Dealing With an Ostomy

Six days after an unremarkable lumpectomy, I had rushed to the local hospital, not so much because of pain but out of concern. I had been eating and drinking as usual, but what was going in was not coming out.

I cursed my faulty plumbing — an operation for ovarian cancer had produced infections and then, in 2009, an ileostomy. I’m one of about half a million Americans whose body wastes are collected in disposable external pouches. And now the pouch was clean and empty, which was a problem.

Unfortunately, I had made the situation worse by forgetting to bring a book to the hospital with me. Within an hour, a nurse named Rachel came to my rescue with a thriller, “The Donor.” According to the flap, Frank M. Robinson’s hero awakens in a recovery room to discover that one of his kidneys has been harvested by a mysterious villain who will next time seize the poor guy’s heart. Sounded perfect.

Rachel’s book, a life preserver, saw me through 12 hours in the emergency room as well as most of the next day, which I spent in a hospital room. I was receiving “rest care”: nothing by mouth, an IV with saline to prevent dehydration. If my intestines did not start working, I would be transferred by ambulance to a major hospital in Indianapolis, an hour and a half away from Bloomington, where I live.

One doctor told me: “You have an 80 percent chance that the obstruction will right itself.”

It was a new experience to look down at the pouch plastered on my belly with alarm that it was clean. Daily since the ileostomy eight years ago, I have struggled with disgust: certainly not the prescribed or healthy response, but mine nonetheless. A bit of intestine — called a stoma — had been pulled out of my body and stitched to my stomach so stool could be evacuated.

Until this stoppage, the productivity of the stoma had revolted me. Every few hours, the bag needed to be emptied. Every few days, I changed the apparatus that, glued to my body, collected waste. Like many others living with temporary or permanent colostomies, ileostomies and urostomies, I hid the pouch beneath my clothes, while I stressed over skin irritation, accidental leaks and mortification.

Was the pouch empty because of something I had ingested? People with ileostomies are warned against fibrous foods. Corn, cauliflower, mushrooms, cabbage, celery, beans, nuts and berries can cause blockages, so I am supposed to follow a diet low in roughage. At my last meal, I had eaten a sprinkling of parsley on a piece of cod, but surely not enough to clog the works.

The gruesome premise of the book I was reading, “The Donor” — of body parts excised from the living — made me wonder if medically engineered, artificial organs might create better solutions for various ostomies caused by a number of maladies: birth defects, injuries, inflammatory bowel disease, ulcerative colitis, diverticulitis, Crohn’s disease and gynecological, bladder or colorectal cancers. Quite a few “ostomates” manage to engage in a full range of activities, but I find it impossible to swim, take baths or exercise vigorously because of anxieties about the adhesive eroding under the pouch.

Around 7 p.m., my alimentary system started working again and I exulted at the prospect of going home.

Before my release the next day, an ostomy nurse arrived with a cart full of brochures and equipment.

“Supplies have changed since 2009,” she said, handing me samples of newly designed products. Too tired and fraught to attempt anything new there and then, I took her card, determined to consult her when my digestion had settled down. Maybe she could make my life easier, for in my experience ostomy nurses crowd the angelic throngs.

One week later, at a post-op consultation about my lumpectomy, the breast surgeon said she thought that even days after the procedure, remnants of anesthesia might have put my small intestines to sleep. “Could have happened to anyone,” she said. It dawned on me that the ostomy was no more or less gross than any other mode of evacuation.

These days, I’m grateful for little acts of kindness from gracious people who leaven the misery of hospitalization. Online I find a grisly medical thriller to send Rachel, along with the book she had lent me. Bolstered by her and the ostomy nurse, I seek, like the protagonist of “The Donor,” to keep hold of my heart.

“Secrecy and shame cannot be kind masters,” my cherished friend Mare says to remind me how many people, with and without cancer, must deal with physical impairments. Art also helps: Carol Chase Bjerke’s “Intimate Apparel” puts on display the usually hidden ostomy pouch as if it were a delicate piece of lingerie. It’s unnerving, but clarifying to see the concealed revealed.

To read this entire article by Susan Gubar in The New York Times, please click here.

Easing the Pain: Palliative Care for Gynecologic Cancers

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 — 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.

WHAT IS PALLIATIVE CARE?

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 — 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 — 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.”

THE PALLIATIVE CARE JOURNEY

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.

DO YOU NEED PALLIATIVE CARE?

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 — 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.”

PUSHING FORWARD

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, plso 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.”

To read this article on CureToday.com, please click here.

Tumor Marker for Aggressive Ovarian Cancer Identified

Patients who expressed the tumor antigen NY-ESO-1 had more aggressive cancers and were more likely to die early from their disease, according to a large study conducted by Roswell Park Cancer Institute researchers and published online ahead of print in the journal Gynecologic Oncology.

