Benefit seen across all subgroups for patients with platinum-sensitive disease.
Ovarian cancer patients with recurrent, platinum-sensitive disease experienced a longer interval without disease progression when bevacizumab (Avastin) was added to niraparib (Zejula), a phase II study found.
Median progression-free survival (PFS) in the combination arm was 11.9 months compared to 5.5 months with single-agent niraparib (HR 0.35, 95% CI 0.21-0.57, P<0.0001), Mansoor Raza Mirza, MD, of Rigshospitalet Copenhagen University Hospital in Denmark, reported here at the American Society of Clinical Oncology (ASCO) annual meeting.
Patients were stratified by homologous recombination-deficiency (HRD) status and chemotherapy-free interval (CFI), and all patients demonstrated a PFS benefit with the combination:
HRD-positive (HR 0.38, 95% CI 0.20-0.72, P=0.0019)
HRD-negative (HR 0.40, 95% CI 0.19-0.85, P=0.0129)
CFI 6-12 months (HR 0.29, 95% CI 0.14-0.62, P=0.0006)
CFI >12 months (HR 0.42, 95% CI 0.20-0.80, P=0.0062)
“Compared with niraparib alone, the combination of the niraparib plus bevacizumab as definitive treatment for ovarian cancer significantly improved PFS, regardless of HRD status and chemotherapy-free interval,” Mirza said, noting that this is the first randomized trial evaluating a chemotherapy-free combination using established agents approved for recurrent ovarian cancer.
Overall response rates were significantly higher in the niraparib-bevacizumab arm than in the niraparib alone arm (60% vs 27%), as were rates of stable disease (79% vs 53%, respectively).
“In the non-curative setting it’s all about preferences,” said ASCO-invited discussant Don Dizon, MD, of Lifespan Cancer Institute in Providence, Rhode Island. “For those patients in whom a PARP inhibitor is not provided in the frontline setting, these are highly relevant data.”
He noted that while there was no increase in treatment discontinuation due to toxicity in the combination arm, hypertension was far more common with bevacizumab (26.5% vs 0%), as was neutropenia (12.2% vs 2.1%).
“Interestingly, it did not translate into any differential aspects of quality of life,” Dizon noted.
The researchers also looked at BRCA mutation status. With wild-type BRCA, the combination arm had a PFS benefit (HR 0.32, 95% CI 0.17-0.58, P=0.0001). For BRCA-mutant disease, where patient numbers were smaller, there was no significant PFS difference between the groups (HR 0.49, 95% CI 0.21-1.15).
The open-label phase II AVANOVA2 study randomized 97 patients with recurrent, platinum-sensitive ovarian cancer to either 300 mg daily niraparib with or without 15 mg/kg bevacizumab, every 3 weeks until disease progression or unacceptable toxicity. Patients were required to have high-grade serous or endometrioid histology. Roughly 60% of patients in each arm were HRD-positive and a similar proportion of patients had a CFI greater than 12 months.
Any number of prior lines of therapy was allowed, as was prior bevacizumab maintenance, and median progression-free survival was the primary endpoint.
Dose reductions were similar in the combination (48%) and single-agent (43%) arms, as was treatment discontinuation due to adverse events (13% vs 10%, respectively). Fifteen patients in the combination arm remained on treatment versus five in the niraparib arm at data cutoff.
“Niraparib and bevacizumab combination therapy was well tolerated,” said Mirza. “Most patients remained on treatment until disease progression.”
A phase III trial — NSGO AVATAR — is planned to test niraparib-bevacizumab and the combination plus TSR042 against standard of care in recurrent, platinum-sensitive epithelial ovarian cancer.
