition

. Certain racial and ethnic groups, such as Ashkenazi Jews, have a higher prevalence of mutations to the BRCA1 and BRCA2 genes associated with breast, ovarian and pancreatic cancers. People with a family history of ovarian cancer may be at higher risk of developing the condition, too, as genetic mutations can be inherited. Some secondary cancers are unrelated to the initial cancer.

Age also plays a role. People like Kimbarow who are first diagnosed with cancer as a child or adolescent, or under age 45, are at a higher likelihood of experiencing a secondary cancer later, as the risk of cancer increases with age.

Exposure to environmental pollutants such as cigarette smoke is also a contributing factor. And some cancers themselves promote a higher risk of secondary cancer. People with chronic lymphocytic leukemia and non-Hodgkin lymphoma, for instance, have a higher than normal risk of developing other cancers such as skin cancers, says Dr. David A. Bond, a hematologist at The Ohio State University Comprehensive Cancer Center in Columbus.

Overall, a decrease in the immune system associated with the initial cancer can increase the risk of developing a secondary cancer, explains Dr. Jennifer A. Woyach, a hematologist-oncologist at Ohio State. This is especially true in cases where the epithelium, the lining of the body’s tissues, is damaged, such as skin cancers associated with damage caused by ultraviolet light.

In general, secondary cancers take at least three to five years to develop, but the majority are seen years to decades after the initial diagnosis of a patient’s original tumor, Schaub says. The risk can depend on many factors such as younger age, genetic predisposition and treatments given for the original tumor.

If it’s genetic, each gene has its own peak in incidence for secondary cancer, mentions Dr. Siddartha Yadav, a breast and gynecologic cancer specialist at Mayo Clinic and an assistant professor of oncology at Mayo Clinic College of Medicine in Rochester, Minnesota.

Adding complexity, it may not always be easy to tell if a new cancer that develops is related to treatment for the first cancer, says Schaub.

The biggest indicators are the type of new tumor that develops, coupled with the prior therapies received. If a teenager with Hodgkin lymphoma is treated with radiation to the chest and later develops a breast cancer within the area that received radiation, the new cancer is likely linked to treatment. However, no pathologic or genetic studies are available to date to prove the association between new and prior cancers, she explains.

That’s the case for Mary Lou Smith. Smith, who is over 70 and lives in the Chicago area, has survived three types of cancer. She received a diagnosis in her early 40s with early-stage ductal carcinoma in situ (DCIS) breast cancer and had a second DCIS 21 years later.

Smith had ovarian cancer about eight years after the second breast cancer, followed by colon cancer three years later. The breast and colon cancers were detected through routine screenings, and the ovarian cancer was found based on Smith reporting symptoms. After myriad treatments and follow-ups, Smith is considered as having no evidence of disease (NED). Two types of genetic testing found nothing to suggest she is at risk of developing cancers, but Smith finds it hard to believe she doesn’t have some genetic predisposition.

“When I got a second breast cancer, I was really angry,” she says. “In my head, I had done that … I was moving on. With the ovarian cancer, I was very frightened. I knew that was lethal, and by the time it’s found there’s not much to do except a lot of treatment. … With the colon cancer, I was just irritated to be honest. Like, 

Cynthia Chauhan says she took her secondary cancer as a sign to do new things. She left her job as a clinical social worker and took up rock climbing, drawing and painting.

Cynthia Chauhan, too, has had several bouts with cancer. Her first cancer was detected in 1998, when she was hospitalized for a surgical procedure and started having significant pain. Imaging tests revealed a tumor in the center of one of her kidneys. Cancer specialists at Mayo Clinic, where she was seen, surgically removed the kidney and continued to monitor her.

Three years later, while waiting to undergo a routine mammogram, Chauhan thought about an aunt who had died from inflammatory breast cancer. The next thing she knew, Chauhan herself was sitting down with a radiologist to discuss the findings, which had identified a DCIS breast cancer.

“It was scary,” says Chauhan, now 79, of Wichita, Kansas. “I (already) had been through a pretty rough sequence with the kidney cancer.” But she mentions she was not overwhelmed by the diagnosis because she felt she was in a good medical center for treatment and care.

Chauhan took her secondary cancer as a sign to do new things. She left her job as a clinical social worker and took up rock climbing, drawing and painting.

“Those are ways that allowed (me) to see myself differently,” she explains, and they enabled her to support herself emotionally while going through radiation treatment.

She also used visualization techniques, calling on her love of gardening. She began thinking of her breasts as a beautiful garden of flowers that had been invaded by a weed that needed removal. Today her status also is considered NED.

Kimbarow, Chauhan and Smith all say their doctors didn’t talk to them about their risk of developing secondary cancers. Cancer still had a lot of stigma attached to it in the 1960s, Kimbarow says: “It was still kind of whispered about. So we really didn’t talk too much about it.”

Smith recalls seeing information about secondary cancers in reading material given to her about the carboplatin and paclitaxel drugs she was prescribed for ovarian cancer.

“By that time it was like, ‘Oh well, what do you want me to do about that? I want to live today, so I’ll take a chance on five years down the road,’” she relates.

Fortunately, times are changing. Woyach and Schaub note that they discuss the risks of secondary cancer with their patients during the initial visit.

“I think sometimes people have this impression like, ‘I already have one cancer, so I don’t need to worry about something else. I have enough on my plate,’” Woyach says. “But it’s really important to continue other recommended, age-appropriate screenings.”