“This is the largest study of NY-ESO-1 expression in ovarian cancer patients, and the first time that expression of this antigen has been identified as a marker for more aggressive disease,” says the study’s first author, J. Brian Szender, MD, MPH, Fellow in the Department of Gynecologic Oncology at Roswell Park.

NY-ESO-1 is one of the few tumor antigens that have restricted expression in normal tissue but become aberrantly expressed in epithelial ovarian cancers and other solid tumors. From January 2002 to June 2016, more than 1,000 patients with ovarian cancer were tested at Roswell Park for NY-ESO-1 expression. Their median age at diagnosis was 61 years, and most patients were diagnosed with stage IIIC or stage IV disease. The research team found that NY-ESO-1 expression was associated with shorter duration of both progression-free survival (22 months versus 25 months) and overall survival (42 months versus 50 months).

During the study period, the Roswell Park scientists enrolled a total of 68 ovarian cancer patients with NY-ESO-1-positive tumors to cancer vaccine trials targeting NY-ESO-1. The researchers found that patients with NY-ESO-1-expressing tumors who were enrolled in cancer vaccine trials had significantly improved overall survival compared to patients with NY-ESO-1 who did not participate in the cancer vaccine trials, and with patients without NY-ESO-1-expressing tumors.

“We suggest that NY-ESO-1 be a high-priority target for future immunotherapy studies, given the high prevalence of NY-ESO-1 expression in ovarian cancer and the association of this tumor antigen with adverse clinical outcomes,” says Kunle Odunsi, MD, PhD, FRCOG, Deputy Director of Roswell Park and Chair of the Department of Gynecologic Oncology. “It is possible that in the coming years, NY-ESO-1 expression in ovarian cancer will be as important to the treating oncologist as HER2 expression is for the treatment of breast cancer.”

To read this entire article on ScienceDaily.com, please click here.

Dueling BRCA Databases: What About the Patient?

“Study finds wide gap in quality of BRCA1/2 variant classification between Myriad Genetics and a common public database.”

Myriad Genetics had been exclusively providing tests, for $3000+ a pop for full BRCA gene sequencing, for 17 years before the Supreme Court invalidated key gene patents back in 2013. Since the ruling a dozen or so competitors have been offering tests for much lower prices. Meanwhile, Myriad has amassed a far deeper database than anyone else, having been in the business so much longer. And it’s proprietary.

CLASSIFYING GENE VARIANTS

Public databases of variants of health-related genes have been around for years too. The best known, ClinVar, collects and curates data from the biomedical literature, expert panels, reports at meetings, testing laboratories, and individual researchers, without access to Myriad’s database. ClinVar uses several standard technical criteria to classify variants as “pathogenic,” “benign,” or “of uncertain significance.” (“Likely pathogenic” and “likely benign” were used more in the past.)

ClinVar lists 5400 variants just for BRCA1. The criteria come from population statistics, how a particular mutation alters the encoded protein, effects on the phenotype (symptoms), and other information. Bioinformatics meets biochemistry to predict susceptibility. The BRCA1 protein acts as a hub of sorts where many other proteins that control DNA repair gather. DNA Science discussed the genes behind breast and ovarian cancers here.

As gene sequences accumulate in the databases and troops of geneticists and genetic counselors annotate them, the proportion of pathogenic and benign entries will increase as that of the unsettling “variants of uncertain significance” — VUS — will decrease. Knowing will outpace not knowing. In the meantime, a woman with a VUS for a gene that confers susceptibility to develop breast and/or ovarian cancer, concerned that her DNA sequence isn’t “normal,” might have her at-risk organs removed. And then she might learn, as the databases grow, that her variant is really benign after all, because while she was being treated for a disease that she didn’t actually have, more patients emerged who have the gene variant but not the related cancers.

The reclassification of a VUS as something more meaningful depends on access to as much information as possible.

How many unnecessary surgeries are happening? Have happened? Myriad estimates hundreds to thousands.

DISCOVERING DISCORDANCE

The news release announced a paper from Myriad just published in The Oncologist that compared 4,250 unique BRCA1 and BRCA2 gene variants in the company’s database to entries in ClinVar, and found that 26.7% of the ratings do not fully agree. (ClinVar lists multiple sources for many of the variants, and 14.5% didn’t agree on all counts and 12.3% on only some.) According to Myriad, most of the VUS listings were in ClinVar. In fact, only 0.5% of Myriad’s BRCA1 sequences and 1.1% of their BRCA2 sequences are VUS. They’re clearly ahead of the game.

The discordance isn’t really news. It echoes earlier reports both from Myriad researchers for the BRCA genes and from a  non-Myriad, multi-center group that also found 26% discordance, but their analysis included several cancer predisposition genes; the most conflicting were CHEK2 and ATM. And another recent study found that about half of women with VUS undergo bilateral mastectomy, concluding that “many surgeons managed patients with BRCA1/2VUS the same as patients with BRCA1/2 pathogenic mutations.” That’s terrifying. It means that the problem isn’t due just to overanxious patients, but also to surgeons who might not be genetics-savvy.