Many complex terms and numerous abbreviations are used in the field of oncology. Many patients likely do not fully understand these terms, whether they hear them during their oncology visits or when reading through information that they find themselves. The purpose of this fact sheet is to explain some of the more commonly used terms in oncology. Other resources are available that provide a more comprehensive and searchable glossary, such as the National Cancer Institute Dictionary of Cancer Terms or the American Society of Clinical Oncology’s Cancer.Net Cancer Terms.1,2
This fact sheet provides the meaning of oncology lingo that patients may commonly hear following a cancer diagnosis.
Diagnosis and Disease Terms
There are 2 major types of cancers, those that are referred to as solid tumors and those that are considered blood cancers. Solid tumors are any cancers that begin within a solid tissue or organ, whereas blood cancers originate with cells that are present in the blood, but do not form a solid mass. A tumor is essentially a group of abnormal, or atypical, cells that form a ball of tissue. Tumors can be cancerous or benign. Benign means that although the cells are abnormal, they are not truly considered cancerous, and there is no risk for it spreading beyond the location of the tumor. Benign tumors are rarely life-threatening.Many patients are familiar with the concept of hereditary cancers, when cancer runs in families and is seemingly “passed on” to family members. In these cases, specific mutations in genes that are associated with cancer are inherited and can (but not always) result in cancer. However, the majority of the time cancer is sporadic, meaning it develops without a clear link to inherited traits. When cancer is diagnosed, it is staged, meaning it is categorized based on severity. When the cancer is staged several factors are typically considered, including the size of the tumor and whether or not it has spread beyond a primary site. Metastatic cancer is disease that has spread beyond the original tumor. Distant metastases include cancers where cancer cells are found in other organs than where the original tumor was found. For example, if the original cancer is lung cancer and a group of cancerous cells are found in the liver, it is considered to be a distant metastasis. Locally advanced cancers are those that have spread beyond the original tumor, but nearby, such as to the nearby lymph nodes or just beyond the border of the original tumor.
Although tumors are identified through imaging, a biopsy is needed to confirm the cancer type and to perform any other tests that may help the health care team decide how it will best be treated. A biopsy is a small piece of tissue that is taken from the original tumor or from a metastatic site. There are several different types of biopsies, and the type that is taken will depend on the type of cancer and where it is located. For example, a fine-needle aspirate is when a biopsy is taken with a needle. An excisional biopsy is one in which the tumor is cut out, which is common with skin cancers. Liquid biopsy is when a liquid sample is taken (blood, saliva, urine) and tested for cancerous cells; however, this type of biopsy is not yet commonly used, and many new tests using bodily fluids are still in development and have not yet been approved by the US Food and Drug Administration (FDA).
Biopsies are used to look at the cells of the cancer under the microscope and to do testing to diagnose the exact type of cancer that is present and sometimes to perform staging, which is important when determining how the cancer should be treated. In addition, the biopsy may be used for testing for gene mutations, which may be referred to as sequencing, mutational analysis, genetic testing, or genomic testing.
Treatment and Prognostic Terms
There are many different types of treatments that are used for cancer, depending on the type and stage. For earlier-stage cancers, surgery is used to remove the tumor. In some cases, systemic treatment — when you take a drug, either orally, by injection, or via intravenous infusion, that affects the whole body — is also used. When systemic treatment is given before surgery, it is called neoadjuvant. When systemic treatment is given immediately after surgery, it is called adjuvant.
For patients with metastatic cancer, systemic therapy is often given alone without surgery. Health care providers may talk about the line of therapy, such as first-line (or frontline) or second-line therapy, which refers to the order of systemic therapies. The first type of treatment given is first-line therapy, and if the cancer does not respond or stops responding, the second type of treatment is called a second-line treatment. Sometimes patients will be given maintenance therapy after their initial treatment, which is to help maintain the response to the original therapy for a longer period of time. There are several major types of therapies used systemically and these include chemotherapy, targeted therapy, hormone therapy, and immunotherapy.
