AN ALARMING 38 PERCENT of women will develop cancer in their lifetimes, a statistic that has remained unchanged since the 1990s. Fortunately, the number of women who will die from cancer has decreased 19 percent over the same time frame. This decline is partly attributed to increased usage of screening tests that can detect some cancers at early stages, when treatments are more effective. For example, since the introduction of the Pap smear in the 1950s, more precancerous changes of the cervix are being detected early, and rates of cervical cancer have been steadily declining as a result.

In 2006, there was another major breakthrough in cervical cancer prevention with the introduction of a vaccine against the human papillomavirus (HPV), a sexually transmitted infection that causes the majority of cervical cancers as well as cancers of other male and female genital organs; it has recently surpassed tobacco use as a main cause of cancers of the oropharynx. The vaccine is highly effective at preventing HPV infection when administered before initial exposure to the virus during sexual contact. It is recommended that all girls and boys receive their first dose of the vaccine at age 11 or 12 years, and get a second dose at least six months later. These vaccines do not treat existing infections, but adolescents who have already been exposed to HPV through sexual contact can still receive it and have some protection against future infections.

Rates of HPV vaccination have been slowly increasing, but only about 50 percent of adolescent boys and 63 percent of girls in the U.S. have started the vaccine series, and only about 30 percent of countries worldwide include the HPV vaccine in their immunization programs. Some of this slow uptake in vaccine administration is due to safety concerns among parents. However, the vaccine has proven very safe, with most side effects being mild and transient, and studies have shown that adolescents who get the vaccine are no more likely to start having sex at a younger age. We are fortunate to have the technology to prevent and potentially eradicate a devastating and lethal disease, but rates of HPV vaccination must increase in the U.S. and worldwide if we are to achieve this goal.

While significant strides in preventing cervical cancer have been made, protecting women against ovarian cancancer remains a major challenge. Ovarian cancer is the ninth most common cancer affecting U.S. women, but the fifth leading cause of cancer deaths in that population. It is often diagnosed at an advanced stage, when symptoms become more apparent but treatments are less effective. A screening test is urgently needed if we are going to decrease ovarian cancer mortality. To date, efforts to discover a suitable screening test have been unsuccessful.

The most promising of these was thought to be for a protein called CA125. It is found at high levels in the blood of over 80 percent of women with advanced ovarian cancer, but in only 50 percent of women with early-stage disease. It is also present at abnormally high levels in about 1 percent of healthy women due to benign conditions. Therefore, measuring CA125 levels in healthy women results in a significant number of incorrect and missed diagnoses. Combining annual CA125 measurements with a pelvic ultrasound that directly visualizes the ovaries has also been evaluated as a screening test, but has not been found to decrease ovarian cancer mortality rates, and false positives may result in women undergoing unnecessary surgeries.

A more reliable strategy may be to track serial CA125 levels over time, and to perform a pelvic ultrasound if the level is increasing. This screening method was tested in over 200,000 women in the United Kingdom. More ovarian cancers were diagnosed at early stages in the group undergoing screening compared with women who received no screening, and while there was a suggestion that mortality rates were lower in those who were screened, the difference was not statistically significant, making the method not effective enough — at least for now &mdash; to adopt for widespread screening. Studies combining tests for CA125 with other tests for other substances in the blood known to be elevated in women with ovarian cancer are also ongoing, but, so far, no panel of tests has proven sufficiently accurate as a screening method. Because of the disappointing results of these studies, various national organizations agree that there are currently no recommended screening tests for ovarian cancer.

Until an ovarian cancer screening test is further refined, annual gynecologic exams and recognition of early symptoms are important strategies for diagnosing this disease. These symptoms include pelvic or abdominal pain, bloating, increasing abdominal size or becoming full quickly while eating. While other causes may explain many of these symptoms, they should not be ignored if they are new and persistent, and should be discussed with a doctor to determine if other tests are warranted. Women may also consult with their doctors about the potential value of more invasive methods of helping to prevent ovarian cancer: using birth control pills for at least five years or undergoing hysterectomy after completing childbearing.

Laurie Brunette, M.D., is a gynecologic oncologist at the University of Southern California, in Los Angeles.

Agustin C. Garcia, M.D., is hematology/oncology section chief, a professor of medicine and the Charles W. McMillin and Richard Paul Grace Chair in Cancer Research at Louisiana State University Healthcare Network Clinic, in New Orleans. His primary clinical and research interests focus on women’s cancers, particularly breast and ovarian, and drug development. 

Articles

Speaking Out

Preventive measures are being sought for cervical and ovarian cancers.

Reducing the Incidence of Women's Cancers

Like many diagnosed with ovarian cancer, RITA FERGUSON did not have obvious symptoms.

The five-year relative survival rate for all types of ovarian cancer is 45 percent. The American Cancer Society estimates that approximately 22,440 women in the United States will be diagnosed with ovarian cancer in 2017.

But ovarian cancer is rare, and it receives less research funding than some other cancers. The American Cancer Society, for instance, is currently funding $26.3 million in grants for ovarian cancer research, compared with $88.2 million in grants supporting breast cancer research.

Not helping matters is the lateness at which ovarian cancer is typically diagnosed, with most women at advanced stages of the disease when it is discovered. Because symptoms — which include bloating, pelvic or abdominal pain, issues with eating or feeling full quickly, and urinary urgency or frequency &mdash; could be associated with the menstrual cycle or any number of conditions, they often don’t send up a red flag until the disease has progressed. In addition, the capacity of the abdominal cavity and the ample protection of the organs within it make it more difficult for women to realize when something is amiss, says Robert L. Coleman, M.D., professor and vice chair of Clinical Research in the Department of Gynecologic Oncology at The University of Texas MD Anderson Cancer Center. “There’s nothing that would specifically indicate something is going on, even if the ovary is getting quite large,” he says. “It’s not that ovarian cancer doesn’t have symptoms, it’s just that none of them are specific for early ovarian change.”

Rita Ferguson thought she had diverticulitis. It wasn’t until she underwent surgery to resect her sigmoid colon that doctors discovered stage 4 ovarian cancer. “I had no expectation of cancer at all,” says Ferguson, who was diagnosed two years ago at age 67 and doesn’t have a BRCA mutation.