The news release doesn’t go to the obvious conclusion, that privatization of the database may be fueling inappropriate surgeries, or at least not preventing them, a point that Sharon Begley made elegantly in Stat News. Many of her expert sources countered the implication that variant classifications from ClinVar are just accepted and delivered to patients without further and often intense research and validation by health care providers.

MOTIVES

In the news release, William Gradishar, MD, from the Feinberg School of Medicine at Northwestern University and lead author on the new study from Myriad, provided the company view (slightly edited):

“The high degree of discordance seen in this study signals a cautionary note … it means that different labs are providing different results to patients for the same genetic mutation … some patients are receiving incorrect results that may have life-changing or -threatening implications… Although efforts are underway to resolve the quality problems within public databases, it is unlikely the issue will be resolved soon and users of public databases likely will continue to encounter discrepancies. At this time, labs should not use public databases in any way in clinical variant classification.”

Ron Rogers, spokesperson for Myriad, wrote in an email that the company provides database access for certain scientific collaborations, but then provided the business view:

“Myriad has invested hundreds of millions of dollars to develop our database over two decades, which is used to classify variants as part of the Company’s specific process. We encourage other commercial labs to make their own investments, which are required to offer a quality product. The problem is that some other commercial labs refuse to make the needed investments. Instead, they are trying to short cut the process by relying on inaccurate public databases, which has the potential to deliver inaccurate results and harm real people.”

If anyone remembers the race to sequence the first human genome, which pitted NHGRI and their public database against Celera Genomics and their proprietary one, the battle over BRCA is a little deja vu all over again.

Rogers added that if patients who have had bilateral mastectomies following a report of a VUS had come to Myriad, “we could have provided many of them with definitive answers and helped to prevent a significant number of these life-changing procedures.” About 85% of the BRCA testing market indeed uses Myriads products.

Myriad’s tests as well as their support (genetic counseling) are excellent. The company helped a friend of mine interpret and confirm BRCA1 test results from 23andMe, which her son had taken on a whim but the unexpected finding of a mutation had sent her family into a tailspin. 23andMe, the direct-to-consumer genetic information company, coaxes customers to provide their results for research (“Be part of something bigger”) and charges investigators for access to the data. Like Myriad, 23andMe also suffered a setback in 2013. FDA yanked some of their health-related carrier tests, but the agency reversed the ban on April 6, 2017.

23andMe and Myriad serve different types of individuals. Many of 23andMe’s customers, like my friend’s son, aren’t distraught over cancer, just curious and acting on their own. So here’s another comparison: Is Myriad’s protecting of their data similar to my reaction to people downloading my books for free? No. I’m just losing royalties.

My mother’s lost battle with breast cancer can’t help but influence my view that impeding accurate diagnosis for profit, to protect assets, may make sense in the business world but is not the right thing to do. I have trouble commoditizing patient tests and sequestering information that might help, and the many rock stars of genetics who have joined the Free the Data movement would agree.

Because the entire discussion makes me queasy, I thought instead I’d illustrate the distinction between a harmful mutation and a VUS, by comparing the BRCA1 gene sequence to the English language.

THE HANDMAID’S TALE

Most genes are thousands of DNA bases long, and therefore can vary in many ways. Gene variants – mutations – can affect health or not depending upon how they disrupt the proteins that they encode.

BRCA1 (the gene) is 125,951 bases long, only 5,589 of which are represented in the protein. Mutations near its ends are more damaging than those in the middle. One of the two Ashkenazi (Jewish) “founder” mutations, 185delAG, removes an A and a G at position 185, near the beginning. Because a gene sequence is read in triplets – every 3 DNA bases encodes an amino acid – adding or deleting a number that isn’t 3 or a multiple of it devastates the protein’s function. 185delAG is, then, a gene variant of very high significance. (My analogy below is not quite on target because the words in a sentence vary in length.)

I entered 125,951 letters into a publishing calculator that translates numbers of alphabet characters into a book of a particular size, and wound up with a 6” by 9” volume of 265 pages. That view of the BRCA1 gene’s enormity corresponds to approximately the length of Margaret Atwood’s dystopian masterpiece “The Handmaid’s Tale.” I’m rereading it, inspired by the “Make Margaret Atwood Fiction Again” signs at the March on Washington January 21.

I took a sentence about as far into the book as the 185delAG mutation is in the BRCA1 gene:

Everything except the wings around my face is red: the color of blood, which defines us.

Removing two adjacent letters – the “ex” in “except” – and then moving the other letters into the word-sizes, clearly disrupts the meaning:

Everything ceptth ewi ngsar oundmy fa ceis re dth: eco lorof bl oodwh ichde finesus

Gibberish, and it would continue to the end of the book. In a gene, the offset sequence would likely lead to a stunted protein, halted when reaching a “stop” signal in the mRNA. And when a BRCA1 gene loses meaning, control of DNA repair falters and other mutations go unchecked. Cancer results.