Some patients will receive radiation therapy in addition to surgery and/or systemic treatment. Radiation refers to a type of high-energy particles or waves that are targeted to a tumor or an area where the tumor was located prior to surgery to kill any additional cancer cells. External radiation is when the radiation is given by a machine that is outside the body, whereas internal radiation, or brachytherapy, is when radioactive material is implanted in the body. Image-guided radiation uses some type of imaging, such as ultrasound or MRI, to guide where the radiation beam should be targeted. Intensity-modulated radiation is when the beam of external radiation is shaped to more closely resemble the shape of the tumor.
Stem cell transplant is another type of treatment, most commonly used for blood cancer. This includes removing the patient’s bone marrow (which is where blood cells are produced) using high-dose chemotherapy and sometimes with radiation therapy. This approach is called induction therapy, because it induces the bone marrow into a state that is necessary for the transplant to occur. The actual stem cell transplant occurs when healthy bone marrow is transplanted. Stem cell transplant is part of consolidation therapy, which is the treatment given immediately after induction therapy to prevent the cancer from recurring.
Consolidation may also include additional chemotherapy. There are 2 types of stem cell transplants: allogeneic, which uses healthy matched tissue from a donor, or autologous, which uses the patient’s own tissue taken prior to induction therapy.
Health care providers may discuss the patient’s prognosis, or the expected outcomes, with different treatment approaches. How well the treatment works, or its efficacy, is often described using terms about survival and response. Overall survival is the length of time a patient survives after starting treatment. The amount of time that the cancer does not group or spread after starting treatment is referred to as progression-free survival. The overall response rate or objective response rate is the proportion of patients whose cancer responds to the treatment; a “response” occurs if the tumor shrinks (ie, a partial response) or disappears (ie, complete response). Some tumors will stop growing as a result of treatment but do not shrink; it this occurs, the patient is said to have achieved what is known as stable disease. A remission occurs when the signs and symptoms of the cancer are temporarily or permanently gone; however, the cancer itself may still be present. Cure is when the patient is restored to full normal health and is sometimes used after a patient is cancer-free for at least 5 years – many oncologists bristle at the term “cure”, as it implies the cancer will never recur. A recurrence or relapse occurs when the cancer returns after a period when it could not be detected. Sometimes a recurrence occurs at the original site of the tumor or at other sites.
Sometimes during treatment for cancer, a tumor can stop responding to treatment that at one point triggered a response—when this occurs, the tumor is labeled refractory. Cancer that never responded to a treatment is called resistant or treatment resistant.
Patients will sometimes receive treatment that is termed palliative, which means that it is used to help improve symptoms of the cancer, but is not expected to stop the growth or spread of the malignancy.
Side-Effect Terms
Side effects that occur during treatment — which may or may not be due to the treatment itself — are called adverse events or adverse effects. To specify that a side effect is due to the treatment, the term is treatment-related or treatment-associated adverse event. Many side effects are acute, meaning short-term, but some can be chronic, or long-term. Late effects can also occur, which are side effects that occur much later after treatment has been completed.
A common side effect of treatment is fatigue, which is extreme tiredness or the feeling of no energy that results in the inability perform many functions. Nausea is also common and refers to a feeling of discomfort or sickness in the stomach. Some other examples of side effects include mucositis, which is inflammation of the digestive track that often causes sores in the mouth, and stomatitis, which is specifically inflammation of the mouth and also causes mouth sores. Pyrexia refers to fever and pruritis is itchiness.
Scientists at Uppsala University and the Sahlgrenska Academy, University of Gothenburg say they have developed a blood test that may provide a more precise diagnostic for suspected ovarian cancer that would eliminate the need for exploratory surgery. This could lead to a reduction in unnecessary surgery and to earlier detection and treatment for affected women, noted the researchers whose study (High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer) was published in Communications Biology.
“Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30–40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations,” the investigators wrote.
“The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85, and specificity = 0.93 for detection of ovarian cancer stages I–IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.