Much research has focused on the development of a noninvasive screening test that would identify the cancer at earlier stages, according to Coleman. Thus far, however, none have proved sensitive or specific enough to affect disease-specific mortality in the general population.

“Across the board, cancer research has seen a decrease in funding due to federal and institutional budget cuts. This has disproportionately impacted ovarian cancer research and clinical trials more than other cancer types,” says Elizabeth Swisher, M.D., a professor in gynecologic oncology and an adjunct professor in medical genetics at the University of Washington School of Medicine and director of the Breast and Ovarian Cancer Prevention Program at the Seattle Cancer Care Alliance. “If we want to make progress with making new drugs accessible to people to help them live longer and save lives, we need support for clinical trials.”

Side Note

Ovarian cancer is rare, and receives less research funding than some other cancers.

Challenges in Developing Ovarian Cancer Treatments

A NEW TARGETED THERAPY compound, mirvetuximab soravtansine (IMGN853), is being investigated as a monotherapy for patients with advanced, platinum-resistant epithelial ovarian cancer with high expression levels of folate receptor—alpha (FR-alpha) in the hopes of providing an effective option for a population facing a difficult prognosis.

The phase 3 FORWARD I trial, which is currently enrolling patients, is seeking to randomize 333 women in a 2:1 ratio to either the experimental mirvetuximab soravtansine or to chemotherapy consisting of investigator’s choice of paclitaxel, pegylated liposomal doxorubicin or topotecan (NCT02631876). If successful, the novel drug would offer an alternative to patients who have not responded to platinum-based chemotherapy, and possibly to individuals who have become resistant to chemotherapy.

“This is a bold initiative to try and bring what we think is a very active drug to market for patients who desperately need therapies,” says Kathleen N. Moore, M.D., a co-principal investigator on the study. “It’s an exciting trial, and we’re hoping for it to accrue quickly, so that we can get this drug to people who need it.”

Mirvetuximab soravtansine is an antibody—drug conjugate that targets FR-alpha, a cell-surface glycoprotein found on approximately 80 percent of epithelial ovarian cancer tumors; overexpression of receptors may be associated with negative outcomes in patients treated with chemotherapy, Moore and colleagues reported in earlier research.

One element that composes the drug is a monoclonal antibody, a laboratory-created protein that can bind to chemicals on the surface of cancer cells — in this case, the FR-alpha receptor. That monoclonal antibody is linked to a chemotherapy agent. Once in the body, the antibody delivers the drug to the tumor cell, where the chemotherapy agent is released; then, the molecule further diffuses into the surrounding tumor cells in a secondary effect.

The FORWARD I study is open to women with advanced epithelial ovarian, primary peritoneal or fallopian tube cancers that have been defined as platinum-resistant, meaning the disease has progressed within six months of treatment with platinum-containing chemotherapy. To be eligible, participants must have received from one to three prior chemotherapy treatment regimens.

Patients with platinum-resistant ovarian cancer currently have a poor prognosis; in the primary setting, the response rate to subsequent therapies is less than 20 percent, and in the acquired resistance setting, median overall survival is 21.9 months.

Mirvetuximab soravtansine “would give another option for standard of care, and it would introduce another drug for patients with platinum-resistant disease where there’s not much that works well at this point,” says Moore, associate director for clinical research and director of the TSET Phase I Drug Development Unit at the Stephenson Cancer Center in Oklahoma. “It would give another line of therapy that really has a very well-tolerated safety profile.”

In a phase 1 expansion study, mirvetuximab soravtansine demonstrated a confirmed objective response rate (ORR) of 26 percent among 46 patients with FR-alpha—positive platinum-resistant ovarian cancer, including one complete and 11 partial responses. The median progression-free survival (PFS) was 4.8 months and the median duration of response was 19.1 weeks. Notably, patients who had received three or fewer prior lines of therapy (n = 23) had an ORR of 39 percent, median PFS of 6.7 months and median duration of response of 19.6 weeks.

FR-alpha expression was determined by immunohistochemistry (IHC) testing on archival tissue, with samples put into categories. Low expression was defined as 25 to 49 percent of tumor cells having a staining intensity of 2 or more; medium meant that 50 to 74 percent of cells had an intensity of two or more; and high indicated that 75 percent of cells or more had a staining intensity of two or more.

Although most patients experienced tumor shrinkage regardless of FR-alpha expression level, participants with medium and high scores were more likely to respond, with median ORR rates of 28.6 percent and 26.1 percent, respectively.

Side effects in the phase 1 trial were generally mild (grade 2 or lower), with diarrhea (44 percent), blurred vision (41 percent), nausea (37 percent) and fatigue (30 percent) being the most commonly observed all-grade treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4 percent). There has been some neuropathy, according to Moore, observed in less than 10 percent of patients, and no reported alopecia compared with chemotherapy.

Similar side effects are expected during the FORWARD I trial, and investigators will be counseling patients about diarrhea and administering prophylactic medications. There is also a risk of keratopathy (a disease of the cornea), which surfaced in 12 patients (13 percent) at grades 1-2 severity in the phase 1 trial. Keratopathy “is 100 percent reversible, but we want to prevent it from happening rather than having it reverse,” says Moore. To achieve this, investigators are mandating the use of steroidal eye drops in the study protocol.

Moore notes that ease of administration is another benefit of mirvetuximab soravtansine treatment. Patients will receive the drug intravenously at a dose of 6 mg/kg every 21 days.

Looking toward the future, researchers also have opened the four-arm phase 1 FORWARD II trial in patients with advanced ovarian cancer, in which mirvetuximab soravtansine is being tested in combination with either the anti-angiogenic drug Avastin (bevacizumab), the chemotherapy carboplatin, the chemotherapy pegylated liposomal doxorubicin or the immunotherapy Keytruda (pembrolizumab).

“The combination studies are aimed at getting a better idea of what the biomarker should be in selecting patients for this treatment, and potentially exploring it in frontline chemotherapy in combination with carboplatin,” says Moore. “I also think there’s potentially a role for this drug in other malignancies where FR-alpha is overexpressed, and there are several studies that are launching across the United States that are exploring those questions.” ImmunoGen, Inc, is developing mirvetuximab soravtansine. The company is working with Ventana Medical Systems to develop an IHC-based FR-alpha assay for use as a companion diagnostic with the drug. Visit 

 to learn about eligibility and enrollment.