A VUS would do something less drastic, such as replacing a letter in a way that doesn’t obscure the overall meaning of the sentence (or gene). Substituting the “g” in “everything” with a “j,” for example, doesn’t alter the meaning. And many changes to a DNA sequence have no effect on the encoded amino acid sequence at all.

So that’s what a VUS is, a DNA sequence of a particular gene of interest that’s rather rare in a population, and that may or may not mean something. And their numbers will decline and then vanish as the databases build and their entries are annotated and validated. But until they do, I think that sharing all that we know about variants of possibly disease-causing genes, to prevent unnecessary treatments, is the only ethical path to take.

To read this article on Plot Blogs, please click here.

Researcher Aims to Eliminate Chemotherapy-Resistant Ovarian Tumors Using Virus Treatment

In some cases, the Lassa virus starts with a fever and general weakness, moving toward headache, muscle pain, possible facial swelling, deafness, and worse. About 15 percent of patients hospitalized with severe cases die.

Lassa fever is contagious, endemic in West Africa, and Dr. Anthony van den Pol thinks he can use it to cure ovarian cancer.

“We can employ microorganisms to do the job for us,” van den Pol said. “Like using penicillin from a fungus to fight bacteria. They can be our friends.”

The version of Lassa virus van den Pol works with has been rendered safe in combination with a variant of vesicular stomatitis virus (VSV). So there is little danger of infection. And with a grant from Women’s Health Research at Yale, van den Pol hopes to prove Lassa-VSV treatment can eliminate chemotherapy-resistant ovarian tumors.

“The body does not recognize ovarian cancer as a foreign invader that would normally trigger the immune system to attack, so the cancer can continue to grow unimpeded,” van den Pol said. “But the reason these viruses can infect cancer cells, and particularly ovarian cancer cells, is that 80 percent of human tumors have a deficient innate immune response. The cancer cell cannot defend itself against a virus.”

About one in every 60 women in the United States will develop ovarian cancer. It is the eighth most common form of cancer for American women and the fifth leading cause of death.

One of the reasons ovarian cancer can become deadly is that it recurs in about 80 percent of patients who receive successful surgery and chemotherapy treatment. And when it comes back, it often invades deep into large portions of the abdomen and pelvis where it is hard to find and difficult to remove surgically. Worse, the cancer often mutates to develop a resistance to chemotherapy.

But the ability of cancer cells to mutate can hold a key to their possible destruction.

Normal, healthy cells detect a virus and generate interferon, a type of protein that signals the presence of a pathogen, increasing the expression of up to 200 genes that then serve to block infections through various mechanisms of the immune system.

Previous research has found that even as advanced cancer with a greater number of mutations becomes more resistant to chemotherapy, the large number of gene mutations within the DNA of the cancer cells make them more susceptible to infection from a virus.

“A virus doesn’t have a brain but it has an evolutionary mission to find things to infect,” van den Pol said. “Viruses also replicate to seek and destroy on their own. They don’t need to know where the tumors are but seem able to find most if not all of them.”

Van den Pol’s team has studied viruses for this purpose over the past 15 years, focusing in part on variants of VSV. However, VSV on its own likes to infect electricity-conducting cells of the nervous system called neurons, causing damage.

So the researchers began testing viruses containing the genes of different unrelated viruses together with some VSV genes to discover any that do not infect neurons. They found that using a combination of Lassa and VSV was completely safe when injected into normal and immune-deficient mice.

And when Lassa-VSV was tested in mice with a brain tumor called glioma, the virus crossed the blood-brain barrier and selectively infected the tumors. Untreated mice died within a month, but those treated with Lassa-VSV survived indefinitely with no trace of the tumors.

In addition, the virus can activate the body’s natural immune system to target cancer cells, eventually taking over the job of killing them.

“The immune system has a very long memory,” van den Pol said. “The virus is only around for two or three weeks.”

And when it’s gone, the virus appears to have no lasting negative effect.

“The virus seems to be completely eliminated,” van den Pol said. “It can’t be detected.”

Now van den Pol is using the WHRY grant to test whether it can have the same safe, positive effect on ovarian cancer. He credits a collaboration with the lab of Dr. Gil Mor, Professor of Obstetrics, Gynecology, and Reproductive Sciences, who has spent years studying ovarian cancer.

“If Lassa-VSV worked for only a small percentage of women or helped women survive longer, it could be dramatically different from any current treatment option,” van den Pol said.

He hopes to eventually secure funding to ensure his virus is safe to test in humans, expressing confidence in the future of viruses as therapy for deadly cancers.

“Microbes scare us,” van den Pol said. “But they can also be beneficial in helping us target and kill cancer cells.”

To read this full article on News-Medical.net, please click here.