“We need to develop more accurate pre-surgery diagnostics. To detect one cancer, we operate on up to five women—yet this is currently the best option when abnormalities are detected by ultrasound and cancer is suspected. There is a great need for a simple blood test that could identify women who do not need surgery,” said Karin Sundfeldt, MD, PhD, professor and senior consultant at the department of obstetrics and gynecology, Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg.
The biomarker profile can also detect borderline cases and early stages of the disease.
“Our results are promising enough to consider screening for early discovery of ovarian cancer. In Sweden, we have a lot of experience screening for cervical cancer. I see great prospects of developing a strategy for screening for ovarian cancer as well, which could save lives and minimize the need for surgery to rule out cancer,” added Ulf Gyllensten, PhD, professor of medical molecular genetics at the department of immunology, genetics and pathology at Uppsala University. “We are now continuing to evaluate the test and are performing a large-scale study of samples collected at all hospitals from the western region and Halland healthcare system.”
Our Clinical Trial Finder is a personalized and online search tool that will help you to find a clinical trial based on your location or clinical situation (i.e. platinum sensitive or platinum resistant, number of previous treatments). We can also help you do this search, or understand how some of the drugs in the trials may benefit your unique situation, by calling us at 858-675-0282.
One obstacle may be the baffling scaffolding scientists erect around their studies. For example, cancer is a disease of aging, but many clinical trials on cancer drugs exclude older people from participating.
In another study on the exclusion of large segments of cancer populations, published last year in The Oncologist, researchers argued that “the criteria for participation in some clinical trials may be overly restrictive and limit enrollment.”
But the problem of low enrollment is often attributed to patient resistance. The reluctance of some patients makes perfect sense to me. Fear about unforeseen side effects escalates when consent forms, like the ones I signed, state that a new regimen cannot cure but might kill patients.
People facing a poor prognosis may not want to squander their limited energy on traveling, undergoing invasive scans or inhabiting hospital environments. The location of trials in urban centers poses a challenge for rural populations. Additionally, eligibility requirements make it impossible to enroll when people don’t have a specific genetic mutation or have previously taken a specific drug.
Yet other qualms seem to be based on persistent delusions. Quite a few people miss out on free, cutting-edge treatment because of spurious suppositions. The commonly held view that patients will be given nothing but a placebo is rarely the case. In a randomized study, people on one arm may not receive the new medicine, but they will get “the best standard of care available” and their progress will be monitored. Placebos cannot be employed when an effective therapy is available. They may be used to test a supplementary protocol, but patients would be informed. And not all trials are randomized.
Why enroll if most trials result neither in medical breakthroughs nor in extending survival rates? One answer: even negative data extend scientific knowledge. Another: the ethical backbone of research (worth repeating) requires that all participants in trials receive “the best standard of care available” for their specific disease. Did I mention that this care is free?
The worries of patients that they will be reduced to guinea pigs should be put to rest by an important principle underscored by the physician, author and cancer survivor Dr. Wendy Harpham. When clinicians care for patients, she explains, they “abide by their professional oath as physicians to act with their patients’ welfare as their top priority.” Should a regimen prove deleterious, patients would be encouraged to drop out. In any case and for whatever reason, enrolled patients are always free to stop participating.
All these inhibitions retard enrollment; however, low rates of participation should also be attributed to insufficient information. While confronting cancer, a situation fraught with terror about personal survival, most men and women simply do not know our options and we do not have the ability to discover them on our own.
Unless oncologists are themselves researchers, they may not guide patients toward clinical trials. It is not in their self-interest to do so and it would take a considerable amount of time. Despite the government’s effort to make its website user-friendly, finding a suitable clinical trial can be exceptionally difficult. Online help sites may steer some patients to the right trials, but not all.
Only recently did I learn about clinical trial navigators, professionals who may be nurses or lay people, and who work to locate and explain trial options, negotiate complex eligibility issues and offer support as decisions are made. There is some evidence that trial navigators can promote the inclusion of racial and ethnic minorities who have been shockingly underrepresented in clinical trials. They are employed at a number of cancer centers, but not at mine in Indiana.