Features

The investigational compound targets overexpressed folate receptor-alpha.

Drug Conjugate Tested in Resistant Ovarian Cancer

A RECENT GUIDELINE for the management of vulvar cancer, issued by the National Comprehensive Cancer Network (NCCN), outlines the use of resection, radiation therapy and chemotherapy based on disease site and stage, even though only two randomized treatment trials have been completed.

In a cancer as rare as this one, “We are fortunate to be informed by a handful of prospective observational studies,” said Wui-Jin Koh, M.D., who presented the new guideline at the 2016 NCCN Annual Conference.

One underlying principle of the guideline is that early-stage disease can often be cured by resection alone. In addition, an evolution from an extensive approach to a more limited, tailored surgery has taken place.

In the guideline, treatment planning issues are considered separately for the primary site and the groin. This construct is driven by a core of observations. In most cases, metastasis in the groin after initial primary treatment occurs early, at a median of six to eight months, “and they’re rarely curable,” said Koh, a professor of radiation oncology at the University of Washington.

“On the other hand, local vulvar failures occurring in a primary site (in the labia) may occur later on in treatment and can often be cured by additional surgery.” While it is possible for patients to develop a second vulvar cancer — not dissimilar to patients with head and neck cancer, who have an elevated risk of lung cancer &mdash; “there is a thought that these are not actually true occurrences as opposed to re-occurrences,” he said.

Observation (or radiotherapy based on other risk factors) is recommended for patients with margins that are clear of invasive disease after excision (surgery). If the patient has positive margins for invasive disease, the guideline recommendation is for re-excision with adjuvant (post-surgical) radiation, which should be used judiciously. “Only if patients have positive margins or unresectable primary disease do we routinely recommend radiation in the guidelines,” Koh said.

Sentinel lymph node (SLN) evaluation is the standard method for assessing whether metastasis has occurred, and informs prognosis. In patients with a tumor of 4 cm or less restricted to one area, and no SLN involvement, the rate of groin relapse is less than 3 percent.

If the lymph node evaluation is negative, no adjuvant therapy to the node is recommended. With two or more positive lymph nodes, the recommended adjuvant therapy is radiation, typically with concurrent chemotherapy.

If patients undergo SLN biopsy, the guideline diverges on adjuvant therapy based on size of SLN metastasis. “If their SLN is less than 2 mm in size for positive, then we believe that adjuvant radiation is appropriate treatment,” Koh noted. “But based on the evolving GROINSS V study, if the SLNs are greater than 2 mm … they should undergo a completion inguinofemoral node dissection, followed by radiotherapy with or without chemotherapy.”

For early-stage tumors, adjuvant radiotherapy is an effective treatment modality that significantly decreases recurrence, especially in surgically resected groins, and leads to improvement in relapse-free survival and overall survival. The greatest independent predictor of groin relapse is groin node involvement at initial presentation.

“We try as much as possible to avoid radiation to the vulva itself, because that is not an area that tolerates radiation well, and it may actually affect the natural history of disease and make pickup of late recurrences or re-occurrences more difficult,” said Koh.

The term “locally advanced disease” applies to patients not eligible for surgery. In these patients, radiotherapy, and often concurrent platinum-based chemotherapy, can shrink tumors and allow surgeries of reduced scope that preserve function, or can even be curative.

In addition to being useful for patients whose disease is too advanced for surgery, chemotherapy plus radiation may help address systemic risk in patients with multiple positive lymph nodes. There is an option in these patients for inguinofemoral lymph node dissection, because it is still unclear whether radiation by itself can sterilize disease in the surgically unresected groin.

Patients with positive groin nodes have a poorer outcome. In those who receive radiation therapy for positive nodes, the rate of locoregional disease resistance or progression is reduced substantially, but distant metastasis “becomes the predominant pattern of (recurrence) and cause of death in patients with groin node-positive disease, hence suggesting a possible role for systemic chemotherapy,” Koh said. Use of intensity-modulated radiation therapy is possible, but the volume should be “generous.”

Treatment changes for the rare illness include less invasive surgery.

NCCN Introduces Updated Vulvar Cancer Guideline

Teri Woodhull has helped to direct her own treatment, recently joining a trial of a PARP inhibitor after learning of its promise in ovarian cancer.

Teri Woodhull is decidedly proactive. A strong family history of breast cancer led her to undergo a preventive bilateral mastectomy at age 30. Seventeen years later, she was diagnosed with stage 3b high-grade serous epithelial ovarian cancer.

“I do have a BRCA mutation, although I didn’t know until I was diagnosed,” Woodhull says, adding that, despite being highly educated and working in the health care field, she had been unaware of the role of BRCA mutations as a major risk factor for ovarian cancer.

While inherited mutations in BRCA1 and BRCA2 — both DNA repair genes &mdash; are often linked with the development of both breast and ovarian cancers, the gene mutations’ connection to breast cancer may be more widely known because of that disease’s higher prevalence and public profile. About 15 percent of women with ovarian cancer develop the disease due to hereditary factors, and BRCA mutations account for the vast majority of those cases.

That connection is becoming increasingly important when it comes to treatments for ovarian cancer: Some of the latest drugs approved, inhibitors of the enzyme poly ADP ribose polymerase (PARP), work specifically in women with BRCA mutations. Encouragingly, PARP inhibitors are also proving valuable for some patients who don’t have BRCA gene mutations. In addition, other drugs have been recently approved for patients with ovarian cancer regardless of whether they have inherited risk factors.

 After an eight-year drought in the development of new drugs for the disease, progress was seen in 2014, with the approvals of Lynparza (olaparib), the first PARP inhibitor, indicated for use by itself in advanced disease; and Avastin (bevacizumab), a targeted anti-angiogenic monoclonal antibody meant for use with chemotherapy in certain recurrent ovarian cancers. While the approvals of the two drugs represented major breakthroughs for the treatment of ovarian cancer, neither drug has proved to prolong survival; instead, both improve progression-free survival (PFS), meaning they can lengthen the amount of time before the disease progresses.