Complete Resection Tied to Improved Survival in Low-Grade Serous Ovarian Cancer

Surgical resection to the point of no residual macroscopic disease significantly improved survival among patients with low-grade serous ovarian carcinoma, based on the findings of a large multicenter retrospective cohort study.

Adjuvant platinum-based therapy, however, did not appear to boost survival in the analysis, Tamayaa May, MD, MSc, said at the annual meeting of the Society of Gynecologic Oncology. “Genotyping and targeted sequencing of low-grade serous ovarian carcinoma often identifies actionable mutations, and treatment with MEK-based combination therapy might be a viable therapeutic strategy in patients with KRAS or NRAS mutations,” added Dr. May of Princess Margaret Cancer Center at the University of Toronto. She and her associates plan to examine more subgroups to determine if genomic alterations predict systemic response, she said.

Low-grade (Silverberg grade 1) serous ovarian tumors are slow growing but tend to resist chemotherapy, making optimal debulking a crucial part of treatment. In past studies, debulking that eliminated macroscopic evidence of disease was associated with a median survival time of about 115 months, compared with about 43 months if patients had residual disease, Dr. May noted.

To further explore outcomes after surgical resection, and to help clarify the role of systemic platinum-based therapy in low-grade serous ovarian carcinoma, she and her associates analyzed clinical data from 714 patients with low-grade serous ovarian carcinomas, including 40 from her institution and 674 from the Ovarian Cancer Association Consortium Registry. Most (60%) patients had stage III disease at diagnosis.

Complete data on surgical outcomes were available for 382 patients, of whom 202 (53%) had residual macroscopic disease and 43% did not. Among 439 patients with complete treatment data, 170 (39%) received first-line platinum-based chemotherapy. For the 391 patients with complete data on progression-free survival (PFS), the median follow-up was 4.9 years and median PFS was 3.1 years (95% confidence interval, 2.6-4.5 years). Residual macroscopic disease correlated with shorter PFS (P less than .001), as did higher tumor stage and baseline CA125 (P less than .001), but platinum-based therapy did not (P = .1).

A multivariable analysis of 333 patients confirmed these findings, Dr. May said. Independent correlates of death or disease progression included residual macroscopic disease (hazard ratio, 2.38; 95% CI, 1.68-3.37; P less than .001), older age (HR, 1.15; 95% CI, 1.02-1.30; P = .02), and stage III (HR, 3.28; 95% CI, 1.87-5.76; P less than .001) or stage IV disease (HR, 5.68; 95% CI, 2.73-11.83; P less than .001), compared with stage I disease. In contrast, platinum-based therapy did not correlate with survival (HR, 0.94; 95% CI, 0.69-1.28; P = .69).

The overall survival analysis also linked mortality with higher tumor stage, increased baseline CA125, and residual disease (P less than .001 for each association), but not with platinum-based therapy (P = .2). The multivariable analysis independently tied mortality to older age (HR, 1.25; P less than .001), stage III (HR, 2.31; P = .006) or IV disease (HR, 3.86; P less than .001), and residual disease (HR, 2.53; P less than .001), but not to platinum-based therapy (HR, 1.05; P = .77).

Data consistency and completeness were issues in this study: most notably, 45% of patients had no PFS data, Dr. May commented. Nonetheless, this type of large retrospective multicenter analysis is one of the best ways to study rare tumors, including low-grade serous ovarian carcinoma, she said.

The Ovarian Cancer Research Fund provides financial support for OCAC. Dr. May reported having no conflicts of interest.

To read this entire article on MDedge.com, please click here.

Recruitment Begins for World’s First Ovarian Cancer Vaccine Trial

UConn Health is beginning to recruit patients for the world’s first personalized genomics-driven ovarian cancer vaccine clinical trial. The goal: to prevent an often deadly relapse of the disease in women diagnosed at advanced stages.

The pioneering injectable vaccine OncoImmunome works by boosting the patient’s immune response to enable it to destroy ovarian cancer cells should they resurface. The FDA approved the human clinical trial testing of the experimental vaccine therapy following published research findings showing its effectiveness in reducing cancer growth in animal models.

The new clinical trial will begin with the enrollment of 15 women with stage III or IV ovarian cancer at initial diagnosis or first relapse who will be closely followed for two years – the timeframe with the highest risk of disease recurrence.

Clinical trial candidates are women diagnosed with advanced stage III or IV ovarian cancer who will have traditional surgery where tumor samples will be collected for vaccine production, followed by standard chemotherapy. If cancer-free after traditional treatment, the women will each receive their personalized vaccine injections once a month for six months. Also, each month their blood will be drawn and evaluated for immune response.

The clinical trial will be led by Dr. Susan Tannenbaum, chief of the Division of Hematology & Oncology at the Carole and Ray Neag Comprehensive Cancer Center at UConn Health. Co-investigators are Dr. Molly Brewer, chair of the Department of Obstetrics and Gynecology and Karen Metersky, APRN.

