Managing Ovarian Cancer Recurrence

When Seana Roubinek, 52, learned in fall 2011 that she had ovarian cancer, her son, Jordan, was just 13 years old. She knew the statistics for her stage 3c diagnosis, but Roubinek’s goal was to survive long enough to see him graduate from high school.

Now, eight years later, she is a few months away from seeing him graduate from college. Roubinek is one of the more than 22,000 women each year who receive an ovarian cancer diagnosis in the United States and also one of the approximately 70% of patients who will experience disease recurrence.

Patients like Roubinek, who are surviving years from diagnosis are a reflection of the treatment advancements made in recent years, according to Dr. Stephen C. Rubin, chief of gynecologic oncology at Fox Chase Cancer Center in Philadelphia. “We have a lot of new and beneficial treatments to offer people that are extending how long they are able to live with ovarian cancer,” he says.

A SURPRISE DIAGNOSIS

In 2006, Roubinek’s family practitioner advised her to undergo genetic testing because both sides of her family have a history of breast cancer. It was then that she learned she has a BRCA1 mutation. BRCA mutations put women at higher risk of developing breast and ovarian cancer and increase men’s risk of breast and prostate cancer. By age 80, about 72% of women with a BRCA1 mutation will develop breast cancer and about 44% will develop ovarian cancer.

Roubinek began getting regular mammograms and breast MRIs, alternating every six months, and was advised several years later to consider the removal of her ovaries and fallopian tubes through a surgery called salpingo-oophorectomy to help reduce her ovarian cancer risk. She elected to have the procedure, and the surgeon incidentally discovered ovarian cancer. She learned how advanced her disease was following debulking surgery to remove the cancer.

In its early stages, ovarian cancer doesn’t typically cause symptoms. But when it does common signs include bloating, abdominal pain and feeling the need to urinate urgently or often. Most women with the disease, including Roubinek, don’t experience those symptoms, which is why more than 70% of cases are diagnosed at an advanced stage.

“Hindsight being 20/20, though, I realized I had been complaining to my family practitioner about chronic fatigue and lower back pain for a couple of years,” says Roubinek, who lives in Rockport, Maine. “Both are symptoms of ovarian cancer, although less common ones.”

Roubinek had serous carcinoma, the most common type of ovarian cancer, which accounts for more than half of diagnoses. Less common types include clear cell, mucinous and endometrioid carcinoma. The rate of recurrence doesn’t vary greatly by disease subtype but rather by the stage.

“Patients with stage 1 disease have a 10% recurrence risk over five to 10 years,” says Dr. Robert L. Coleman, a professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center in Houston. “In contrast, patients diagnosed at stage 3 or 4 have an 80% chance for recurrence over the same time frame.”

How quickly the disease recurs depends on several factors, such as BRCA mutation status, tumor grade, how much of the tumor could be surgically removed and whether the tumor responds to a common class of initial treatments called platinums.

DISCOVERING RECURRENCE

In 2016, Philadelphia native Lizbeth Brunswick found out her ovarian cancer had returned about two years after completing her initial treatment for stage 3 ovarian cancer at Fox Chase under the care of Rubin. Similar to Roubinek, Brunswick has a BRCA mutation. However, her mutation is somatic, meaning she did not inherit it. Women with somatic BRCA mutations tend to receive cancer diagnoses at an older age compared with those with inherited mutations.

“I really thought I would be the girl who would go into remission or whose cancer would go away, because I was always pretty fit and healthy,” says Brunswick, who is now 66. “But I know my body pretty well, and I could always tell when something wasn’t right.”

The current standard of care for patients who complete initial chemotherapy and go into remission is to undergo blood screening every three months to check levels of cancer antigen 125 (CA 125). This protein can be elevated in patients with ovarian cancer before they experience any physical signs, according to Dr. Ursula A. Matulonis, chief of the division of gynecologic oncology at the Dana-Farber Cancer Institute in Boston.

“Follow-up imaging with CT scans is not recommended to be done on a routine basis,” Matulonis says. “I order a baseline scan after chemotherapy has been completed, but for the most part, we are following the patient history, CA 125 level, how the patient is feeling and findings on physical exams.”

Brunswick’s intuition was correct. During a follow-up visit, Rubin told her that her CA 125 levels were rising and her cancer was back.

“There was a trial published several years ago that looked at CA 125 and showed that its early detection did not improve overall survival but instead increased patient distress,” Matulonis says. “However, as more effective treatments are becoming available, physicians should not be waiting until patients develop symptoms of their cancer recurrence to start treatment.”

Roubinek had a similar experience. She underwent initial treatment for her ovarian cancer as part of a clinical trial testing IV delivery of chemotherapy compared with intraperitoneal delivery, in which the drugs are adminis- tered directly into the area of the abdominal organs.

More importantly, everyone on the trial was treated with the drug Avastin (bevacizumab), which was not approved for ovarian cancer at that time. Avastin is designed to help cut off the tumor’s blood supply.

“The treatment worked beautifully, and I had very few side effects,” Roubinek says.

The regimen kept her cancer-free for two years. During that time, she continued working and even completed the Boston Marathon. About one month after the race, Roubinek went for her every-three-month examination and bloodwork, which showed elevated CA 125 levels. A CT scan confirmed the cancer’s return.

WHAT NOW?

“One of the biggest unmet needs in ovarian cancer is coming up with effective therapies that can cure patients after disease recurrence,” Coleman says. “But that doesn’t mean that we haven’t made incredible progress in the last 15 years.”