In December 2016, more FDA approvals came through for ovarian cancer treatments, again for advanced disease: the PARP inhibitor Rubraca (rucaparib), along with a companion diagnostic to test for BRCA mutations, and an expanded approval for Avastin.

Designed for women with BRCA mutations, Rubraca was shown in trials to shrink ovarian tumors, but studies did not seek to determine whether it prolonged survival; that is being investigated. Avastin, not specifically for those with BRCA mutations, was shown to improve PFS and, in one study, suggested an improvement in overall survival, although that was not considered statistically significant.

The need for a host of new drugs for ovarian cancer stems from the complexity of the disease. “Our therapies tend to work well initially, but the cancer becomes resistant, and so it’s a tricky cancer to work with because it’s very heterogeneous. It’s got a lot of resistance mechanisms built in, and so it always seems to be able to evade what we do and pop back up with a resistant version,” says Elizabeth Swisher, M.D., Dream Team co-leader for the Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition.

After debulking surgery, which was meant to get rid of as much tumor as possible, Woodhull enrolled in a clinical trial for Avastin, several years before the drug’s approval. Following 23 treatments taken every three weeks for 10 months after aggressive chemotherapy, she was deemed to have no evidence of disease.

Anti-angiogenics like Avastin work by inhibiting the development, growth and maintenance of blood vessels that feed cancerous tumors. Avastin does this by specifically binding vascular endothelial growth factor (VEGF) molecules, which would otherwise serve as a stimulant to develop new blood supply and growth to tumors. “It’s sort of like a sponge that is trying to sop up all the VEGF,” says Robert L. Coleman, M.D., professor and vice chair of clinical research in the Department of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center in Houston.

Avastin was initially approved for ovarian cancer that did not respond well to platinum-based chemotherapy. Its most recent approval to treat ovarian cancer allows its use in patients who do respond to a platinum-based regimen, but who experience a recurrence after six or more months of treatment with the chemotherapy.

 Having been an investigator in multiple studies of Avastin, Coleman says potential side effects include hypertension; protein in the urine, which can indicate illness; and a low but serious risk for bowel perforation — a risk heightened for patients with recent abdominal surgery, pre-existent inflammatory bowel disease or certain other risk factors. “But overall, it’s a relatively well-tolerated drug in the space where it’s indicated,” Coleman adds.

While other anti-angiogenics have been studied, none to date have demonstrated the overall treatment effect of Avastin in ovarian cancer.

“In multiple clinical scenarios, Avastin, alone and in combination with other chemotherapeutics and biological agents, has demonstrated a significant impact on response, symptom control and survivorship. However, as with most treatment approaches in this disease, resistance and adaptation emerges, driving the great need to understand the effects of treatment in the microenvironment and how to improve efficacy. New anti-angiogenesis drugs and anti-angiogenesis drug combinations are an active area of contemporary research,” says Coleman.

About two years after completing the Avastin trial, cancer returned in Woodhull’s abdominal cavity. “Because I’d been in a clinical trial, I was being followed more closely,” she says, “so they caught it really early.”

From there, Woodhull received 18 weeks of standard chemotherapy treatment with carboplatin and Taxol (paclitaxel). “To our shock and surprise, when I had the CT scan after the chemo, they found new masses that had developed during the chemo,” she explains.

Having dived into educating herself and getting deeply involved with the patient advocacy group Facing Our Risk of Cancer Empowered (FORCE), Woodhull knew that PARP inhibitors had shown promise in ovarian cancer. She embarked on a quest to locate a trial in which she could enroll, visiting major cancer centers until she found a fit with a San Francisco study of the then-experimental PARP inhibitor Zejula (niraparib). The study assessed niraparib as a maintenance drug, meaning that Woodhull is taking it after completing other treatments, in order to help prevent or delay cancer progression or recurrence. She says the drug has kept her cancer stable for more than a year and a half, also shrinking her tumors by 20 percent. In late March, Zejula was approved by the FDA as a maintenance treatment for with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers who are in a complete or partial response to platinum-based chemotherapy; it joined Lynparza and Rubraca as available PARP inhibitors for ovarian cancer.

The phase 3 trial results for Zejula, presented in November 2016, showed a significant improvement in PFS for those taking the drug versus placebo, with median PFS at 21 months and 5.5 months, respectively. “For ovarian cancer, that’s a big deal,” says Woodhull. “That’s just a flavor of how these PARP inhibitors are so exciting for ovarian cancer patients.” Thomas J. Herzog, M.D., clinical director of the University of Cincinnati Cancer Institute in Ohio, who was a researcher on the Zejula study, echoes Woodhull’s excitement over the new treatment option. When it comes to comparing the PARP inhibitors, he notes that subtle differences exist in the drugs’ efficacy and toxicity profiles. “In essence, I think we need more experience with these and ... how they play out in real-world use in terms of toxicity, convenience and everything else we consider for patient use. I personally think that costs may end up being a deciding factor...with respect to PARP inhibitor selection, because from what we know right now ... they behave more similarly than they do differently regarding efficacy,” says Herzog.

 Side effects of PARP inhibitors can include nausea and fatigue, with disturbances to blood counts occurring at higher doses or in combination with chemotherapy.

The drugs work by preventing cancer cells from repairing their DNA, which can be damaged by chemotherapy or radiation. Their indication in women with BRCA mutations is aimed at exploiting the lack of DNA repair capabilities in BRCA-mutated cells, which, when bolstered by PARP inhibitors’ prevention of DNA repair, results in something called synthetic lethality. That occurs when, due to problems with the expression of two or more genes, cancer cells die, whereas they could live if only one gene was experiencing such glitches.

Sometimes PARP inhibitors are used in combination with anti-angiogenesis drugs, even in women who don’t have inherited BRCA mutations.

According to Coleman, anti-angiogenesis drugs, as well as targeted drugs known as the VEGF tyrosine kinase inhibitors — which are also showing some promise in ovarian cancer &mdash; cause hypoxia, or a lack of oxygen, in the tumor microenvironment by blocking VEGF, which reduces vascularization. Hypoxia can reduce the efficiency through which homologous recombination DNA repair occurs, mimicking an environment like a BRCA mutation in patients who don’t have one. “That’s the hypothesis as to why using PARP inhibitors with an anti-angiogenesis inhibitor might be of value,” says Coleman.