A cherished member of my cancer support group, Trudy Brassell, desperately wanted a clinical trial navigator but was unable to find one.
Trudy, assiduous in her fact-gathering, eventually became exceptionally knowledgeable about which physicians were conducting trials in ovarian cancer and where; however, she faced a host of difficulties as she sought to find one to cope with her disease. Some required weekly trips to a faraway hospital, some ruled her out on the basis of earlier treatments, some were closed, and some were run by incompetents who informed her that she was eligible but determined later that she was not. The months spent emailing, phoning and traveling escalated her anxiety while her tumors continued to grow.
While she was dying, she continued to wonder how she could have evaluated drugs she had never heard of and procedures she did not comprehend. At her memorial, her family and friends sang the hymn “Jerusalem,” based on William Blake’s stirring poem, because even under frightful circumstances, Trudy never ceased from “mental fight.”
Trudy died in 2018, two years after Congress authorized $1.8 billion in funding for research known as the Cancer Moonshot. It seems to me that no amount of talk about moonshots will be productive until a much larger proportion of patients enlist in clinical trials, as is the norm in an area known for research breakthroughs: pediatrics.
The majority of pediatric patients — 60 percent of babies, children and young adults — are treated in clinical trials. In the past 50 years, the overall survival rate for children has increased from 10 percent to over 80 percent, a heartening statistic not totally attributable to clinical trials but surely related to them.
Why do children and adults have such different participation rates in trials? Dr. Mitchell S. Cairo, the chief of pediatric hematology, oncology and stem cell transplantation at New York Medical College, said that one factor may be that 85 percent to 90 percent of children are treated at academic centers, whereas only about 10 percent to 15 percent of adults are. Despite childhood and adulthood differences in cancer histology and genetics, Dr. Cairo said, “increased accrual of adults onto cutting-edge clinical trials would likely increase the survival rates in a subset of adults with specific malignancies.”
What if adult cancer patient were given the opportunity to consult with a trial navigator who would address rational and irrational concerns, provide a personalized list of available trials, and discuss their suitability? Perhaps pediatric oncology should become the paradigm for adult cancer care and the dictum of Isaiah our watchword: “and a little child shall lead them.”
Susan Gubar, who has been dealing with ovarian cancer since 2008, is distinguished emerita professor of English at Indiana University. Her latest book is “Late-Life Love.”
Does talc cause cancer? At least 13,000 people think so, and have filed lawsuits against Johnson & Johnson, the manufacturer of several talcum-based products. Yet so far, juries and scientists have been divided on the issue. Although in March 2019, a New Jersey jury ruled1 that the company’s baby powder didn’t cause a consumer’s mesothelioma, last summer, a Missouri circuit court ordered Johnson & Johnson to pay $4.69 billion to 22 women and their families who claim the product caused them to develop ovarian cancer.2
Prospective studies on talc and cancer are necessary to fully form our collective understanding of talc’s risks.
That question intrigued Wayne State University researcher Ghassan Saed, PhD, of the Karmanos Cancer Center in Detroit, Michigan. Like millions of women who apply talcum powder in the genital region, he also thought that talc, the clay mineral often used in combination with corn starch in baby powder, was chemically inert and harmless.
Yet in new research that was presented at the 2019 Annual Meeting of the Society of Gynecologic Oncology, Honolulu, Hawaii, Dr Saed’s team showed a link between talc and inflammation in normal and ovarian cancer cells. Specifically, the researchers identified the mechanism of action by pinpointing how the powder induced mutations in the CAT, NOS, and GPX1 genes. “I went to the lab, took the powder and added it to ovarian cancer cell lines. We found that it created an increased oxidative state,” said Dr Saed, who is an associate professor in obstetrics and gynecology and cell biology. The surprising part, he said, was that healthy fallopian cells reacted in a similar pattern – a key connection in light of the emerging scientific consensus that ovarian cancer begins in the fallopian tubes. “This is the first in vitro study that shows a direct biological effect on what’s thought to be an inert substance on ovarian cancer cells and most importantly, normal cells coming from the fallopian tubes,” he said.