One of the biggest improvements in care, he explains, is the growing specialization of gynecologic oncologists, who are trained in the use of surgery and chemotherapy for cancers of the reproductive organs. One study showed that women with ovarian cancer who live farther from a practicing gynecologic oncologist had significantly higher ovarian cancer death rates than nearby patients.

In the past, a second surgery may have been performed to remove as much cancer as possible before restarting chemotherapy. However, at least one large study showed that this additional surgery did not extend life for patients with recurrent disease.

Instead, chemotherapy or a targeted therapy is almost always the treatment of choice, says Rubin. Whether a patient receives additional chemotherapy often depends on length of remission, known in medical terms as “disease-free interval.”

“Our standard front-line drugs are typically carboplatin and Taxol (paclitaxel), with or without the addition of bevacizumab,” Rubin says. “If people go more than a year or

so in remission after these drugs, which is quite common, then they are very likely to respond again to re-treatment with carboplatin.”

Patient preference is also an important factor in chemotherapy selection, according to Matulonis. “You can use a lot of different drugs in combination with carboplatin,” she says. “Paclitaxel, for example, will lead to hair loss and/ or neuropathy. If your patient does not want to lose her hair again or already has neuropathy, you are probably going to want to stay away from paclitaxel and choose a different drug in combination with carboplatin.”

After recurrence, Avastin may also be combined with chemotherapy. Adding Avastin has been shown to extend progression-free survival by about four months compared with chemotherapy alone.

Many patients who respond to this second chemotherapy treatment will be advised to begin a PARP inhibitor as maintenance therapy, designed to keep the cancer away. “PARP inhibitors are oral agents that have considerable activity in ovarian cancer, particularly in women whose cancer occurred as a result of (a) BRCA mutation,” Rubin says.

About 50% of high-grade serous ovarian cancers have homologous recombination deficiency, a weakness in DNA repair. Its presence may predict response to PARP inhibitors. “We are learning more in the last year or two which patients are the best candidates,” says Rubin.

The Food and Drug Administration has approved three PARP inhibitors as maintenance therapy in ovarian cancer:

Zejula (niraparib), Lynparza (olaparib) and Rubraca (rucaparib). Rubraca is also approved for women whose cancer comes back a third or fourth time. All three drugs have been shown to extend a patient’s disease-free interval compared with no maintenance therapy.

Although PARP inhibitors are used only after disease recurrence, slowly mounting evidence suggests that they may be effective as an initial treatment for all patients with ovarian cancer.

After her recurrence in 2014, Roubinek re-treated her disease with carboplatin and liposomal doxorubicin, then enrolled in a clinical trial testing Lynparza as a maintenance therapy. The trial randomly assigned some patients to the PARP inhibitor and others to a placebo, but, based on her side effects, Roubinek is fairly confident she received Lynparza.

Gastrointestinal issues, nausea, fatigue and bone marrow suppression are the major side effects of PARP inhibitors, according to Coleman. At some higher doses, patients may experience anemia, low white blood cell counts or myelosuppression, a condition in which bone marrow activity is decreased.

“Some symptoms, like fatigue, can be mitigated with dose interruptions or reductions,” Coleman says. “Patients should be made aware ahead of time of what symptoms may be coming.”

Brunswick also re-treated her cancer with her front-line regimen, carboplatin plus Avastin, and then was given Zejula.

For maintenance therapy, Avastin also has benefit, but that benefit may be somewhat less than that seen with PARP inhibitors, Rubin explains.

Roubinek and Brunswick both had platinum-sensitive disease, meaning their cancer responded to treatment with platinum drugs. For women who are platinum-resistant, it’s a bigger challenge to determine the best second-line treatment. Some patients with platinum-resistant disease will undergo single-agent chemotherapy with a nonplatinum drug.

The common regimens include pegylated liposomal doxorubicin, Taxol, Gemzar (gemcitabine) and topotecan. In addition, treatment with Avastin combined with pegylated liposomal doxorubicin, Taxol or topotecan has some activity in women with platinum-resistant ovarian cancer recurrence. Finally, there is some evidence that women with platinum-resistant disease who have a BRCA mutation may respond to treatment with a PARP inhibitor.

Ultimately, finding the best option includes consideration of the patient’s treatment history, including side effects; convenience of treatment; cost; and patient preference.

LIFE WITH RECURRENT DISEASE

Having each faced two recurrences, Roubinek and Brunswick say the disease has changed their lives. “The first (recurrence) really socks you in the gut,” Roubinek says. “Each time you hear it is back is horrible, but with my second recurrence, I wasn’t as surprised, and I was able to more quickly focus on what needed to be done.”

She credits her ability to do that on the support she received at the Dempsey Center, located in Lewiston, Maine, which offers free programs and support to people affected by cancer. Roubinek and her son took advantage of the services, and she found that her participation with the center and the Ovarian Cancer Research Alliance, an advocacy organization, made her a more informed patient.

“Becoming knowledgeable, at least for me, has made having this disease less stressful,” she says. “I learned to advocate for myself when it comes to my health and to put myself at the top of the list of things to take care of.”

In contrast, Brunswick reveals that she put her faith in Rubin and his team. She turned to family and friends for much of her support. “So many people ask me how I have gotten through this, and I really believe that you have to be positive and make the most out of your life,” she says. “I didn’t want to stop enjoying my life just because I had this cancer, so I have tried to continue to live as normal a life as possible.”