Another reason PARP inhibitors may work in women without hereditary BRCA gene mutations is that some patients with ovarian cancer develop acquired alterations to BRCA1 or 2, as well as DNA repair defects. In all, half of high-grade ovarian tumors carry one or both of those changes, according to the My Cancer Genome database.

“Paradoxically, even though (the BRCA mutation) helped the cell become a cancer, it makes the cancer more vulnerable to certain types of treatments, such as PARP inhibitors and also chemotherapy,” explains Swisher, who is also a professor in gynecologic oncology and an adjunct professor in medical genetics at the University of Washington School of Medicine and director of the Breast and Ovarian Prevention Program at the Seattle Cancer Care Alliance. “When you give chemotherapy, you’re damaging DNA in your normal cells and your cancer cells. Now, if the cancer cell has less ability to repair the DNA than your normal cells, the normal cells can recover from the chemo and the cancer cells can’t.”

According to Swisher, PARP inhibitors are being explored in combination with a number of other agents, some of which have yet to be approved on their own. One caution is that, because cancer cells have the ability to self-modulate their DNA-repair capacity, the cells can sometimes outsmart PARP inhibitors, Swisher points out. This resistance mechanism, she says, highlights why drug combinations are constantly being studied.

Looking ahead, a new strategy for treating ovarian cancer is the use of monoclonal antibodies to target folate receptor alpha, an antigen that is often found on the surface of ovarian cancer cells. These drugs disable the receptor and prevent it from fueling the cancer.

 Several such drugs are being tested in clinical trials, but mirvetuximab soravtansine (IMGN853), being tested in a phase 3 clinical trial, is the furthest along in the development process.

Scientists are also finding that many ovarian cancers overexpress the cyclin E1 gene, creating a potential target for treatment. Investigation into this strategy is very early, but has included the use of a CDK2 inhibitor and Velcade (bortezomib), a proteasome inhibitor often used in the treatment of the blood cancer multiple myeloma.

One idea arising out of early studies is that tumors that overexpress cyclin E tend to be resistant to PARP inhibitors, so treating them should involve finding a way to make the tumors responsive to PARP inhibitors. A 2016 study in cell lines showed that the histone deacetylase inhibitor Farydak (panobinostat) worked in that capacity. Immunotherapy approaches in early phases of study include PD-1 checkpoint inhibitors such as Keytruda (pembrolizumab); vaccines; and adoptive T cell transfer, in which immune cells are taken from a patient, genetically engineered in a lab to make them more effective in recognizing and fighting cancer, and then returned to the patient.

With all that the medical community now knows about ovarian cancer and its available treatments, genetic testing for everyone diagnosed with the disease is becoming ever more important. For one thing, Swisher says, finding out who has inherited genetic mutations can contribute to prevention strategies, which may include methods such as prophylactic removal of the ovaries.

“There’s about 20 percent of ovarian cancer that’s hereditary, and we are trying to improve access to genetic risk assessment so that we could be preventing all the predictable cancers that are hereditary,” she says. As for Ferguson, she said if it turns out that she needs additional therapy, she would first like to see another biopsy, as well as another gene profile. “Now, as cancer treatments move forward, they can take a look and know what treatments would be of benefit to you and which would not based on your profile,” she says. “It’s really amazing.”

According to Swisher, improving access to genetic testing means not only removing cost barriers, but making information about the process more available and eliminating the red tape involved in getting assessed. Disproportionate numbers of minorities, women in lower socioeconomic strata and those in rural areas are less likely to receive genetic testing, she says.

“We are very interested in making it much more widely available,” she says, adding, “We want to do two things: We want to decrease the number of women who get ovarian cancer and we want to improve the cure rate of those who do get it.”

After eight years with no new treatments for ovarian cancer, PARP inhibitors and anti-angiogenics are benefiting patients.

Ending a Dry Spell of Years Without Treatment for Ovarian Cancer

“My internal radiology doctor and main oncologist said they never saw a tumor shrink so quickly. It was really a blessing, and now I’m five years cancer-free.”

Jane Fitch and Sharica Lewis are two women living in different parts of the country, born 20 years apart, who share a common memory. They both endured the grueling experience of radiation therapy as treatment for their cervical cancer — and today count themselves among the 1.3 million survivors of gynecologic cancer in the United States.

Radiation therapy — also known as radiotherapy, irradiation and X-ray therapy &mdash; uses highenergy particles or waves to kill cancer cells. The energy from X-rays, gamma rays, electrons or protons damages cells by making small breaks in their DNA. This damage prevents the cells from dividing, and they eventually die after days or weeks of treatment. While radiation therapy selectively affects rapidly growing cancer cells, normal cells and tissue can also be damaged. This method is often used to treat gynecologic cancers including malignancies of the cervix, uterus, vulva and vagina.

Fitch, a 57-year-old resident of Charlotte, North Carolina, first started to worry when she noticed persistent and severe vaginal bleeding in May 2011. She thought it might be related to menopause, but on the fourth day, she fell unconscious in her bathroom. After waking up in the intensive care unit, a surgeon broke the news: Fitch had stage 2b cervical cancer, and her tumor was the size of a grapefruit.

Similarly, Lewis’ diagnosis came after a bout of intense vaginal bleeding. In February 2015, the 37-year-old native of Cleveland, Texas visited her gynecologist, who performed a biopsy and discovered stage 1b cervical cancer.

“From that point, I mentally prepared myself for what I was about to go through,” says Lewis. “I went to my doctors at MD Anderson Cancer Center, and they began to discuss my treatment plan and what was going to happen with me.”

For gynecologic cancers, radiation therapy is administered as a primary treatment, after surgery or to treat a recurrence; it can be given either in conjunction with chemotherapy (called chemoradiation) or alone. Two methods of delivery exist: external beam radiation therapy (EBRT), which uses a machine outside the body to send radiation toward the cancer, and brachytherapy, which uses a radioactive substance placed directly into or near the cancer. In some cases, both methods are used — usually EBRT first, followed by brachytherapy.