Depending on the type of treatments given, there may be adjusted screening recommendations to allow for earlier detection and/or prevention of secondary cancers, explains Schaub.

Throughout the cancer journey, whether secondary or primary, support and self-advocacy are crucial, Chauhan and Smith note.

“It’s important to have a caregiver who is very supportive and to understand that you are the most important person in your cancer care team,” Chauhan says. “You have a right and almost a responsibility to advocate for yourself, … to ask questions and to expect to get meaningful, understandable answers to those questions, and then to really focus on how you can best take care of yourself as you go through this.”

For example, back when Chauhan’s physician told her he was 98% sure she had kidney cancer and wanted her to schedule surgery the next day, Chauhan asked to hold off so she could do her own research, make a list of questions and have all her concerns answered before the procedure. “The surgeon reluctantly agreed,” she says.

Smith added her own advice: Make sure you attend all appointments for treatments and follow-up care and keep track of your health. “It is important to know your own body. If you feel there’s something
that isn’t going the way it should, then tell someone.”

Secondary cancers generally are diagnosed based on a patient’s symptoms or routine screenings and follow-up care. Oncologists monitor some cases more closely, Yadav points out, such as for patients who receive chemotherapies known to be associated with second cancers or who receive PARP inhibitor drugs associated with blood-based cancers.

Some secondary cancers identified early, such as skin cancers, are more likely to be curable and can be screened for easily, Woyach explains. But blood cancers such as myelodysplastic syndrome or acute leukemia tend to be more subtle and come on slowly, and don’t have as many screening tests.

Treatment for secondary cancers generally is the same as for primary cancers, but there are times when oncologists have to consider additional options. Prior cancer therapies may have limited a patient’s reserves to tolerate a full dose of radiation therapy, Schaub says, or make it more difficult to perform surgery in a particular area. Chemotherapies also may be limited. One routinely used in breast cancer called doxorubicin should only be prescribed as a limited dose over a lifetime, according to Yadav. If a patient develops a secondary cancer for which the standard of care would be giving them the same drug, it becomes challenging.

“Really, it does become an individualized, thoughtful approach to patient care,” Schaub says. “There’s definitely no exact textbook (recommendation) for how to treat them.”

Kimbarow has been taking anti-cancer medications off and on since 2018 for lung tumors thought to be a metastasis from his 2006 parotid tumor. But he doesn’t worry about it or let it slow him down, saying he has two mantras: “The first is that I refuse to stop living before I die. And the second is that I’ve yet to read any scientifically peer-reviewed study that shows or demonstrates that sitting in a dark room feeling sorry for myself will improve my outcome. Until I do, there’s no point in it, so I just move forward day by day and enjoy it.”

Although no surefire way exists to prevent the development of subsequent cancers, cancer survivors can take steps to boost their health. Most important, mentions Woyach, is to undergo any recommended cancer screenings. Any young woman who had radiation to the chest under the age of 30 should be screened twice a year for breast cancer beginning eight years after completing radiation, using MRI and mammograms, notes Bond. Survivors of chronic lymphocytic leukemia and low-grade lymphomas should undergo skin cancer screenings at least annually, he says.

Also understand that if a patient has a genetic profile that increases their chance of developing a secondary cancer, they should be screened, Yadav says. If they haven’t had genetic testing, Yadav recommends they ask their oncologist if that might be right for them.

If there are no related genetics or family history, patients are advised to control other lifestyle and environmental factors. Experts advise patients the following: don’t smoke; limit sun exposure and use sunscreen; eat a healthy diet; increase consumption of fruits, vegetables and other vegetarian foods; and decrease consumption of meat.

Exercising also may reduce the recurrence of cancers, Yadav explains. “This can be just walking around … it does not have to be full cardio exercise, but it should be a minimum of one hour, three to four times a week,” he advises.

Cancer researchers are continuously working to develop newer treatments with fewer side effects while also trying to understand their association with risks for developing secondary cancers. Proton therapy, a newer form of external beam radiation therapy that minimizes radiation to healthy tissues surrounding a tumor, or immunotherapies that reinvigorate the body’s natural immune system to fight cancer eventually may be affiliated with fewer secondary cancers.

Research in breast and other cancers focuses on the genetic risk of developing secondary cancers, Yadav says. He also notes that over the past 20 years or so, scientists have found that genes such as ATM, CHEK2 and PALB2 cause breast cancer and are associated with secondary cancers. Current studies are looking to pinpoint what an individual’s risk is and what factors can modify that risk. Other studies are focused on the nature of secondary cancers and potential prevention.

“Right now, our recommendations are saying, ‘OK, if you’re genetically predisposed to developing ovarian cancer, we need to take the ovaries out,’” Yadav explains. “But are there other ways beyond doing surgeries? It’s not quite (at the point) where we can take certain medications and prevent secondary cancers … but that’s the goal.”

Kimbarow’s attitude has been so positive that his oncologist featured him as one of three patients in a talk on people who didn’t give up and showed remarkable response to treatment.

“Don’t stop living before your body gives out on you,” Kimbarow says. “You never know what the next therapy is that’s right around the corner. … The advances in science are amazing.”

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Although certain cancer treatments have been linked to an increased risk of a secondary cancer years later, an expert notes there are no genetic or pathologic studies that prove the association between new and previous cancers.

Karen Blum

Maintenance Therapy the 'Biggest Breakthrough in Decades' for Ovarian Cancer

What Happens When a Patient Develops a Secondary Cancer Years After Undergoing Treatment?

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