“We are pleased that this moment has come,” says the vaccine’s inventor and immunotherapy expert, Dr. Pramod K. Srivastava, director of the Neag Comprehensive Cancer Center at UConn Health. “This clinical trial will test the power of a patient’s own immune system to prevent recurrence of this often fatal disease. We hope this vaccine can fill the huge gap in therapy options for ovarian cancer patients and potentially bring a long-term solution and cure for women battling the disease.”

Srivastava adds: “Since this trial is a first of its kind, there are a lot of unknowns. We are hopeful the study will answer some of them.”

Each vaccine is individualized for each woman and created using samples of her own DNA from both her unhealthy cancer cells and her healthy blood cells. Over a period of about two weeks, scientists sequence and cross-reference the entire DNA from both sources to pinpoint the most important genetic differences. These genetic differences constitute the ID card, or fingerprint, of that particular patient’s cancer, which is unlike the ID card or fingerprint of any other person’s cancer. Based on the cancer’s fingerprint, bioinformatic scientists led by Ion Mandoiu, PhD, of the School of Computer Sciences and Engineering at UConn in Storrs design the personalized vaccine to target the patient’s cancerous cells specific genetic mutations.

According to Srivastava, this immunotherapy trial has the potential to lay the foundation for similar genomic-driven personalized cancer vaccines against other major cancers such as prostate, bladder, stomach, colon, breast, lung and other cancers.

This year, the American Cancer Society estimates that about 22,440 women will be diagnosed with ovarian cancer and approximately 14,080 women will die from the disease. Why? Currently, there is no early-screening test for ovarian cancer and no effective long-term treatment. It is often diagnosed at advanced stages following the surfacing of non-specific abdominal symptoms such as bloating. But even after a woman is successfully treated with traditional surgery and chemotherapy, the disease has a very high chance of coming back. Tragically, most women die within five years of their diagnosis.

To learn more about the new clinical trial and its enrollment, please visit here.

To read this entire article by MedicalXpress.com, please click here.

Genetic Testing Rates for Ovarian Cancer Low Across Ontario

Nearly 3,000 Canadian women will be diagnosed with ovarian cancer this year. Often undetected, until it progresses to late stages, the disease is the fifth most common – and the most serious – cancer in women.

Symptoms of ovarian cancer generally appear after it has already spread within the pelvis and abdomen and, once it has spread, the cancer is difficult to treat. In these later stages, it is often fatal. Early-stage ovarian cancer, in which the disease is confined to the ovary, is more likely to respond to treatment – an indication early detection and intervention could be key in increasing treatment and survival rates.

Genetic consultation in ovarian cancer testing – which has shown promising potential for life-saving benefits – isn’t as common as it should be, according to Western researchers.

In a recent study, published in the March issue of the International Journal of Gynecological Cancer, Dr. Jacob McGee, a professor in the Schulich School of Medicine & Dentistry and a gynecology oncologist at London Health Sciences Centre (LHSC), found that, on average, less than seven per cent of Ontario women with the most common type of ovarian cancer were seen for genetics consultation within two years of diagnosis.

Women at the highest risk of developing high-grade serous ovarian cancer (HGSC) are those with a mutation in their BRCA (tumour suppression) genes, which can be identified through genetics consultation.

Given the results of the study, McGee and his colleagues were able to demonstrate that by changing the way women are referred for ovarian cancer genetic consultation, it is possible to increase genetic testing rates from less than 20 per cent to almost 80 per cent, potentially increasing diagnostic and treatment outcomes.

The identification of the BRCA mutation can mean the difference between life and death for family members of the affected individual. For women with the BRCA mutation, there is a 50 per cent chance they will pass that mutation on to their children and grandchildren. If the hereditary gene can be found in the affected individual, and then identified in their family members, it can be followed by life-saving interventions including surgically removing the ovaries and fallopian tubes, before there is a diagnosis of cancer. This preventative procedure has been shown to drastically reduce mortality rates, McGee explained.

Identification of the gene also allows for consideration of treatment with a PARP (poly-ADP-ribose polymerase) inhibitor, a new class of medication found to be beneficial only for women with this mutation.

McGee and his research team cite an intervention at LHSC’s London Regional Cancer Centre (LRCP), which has increased the rate of consultation in London to well above the provincial average.

In London, the genetics referral process for patients with HGSC was altered from an ‘opt-in’ to an ‘opt-out’ process. This involves automatically forwarding the list of new HGSC ovarian cancer patients to the cancer genetics clinic through an advance directive. Seeing a genetic counsellor or geneticist becomes the default, with patients stepping outside of the referral process only if their physician cancels the consultation with genetics. In the first year of implementation, 77 per cent of patients at LRCP diagnosed with HGSC completed genetics consultation, well above the provincial average identified in McGee’s study.