Wanting to help others like herself, Sharica Lewis started a chapter of the National Cervical Cancer Coalition in her town. - PHOTO BY: SHEILA HEBERT

Lewis and Fitch had treatment plans that included both types of radiotherapy and the chemotherapy drug cisplatin. After primary treatment consisting of six weeks of chemoradiation and two sessions of vaginal brachytherapy, Lewis was found to have no evidence of disease in September 2015. Fitch had radiation following a dilation and curettage (D and C) procedure to remove tissue from inside her uterus. Because of her more advanced stage of cancer, she went through 36 EBRT sessions, six rounds of cisplatin and almost a week of cervical brachytherapy. Then, she underwent a hysterectomy.

“My (brachytherapy) doctor and main oncologist said they never saw a tumor shrink so quickly,” Fitch says. “It was really a blessing, and now I’m five years cancer-free.”

EBRT, one of two main methods of radiation therapy used in women with gynecologic cancers, aims powerful X-rays at the cancer from outside the body, similar to the procedure of getting a regular imaging X-ray but at a much stronger dose.

Once the patient is positioned in the right place, each treatment lasts only a few minutes. When radiation is the primary treatment for cervical cancer, it’s given in sessions five days a week for five to seven weeks,often combined with a low dose of the chemotherapy drug cisplatin. For endometrial cancer, sessions are five days a week lasting four to six weeks. The X-rays are emitted from a machine called a linear accelerator.

Three-dimensional conformal radiation therapy (3-D CRT) is a type of EBRT that uses medical imaging techniques such as computed tomography (CT) to see the size, shape and location of the tumor and surrounding organs. With this information, the radiation oncologist can use software to visualize the treatment area in three dimensions and specifically shape the radiation beams’ direction and intensity.

 A more advanced type of 3-D CRT, called intensity modulated radiation therapy (IMRT), takes the tailoring of radiation delivery a step further by modifying the intensity within each beam and using computer-controlled collimators within linear accelerators. With IMRT, a single radiation beam is broken up into many “beamlets” that may then be adjusted individually. It allows for more precise adjustment of radiation to the tumor itself while limiting the amount given to nearby healthy tissue.

“We used to do 2-D radiation, and then we moved to 3D-CRT, where we can see the tumor, bladder and rectum with a CT scan to do a better job shaping our fields,” says Jonathan Strauss, M.D., MBA, an assistant professor of radiation oncology at Northwestern University’s Feinberg School of Medicine. “Now there’s IMRT, a new form of radiation delivery that builds on 3D-CRT. You’re still using a CT scan for planning, but IMRT delivers the beam in more complex ways with the hope that it carves out the tumor area better and reduces toxicity further.”

However, the evidence that IMRT improves outcomes over 3-D CRT for gynecologic cancers has yet to be published. Two phase 3 trials evaluating post-operative IMRT in patients with cervical or endometrial cancer are currently ongoing, one of which presented early results at the American Society for Radiation Oncology (ASTRO) 2016 Annual Meeting. The multicenter, randomized TIME-C study included 278 women with cervical or endometrial cancer and found that patients who had pelvic IMRT experienced less acute gastrointestinal (GI) toxicity than those who had conventional four-field radiation therapy. The other trial, PARCER, had its interim findings presented at the previous year’s ASTRO Annual Meeting. Postoperative IMRT was associated with a 14 percent reduction in moderate to severe bowel side effects in comparison with 3-D CRT, but the difference failed to reach statistical significance.

The second method of delivery is brachytherapy, or internal radiation therapy, which is sometimes used after EBRT in the treatment of vaginal, cervical and uterine cancers. Brachytherapy puts a source of radiation in or near the cancer to reduce exposure to surrounding tissues. After hysterectomy for endometrial cancer, a cylindrical applicator is placed in the vagina. For the definitive treatment of cervical cancer, an applicator is placed into and against the cervix. In each of these situations, a radioactive source is then fed through the applicator, stopping for precise periods of time along different dwell positions to optimally distribute the radiation dose.

Low-dose rate (LDR) brachytherapy occurs over the course of a few days, but the patient must remain immobile throughout this time in a hospital bed while the device stays in place. On the other hand, high-dose rate (HDR) brachytherapy uses a higher dose of radiation for less than an hour per session. For endometrial cancer, HDR brachytherapy is given weekly or even daily for at least three sessions.

A recent study by Strauss and his colleagues found better survival in women with stage 1 endometrioid adenocarcinoma of the uterus who had vaginal brachytherapy, as compared with patients who received no form of radiotherapy.

 “The data suggested that vaginal brachytherapy appeared to be more valuable than we had thought in stage 1 endometrial cancer,” he says. “What was also clear from the data is that, nationally, we did not have particularly good compliance with the current guidelines,” meaning that many women in this population were not being treated with any radiotherapy at all.

While vaginal brachytherapy is recommended for women with higher-risk stage 1a or any stage 1b disease, the study noted that 88 percent of those in stage 1a and 52 percent of stage 1b did not receive radiation therapy. Strauss points to issues of availability, given that brachytherapy isn’t found as often outside of large medical centers.

In other advances, more cancer centers are using magnetic resonance imaging (MRI) for treatment planning in brachytherapy. Ordinarily, the physician would use two-dimensional imaging to best cover the target area and minimize dose to any organs in the vicinity. In the past decade, several studies have found that the clinical outcome of patients with cervical cancer who receive MRI-guided brachytherapy will be improved compared with those who receive traditional 2-D planning.

“With MRI-guided brachytherapy, we get a clearer 3-D view of patient and tumor anatomy, so we can better define tumors and decrease patient toxicity,” says Omar Ragab, M.D., assistant professor of clinical radiation oncology at Keck Medicine of the University of Southern California.

Radiation therapy can also be used as a palliative treatment for those patients with advanced disease, as an effective way to stop bleeding and alleviate pain. Although radiotherapy is most often used in the curative setting, there are instances when the highest quality of life for the patient takes precedence over destroying her cancer.

“Palliative radiation is a very strong tool that we have for all disease subsites,” says Ragab. “In gynecologic malignancies, we tend to use it for very painful lesions like in a bone or for patients that have bleeding from a tumor.”