Approximately 22,240 women in the United States were diagnosed with ovarian cancer in 2018, and 14,070 women died the same year, according to government surveillance data.3 So far, most of the evidence linking a woman’s use of talcum powder to an increased risk of developing ovarian cancer comes from 2 case-control studies in 2016 in which researchers asked women who already had ovarian cancer about their grooming routines.
For example, the African American Cancer Epidemiology Study compared 584 African-American women with ovarian cancer to 745 healthy women and found that those who had reported using talc in the genital area were 44% more likely to have been diagnosed with ovarian cancer.4 And another study came to a similar conclusion after questioning 2041 women living in Massachusetts and New Hampshire who had been diagnosed with ovarian cancer with a control group of 1578 women without cancer.5
Yet a 2017 meta-analysis of 24 case-control studies and 3 cohort studies found that the current scientific evidence of a link between genital use of talcum powder and ovarian cancer was not consistent. “Our conclusion was that the evidence was a bit ambiguous and doesn’t clearly go one way or the other,” said coauthor Paolo Boffetta, MD, MPH, professor of medicine, oncological sciences, environmental medicine, and public health at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York, New York. “There are elements suggesting there might be an association. On the other hand, there are elements in the data that the relationship might be due to other factors.” He said the ideal “methodically stronger” study would be to enroll healthy women, ask them about their talcum use and see how many eventually develop ovarian cancer.
Dr Boffetta said the challenge of the Wayne State University study was that it’s hard to know if the cells that were exposed to talc in the lab would react the same way in a woman’s body. “It’s one thing to experiment with cells in an artificial environment, but we don’t know if the same thing happens in vivo in an actual woman’s ovary,” he says. “[These] data [are] interesting, of course, but I’d like to see more prospective studies. That’s what is missing in our collective understanding.”
For Dr Saed, his next project will involve injecting talcum powder directly into rats’ reproductive systems. “Hopefully these next studies will confirm our findings and provide important information to share with the public to tell them to stop using talcum powder,” he said.
In-situ vaccine may enhance immunotherapy response in resistant cancers, study shows.
A novel approach to cancer immunotherapy injects immune stimulants directly into a tumor to “teach,” induce the immune system to destroy the cancer and other tumor cells throughout the body. The three-step approach works as an in-situ cancer vaccine, researchers said.
A preliminary study could point to a new way of making immunotherapy more effective in cancers that have proven to be resistant to treatment and also enhance the effects of checkpoint blockade.
“The in-situ vaccine approach has broad implications for multiple types of cancer,” the study’s lead author, Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told the Reading Room. “This method could also increase the success of other immunotherapies, such as checkpoint blockade. The in-situ vaccine has multiple benefits: it’s simple, more practicable, costs a fraction of a personalized vaccine [does], and lets us optimize therapy.”
So far, Brody and colleagues have treated 11 patients, median age of 54, with indolent non-Hodgkin lymphoma (NHL), a cancer that, in general, does not respond to immunotherapy. Of the 11 patients who received the experimental therapeutic vaccine, one had a complete remission, two had partial remissions, and six had stable disease.
“This adds a new way to make anti-programmed death-1 (PD-1) agents effective in tumors where they are generally not effective,” Brody said. “PD-1 blockers help 20% of NHL patients, but that leaves the other 80% without effective immunotherapy. This is a novel solution to fix that problem. We have seen dramatic results in the laboratory to make PD-1 blockers more effective, and the vaccine induces systemic clinical remissions that can last for months.”