“This process has been surprisingly easy to implement, and we think it could be a good fit for other centres across the province,” said McGee, a Lawson Health Research Institute scientist.

Despite the province’s expanding genetic counselling eligibility in 2001 to all women with HGSC ovarian cancer, consultation rates in Ontario remained low during the study period, between 1997 and 2011. The rates did rise, peaking at 13.3 per cent in 2011, however, the numbers remained well below where McGee believes they should be.

“These numbers show no matter what centre you are in, there have to be better interventions to help patients see a genetic counsellor,” he said. “This is something absolutely worth doing because of the impact it has for both the patient’s current treatment and in preventing ovarian cancer cases down the road.”

To read this article on MedicalXpress.com, please click here.

Amid PARP Advances, Chemo Remains Critical in Ovarian Cancer

In the frontline setting, chemotherapy regimens are still the go-to option for patients with ovarian cancer—and likely will be for years to come, explains Heather Dalton, MD.

While PARP inhibitors, such as rucaparib (Rubraca) and niraparib (Zejula), have demonstrated impressive results in later lines of therapy, a carboplatin/paclitaxel regimen is still holding the reigns as a first-line treatment.

Dalton adds that researchers continue to wait for long-term survival data from the Gynecologic Oncology Group (GOG)-252 trial, in which preliminary findings did not demonstrate that intraperitoneal (IP) chemotherapy was superior to an intravenous (IV) regimen.

In an interview during the 2017 OncLive^® State of the Science Summit on Ovarian Cancer, Dalton spoke about the first-line treatment options currently available for patients, pivotal data that have solidified standard approaches, and why chemotherapy will likely always remain critical in the ovarian cancer sphere.

OncLive: What are the options for patients in the first-line setting with ovarian cancer?

Dalton: Unfortunately, most of our patients with ovarian cancer are advanced when they are diagnosed, so we are always left with a conundrum on how to treat them. There has been a lot of research done about the best way to treat these patients. We have moved a long way from initially doing cytotoxic doxorubicin, to around 2003 where carboplatin and paclitaxel became the backbone for our ovarian cancer treatment. Since then, we’ve been looking at different ways to give it and ways to improve progression-free survival (PFS).

Unfortunately, some of those trials have had more success than others. The trial that led to our new standard of therapy was GOG-172, which looked at IV carboplatin and paclitaxel versus IP therapy. The IV method results in significant PFS and (overall survival) OS. That became our new standard of care and we were very excited about.

Subsequently, we have tried to combine that with different types of chemotherapy and different ways to give it. One of those was first actually done in Japan; they looked at giving standard IV chemotherapy compared with what we called dose-dense therapy—which is giving weekly paclitaxel in combination with carboplatin on day 1. We saw a significant improvement with PFS and OS in that study, so we were all very excited about that because the OS difference was even more so than we initially saw in GOG-172.

That was a little bit limited because it was a Japanese study, so how much does that directly apply to our populations here? That population has more clear cell histology, while Americans have more serous histology. Those are some constant criticisms of the study.

Therefore, we repeated that study here in the form of GOG-262, but we added bevacizumab (Avastin). Unfortunately, the bevacizumab seems to have muddied the waters. Most patients got bevacizumab; however, those patients did not experience that big of a difference in OS that we were hoping for. In the subgroup that didn’t actually receive bevacizumab, that improvement in OS was still significant. Basically, we concluded that bevacizumab doesn’t really help in this setting.

Now, we have 2 kinds of conflicting studies—dose-dense and IP—that have never been compared. That was the trial that we were all looking forward to so much, which was GOG-252, that compared standard chemotherapy versus IP chemotherapy plus the dose-dense therapy. We thought this would answer all of our questions that we had and, because bevacizumab saw good results in some trials, we added bevacizumab to the mix. Unfortunately, while the data is not mature, there doesn’t look to be any improvement in PFS in those groups.

The initial enthusiasm for IP chemotherapy has waned somewhat because, now, we haven’t been able to replicate what we saw in GOG-172. Dose-dense therapy is a more tolerable regimen for a lot of people, so now there is no great consensus on how to best treat those patients in the upfront setting. Dose-dense therapy is reasonable, but IP chemo is not unreasonable. We need more data; that is where we are up to speed in the ovarian cancer clinical trials world.

Are you looking to combine chemotherapy with some novel agents, such as the PARP inhibitors, in the frontline setting? 

There are currently multiple ongoing trials in the frontline setting coming out about maintenance PARP inhibitors after receiving frontline standard chemotherapy. Most of the data is still accruing, so we don’t have a great answer. Certainly, our hope is that we will get some great benefit. Most clinical trials start in the recurrence setting, and then move into the frontline setting as we get better and better results. We have seen good results in the recurrent settings. We were hoping to move some of that forward to the initial setting and hopefully be able to benefit some of our patients, in terms of maintenance.

What other interesting ongoing trials are being conducted in this area?