Despite the many recent advances in radiation therapy, it can still harm surrounding normal tissue and lead to many unwanted side effects. For instance, both Fitch and Lewis felt extremely tired and nauseated, and lost their appetites during treatment. Side effects of EBRT include fatigue, upset stomach, diarrhea, nausea/vomiting, vaginal pain, menstrual changes and low blood counts. Brachytherapy can have many of the same side effects as EBRT, such as fatigue, diarrhea, nausea, irritation of the bladder and low blood counts, but also may cause irritation of the vagina and vulva. Also, when chemotherapy is given with radiation, side effects like low blood counts, fatigue and nausea tend to be worse.

To improve quality of life, stratifying patients based on risk factors is one way to dole out only that treatment which is necessary, explains Dattatreyudu Nori, professor and executive vice chairman of the Radiation Oncology Department at The New York-Presbyterian Hospital/Weill Cornell Medical College. Instead of placing every woman on the same regimen, some studies show that giving radiation alone without chemotherapy may be adequate for certain low-risk patients.

 “The knowledge in radiation oncology for gynecologic cancer is continuously refined in terms of when to apply radiation, especially in endometrial cancer,” he says. “We have many randomized trials showing exactly which patients will benefit from radiation, so it’s not only the technological advances that help.”

In cervical cancer, Strauss notices a similar trend toward identifying an individual patient’s response to radiotherapy throughout treatment. For example, serial MRI could track and identify the subset of women whose disease responds more slowly. These patients could be likely to recur and might benefit from having a hysterectomy after radiation.

For some patients, such individualized treatment could help lessen short-term and long-term side effects. Long-term side effects of pelvic radiation can include vaginal stenosis or dryness, weakened bones and lymphedema (swelling) in the legs. Fitch is currently on disability due to problems with her bladder and colon, and Lewis suffers from occasional urinary incontinence due to her brachytherapy.

Nevertheless, both women remain active in cervical cancer outreach and promote prevention through education about early vaccination, Pap testing and human papillomavirus (HPV) testing when recommended. Today, Fitch leads her local chapter of the National Cervical Cancer Coalition (NCCC) and works as a holistic health practitioner. Similarly, Lewis started an NCCC chapter in her town to get the word out about cervical cancer and how to prevent it. Perhaps the most important method is to make sure that preteens get vaccinated against HPV; although this could prevent most cases of the disease, the vaccine series is vastly underused.

“I don’t want anybody to have to go through what I went through, because it was brutal, and there were times I didn’t think I would make it,” says Fitch. “But I always knew that, right off the bat, if I made it through this, my goal was to help someone else and let them know that there is hope.”

Improvements to radiation therapy aim to better target gynecologic tumors while sparing healthy tissue.

Making Waves: Improving Radiation in Gynecologic Oncology

They have medication to stall the nausea, but that also has side effects. I am a big believer in complementary medicine, if it is supplemental to what someone’s physician would suggest.”

— CAROL GOLDSTEIN, patient - PHOTO BY: KAELA GREEN

For at least a year, Carol Goldstein experienced gastrointestinal pain. Curious as to what was going on with her body, she mentioned it to her primary care physician, who put her on Prilosec to treat potential reflux. Then one day, while hiking with her family, she had upper-abdominal pain so severe that she thought she was having a heart attack. Her cardiologist had her come in immediately for testing. The heart attack was ruled out, but instead Goldstein heard: “I see something on your ultrasound.”

Goldstein, a Ph.D. nurse, followed up with Sue Davidson, M.D., head of gynecologic oncology at The Center for Surgical Innovation at the University of Colorado in Denver. After an examination, Davidson confirmed the news no one wants to hear: Goldstein had metastatic ovarian cancer. That was in August 2012.

“Like every other woman who has ovarian cancer, I had symptoms that I did not recognize because, as we say in the field, common things are commonest,” says Goldstein. “No woman of my age — I’m now 74 &mdash; does not have some bloating or frequent urination.”

Days after her diagnosis, Goldstein was in the operating room for a debulking. In this common surgery for ovarian cancer, the surgeon hopes to locate and remove as much of the tumor tissue as possible. Goldstein’s surgery was followed by seven weeks of chemotherapy.

 “I know that surgeons and most physicians want to cure,” she says. “They want to do everything they can to fix whatever is wrong with you, but (late-stage) ovarian cancer is really not fixable.”

Having been in the medical field for 50 years, Goldstein knew she could seek palliative care. She signed up to be a patient of Carolyn Lefkowits, M.D., also at the University of Colorado, in Aurora, a gynecologic oncologist who is also a palliative care specialist.

Palliative care, sometimes called supportive care, is given to relieve side effects and optimize overall functioning and quality of life of patients who have a serious or life-threatening disease. Specialists prefer to begin this care as early as possible after diagnosis to prevent or treat symptoms.

A palliative care team — made up of specialists such as physicians, nurses, physical therapists, pain management experts, massage therapists, chaplains, dietitians, social workers and psychologists &mdash; can also help patients with psychological, social and spiritual problems. All this can be done simultaneously, and in coordination with, appropriate cancer-directed treatments.

However, there is a common misconception among patients, caregivers and even some oncologists about what palliative care is. In fact, a 2011 survey conducted by the Center to Advance Palliative Care found that 70 percent of people had little accurate knowledge about it.

Palliative care is often confused with hospice or “end-of-life” care, which tends to be administered in the home when a patient is deemed to have terminal disease, with an estimated six months or less to live.

Palliative care, however, is “this place to augment — not replace, not undermine, but augment &mdash; the care that traditional oncology services can provide to enhance the comprehensiveness of the care for patients,” says Lefkowits. “It takes some of this supportive care off the plate of the oncologists, and it is greatly underutilized.”

Playing their parts in that disconnect have been a lack of education about palliative care, and the lack of a national calling for it. Not until a few years ago were there even defined curricula on palliative care. Now, physician fellowships, where this type of care can be learned, are up and running.

“Maybe they don’t have uncontrolled pain that day, but maybe six months later they do,” Lefkowits says of patients. “If you’ve oriented them to the option of seeing a supportive care specialist for symptom management, then when they do develop those symptoms, they can recognize that they have unmet needs.”

Goldstein took advantage of the fact that the University of Colorado Cancer Center has a thriving palliative care program. In addition to her treatment from her oncologist, she saw a psychologist and relied heavily on a dietitian to ease side effects of her treatment that included diarrhea, constipation and gastrointestinal pain.

Yoga and meditation became part of her routine, as did acupuncture, with which Goldstein had had previous experience during a decade of residence in Hong Kong.

“I saw my acupuncturist every week before my chemotherapy, and I did not feel nauseous or throw up once,” Goldstein says. “They have medication to stall the nausea, but that also has side effects. I am a big believer in complementary medicine, if it is supplemental to what someone’s physician would suggest.”

Treatments for gynecologic cancers vary based on disease type and stage, but they may include various chemotherapies, such as the drugs Taxol (paclitaxel) and carboplatin; surgery; radiation therapy, which can sometimes involve intracavity treatment, where a device is placed in the vagina containing radioactive material; and hormonal therapies.

Many side effects are associated with these treatments, including lower-extremity lymphedema, sexual function problems, early menopause, bowel obstruction, chemotherapy-induced peripheral neuropathy, post-chemotherapy cognitive dysfunction (“chemobrain”), hair loss, and, most commonly, fatigue.

For Beverly Waite, it was severe back pain and bowel obstruction that she found the most unbearable. Diagnosed with endometrial cancer nine years ago, at age 59, she found herself turning to palliative care a few years later.

She was first introduced to the idea after developing side effects during a clinical trial at Dana-Farber Cancer Institute in Boston.

“They tried all kinds of medications,” says Waite. “Then they said, ‘Let’s send her to Dr. Brandoff at pain management.’ He’s been the best thing that has ever happened in my treatment.”

“He talked to me and explained thoroughly about managing pain, which drugs to use and the combination of drugs,” she says of Douglas E. Brandoff, M.D., an oncology-trained palliative care specialist at Dana-Farber. He also asked about her treatment and personal life, Waite adds.

 Not only physical side effects can occur due to anticancer treatments, but emotional and psychological ones, too. Women with gynecologic cancer may experience anxiety, stress and depression as a result of what is happening to their bodies. The various aspects of palliative care can be useful in all of these areas, yet these services remain underutilized. This trend is apparent among all patient populations with cancer, not just women with gynecologic cancers.

“Palliative care would particularly benefit women with advanced ovarian cancer, because they typically are debilitated and they have to take complicated treatments,” says William Robinson, M.D., Maxwell E. Lapham Professor of Gynecologic Oncology at Tulane Cancer Center in New Orleans, Louisiana. “We know most patients with ovarian cancer will live four or five years, or more, but they will be on treatment for most of that time, so they clearly would benefit from a supportive program.”

Robinson also feels women with locally advanced cervical cancer would specifically benefit from palliative care.

“These are women who are in stages 2b through 4a, which means that it has grown beyond the cervix, but it has not metastasized. That group is unique because they, too, need a complex treatment plan that includes radiation plus chemotherapy,” he adds.

Dealing with a cancer diagnosis and treatment and assessing your own need for palliative care can be challenging. While patients should advocate for their own health and care, nurses, social workers and caregivers can help to assess the situation.

For instance, Robinson says a social worker can use a distress thermometer — a questionnaire created by the National Comprehensive Cancer Network &mdash; to determine what problems a patient may be facing at that specific time.

Caregivers may also suggest that the patient they’re helping could benefit from counseling, stress-reducing activities or other palliative care. “If you realize how much stress you’re under, then put that together in your mind with what somebody who is actually receiving a treatment and has the disease is feeling, you can tell pretty quickly who’s going to benefit,” Robinson says.

The levels of palliative care available vary from institution to institution. National Cancer Institute-designated cancer centers are among the most likely facilities to have palliative care programs. Lefkowits says it may be best for patients to first ask their oncologists what resources are available within the places they are being treated, and then to reach out to social workers or organizations if more resources are needed. But, she adds, it is also important for an oncology team to ask questions.

 “We’re not good at predicting that all patients with this kind of cancer, at this stage, getting this treatment, are going to have unmet palliative care needs,” she says. “The best thing to do is just ask people where they are in terms of their symptoms and how they are coping. That should be a routine part of cancer care.”

Studies conducted on early-in-treatment palliative care show that these techniques may not only improve quality of life but also prolong survival. A study of patients with metastatic non-small cell lung cancer, for instance, determined that patients who started palliative care early on lived longer than others, and had better quality of life and mood. Although not many studies on palliative care specifically in gynecologic cancers have been completed, a Brazilian study demonstrated similar findings in patients with advanced breast or gynecologic cancers.

“While each patient’s experience is different, the idea is that a diagnosis of a potentially life-limiting illness and the treatments that come with it are going to result in symptoms, struggles and coping challenges for a patient and their family,” says Lefkowits.

Most insurance companies, and Medicare and Medicaid, will cover palliative care, just as they would cover other hospital or medical costs. However, coverage may vary when it comes to integrative therapies like massage therapy, yoga or acupuncture. Patients can reach out to social workers, who may be available to talk about cost or financial concerns.

“Get into palliative care as soon as possible,” Waite advises. “Not only do they manage your pain, they also can refer you to social workers and a whole group of other professionals for support.”

A state-by-state report card, released in 2015 by the Center to Advance Palliative Care and National Palliative Care Research Center, detailed access to palliative care in hospitals in the United States, showing that access varies based on where a patient resides. The worst reports emerged from the South, as well as from Alaska, Kansas, New Mexico and Wyoming.

“Clearly, palliative care has been an overlooked part of cancer care,” says Robinson. “But I would tell people to look at it like you are using any other consultant. There should be no stigma. There wouldn’t be stigma with seeing a cardiologist, so why should there be a stigma for seeing a palliative care specialist?”

Goldstein lobbies for change as both a patient and a registered nurse. She suggests more academic peer-reviewed studies, in addition to well-designed short courses that would be mandatory for all physicians and nurses, helping them to become familiar with palliative care and how to give more patients access to it. “What I don’t want for myself, and what I think most people don’t want, is to die in pain,” says Goldstein. “We are all going to die. None of us live forever. What I want for myself and my family is to have a peaceful death with as little pain as possible.”

Early introduction of palliative care can improve quality of life for patients with gynecologic cancers.

Women's Cancers 2017 | CURE