I will be interested to see what matures out of GOG-252; that survival data is not yet mature. We still don’t have a great answer. Really, a lot of us would like to see a head-to-head comparison of dose-dense therapy versus IP chemo without bevacizumab. That would really answer our question because those trials are very hard to accrue. The more moderate thinking with PARP inhibitors and bevacizumab is hard. I don’t know if we will ever be able to answer that question, but it would be awesome if we could.

Do you foresee chemotherapy always having such a significant role for these patients?

I do think it will always have a role, unfortunately. Especially in the upfront setting, cytotoxic therapy is so important. Targeted therapies and immunotherapies are going to have a big role, but it will be adjunct to the initial backbone. Then, hopefully, we can really implement those as maintenance strategies, especially with things like PARP inhibitors and all of these others that are coming down the pipelines—like immune modulators that regulate the tumor microenvironment. I don’t know if, in my lifetime, we will see standard chemotherapy go away.

Is it worth testing another angiogenesis inhibitor in some of these trials, such as ramucirumab (Cyramza)?

We have looked at other angiogenic drugs; most of those trials have been in the recurrent setting and not upfront. Much like bevacizumab, we were all very excited about it initially. We have realized that it is a good adjunct in some situations, but I don’t think angiogenesis alone is going to be the answer. This also goes for targeting members of the VEGF family or the receptor, or other members of the TKI family that affect angiogenesis. The tumors are smart, it’s complex, and we need more than that.

What else could the future treatment landscape of ovarian cancer hold?

It will still be a backbone of a platinum-based therapy and paclitaxel. It is going to move more toward a dose-dense setting and that is an easier regimen for patients to tolerate.

We are going to move much more toward a maintenance setting and, with BRCA, the PARP inhibitors coming out, and the homologous recombination deficiency families of mutations that we’re able to target now we hope that we will have a solid maintenance strategy to offer these patients. Ideally, we are then starting to move the PARP inhibitors and other agents into the frontline setting with initial chemotherapy followed by maintenance. That is where things are going to head over the next few years.

To read this entire article on OncLive, please click here.

Hypertension Linked to Better Outcomes for Subset of Ovarian Cancer Patients

Hypertension, or high blood pressure, may come with a plus side, at least for a subset of women with ovarian cancer. New research from epidemiologists at Roswell Park Cancer Institute, published in the journal Cancer Causes & Control, provides evidence that hypertension and diabetes and the use of medications to treat these common conditions may influence the survival of ovarian cancer patients -; sometimes in a detrimental way, but in the case of hypertension medications, perhaps as a benefit.

Using pooled data from 15 studies that were part of the Ovarian Cancer Association Consortium, an international team of collaborators led by Kirsten Moysich, PhD, MS, and Albina Minlikeeva, PhD, MPH, retroactively examined the associations between survival among patients diagnosed with invasive epithelial ovarian cancer and those patients’ history of hypertension, heart disease, diabetes, and medications taken for those conditions.

They found that while a history of diabetes was associated with a 112% higher risk of mortality across more than 7,600 cases, no significant mortality associations were observed for hypertension or heart disease. In fact, the authors report, among women with endometrioid ovarian cancer, a subtype of epithelial ovarian cancer typically associated with better outcomes, hypertension -; a condition that applied to nearly 26% of women in the pooled analysis -; was associated with 46% lower risk of ovarian cancer progression.

“This is a coincidental and unintended consequence of hypertension and its treatment, but it’s a silver lining to a serious but largely manageable medical condition that has reached epidemic prevalence in the U.S. and many other countries worldwide,” says Dr. Moysich, Distinguished Professor of Oncology in the departments of Cancer Prevention and Control and Immunology at the Buffalo cancer center.

This study is the first to highlight the role of comorbidities in relation to ovarian cancer survival by histological subtype, and confirmed previous findings linking a history of diabetes to increased risk of death among ovarian cancer patients. It’s possible that commonly prescribed antihypertensive medications, including beta blockers, may influence the growth of ovarian tumors. But the team also documented a higher overall risk of death for patients who had ever taken beta blockers, and notes that further study is needed to better understand these processes and interactions.

“Our results suggest that it is important to investigate factors that explain the difference in cancer outcomes among women with different types of ovarian cancer. Most studies only consider clinical characteristics at diagnosis, such as stage and histology in relation to ovarian cancer prognosis,” adds Dr. Minlikeeva, a postdoctoral Research Affiliate with Roswell Park’s Department of Cancer Prevention and Control. “Our findings emphasize the importance of understanding the full clinical profile for women with ovarian cancer in order to predict ovarian cancer outcomes.”

Approximately 22,300 new cases of ovarian cancer are diagnosed each year in the U.S., with an estimated 14,200 women dying from the disease each year. Endometrioid carcinoma accounts for about 20% of all epithelial ovarian cancers.

To read this entire article on News-Medical.net, please click here.