As immunotherapy continues to benefit from novel approaches to cut immune brake pedals, such as anti‐PD-1 and anti‐cytotoxic T-lymphocyte antigen 4 antibodies, there will be an increasing need to develop immune “steering wheels,” such as vaccines to guide the immune system specifically toward tumor-associated antigens, he noted. One hurdle in cancer vaccines has been the identification of universal antigens to be used in “off‐the‐shelf” vaccines for common cancers. Another hurdle is production of individualized whole tumor cell vaccines.
The new vaccine essentially turns the tumor into cancer vaccine factories by teaching the immune cells to recognize the cancer cells, said Brody. Once identified, the immune cells actively seek out all the cancer cells of the body and kill them. The three-step approach consists of (1) recruiting dendritic cells, (2) loading dendritic cell tumor antigens, and (3) activating the antigen-loaded dendritic cells.
The treatment consists of administering a series of immune stimulants directly into one tumor site. In the first step, a human protein form of FMS-like tyrosine kinase-3 ligand (FLT3L) recruits dendritic cells, which are important immune cells that act like generals of the immune army, Brody explained.
In the second step, low-dose radiation therapy activates the dendritic cells, which then instruct T cells, the immune system’s soldiers, to kill cancer cells and spare non-cancer cells.
In the third step, a toll-like receptor-3 agonist activates the dendritic cells and stimulates the immune army to recognize features of the tumor cells so it can seek them out and destroy them throughout the body.
In laboratory tests in mice, the vaccine drastically increased the success of checkpoint blockade immunotherapy. PD-1 blockade didn’t cure any large tumors, but after adding the vaccine, the cure rate increased to 75%. Side effects were grade 1 or 2 flu-like symptoms and muscle aches that last for a day. “We did not see any autoimmune adverse events,” said Brody.
Clinical Trial Ongoing
A clinical trial for lymphoma, breast, and head and neck cancer patients opened in March 2019 to test the vaccine with checkpoint blockade. The in-situ vaccine is also being tested in the laboratory in liver and ovarian cancers.
“Literally hundreds of immunotherapy trials are accruing thousands of patients each year to understand how to better whip T cells into shape and to get immune soldiers to do their job harder,” said Brody. “Clinical oncologists are frustrated that the majority of patients don’t respond to PD-1 blockers. We may be able to potentiate PD-1 blockade with this in-situ vaccine.”
In a 2018 review of in-situ vaccination, Mee Rie Sheen, PhD, of Harvard Medical School in Boston, and Steven Fiering, PhD, of the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, noted that local administration of immunostimulatory reagents into a recognized tumor by in-situ vaccination can generate systemic antitumor immunity to fight metastatic disease. “Conventional vaccines contain antigens and immune adjuvants. With in-situ vaccination, the tumor itself supplies the antigen, and the treatment only applies immune adjuvant directly to the tumor,” the authors stated.
They explained that current immunotherapy often fails to eliminate cancer because of local immunosuppression mediated by tumors. In-situ vaccination, in effect, “changes the tumor microenvironment from immunosuppressive to immunostimulatory, stimulates presentation of tumor antigens by antigen‐presenting cells to T cells, and generates systemic antitumor immunity that promotes antigen‐specific effector T‐cell attack of both treated and importantly, untreated metastatic tumors.”
Sheen and Fiering concurred with Brody about the advantages of in-situ vaccination — i.e., that it:
Is simple and cost‐effective
Has minimal systemic side effects
Is a feasible and flexible adjuvant delivery system
Exploits all tumor antigens in the tumor to avoid the need to identify antigens
Utilizes all antigens in the tumor to minimize immune escape
Has potential synergy when combined with other therapies
An analysis of the phase III SOLO1 trial found no new safety signals when the PARP inhibitor olaparib was given as maintenance therapy for women with newly diagnosed advanced ovarian cancer and a BRCA mutation. Nausea, fatigue, and several other toxicities, including anemia, usually occur early in the course of treatment, suggesting better monitoring is needed in that early period.
“The tolerability profile of maintenance therapy with the PARP inhibitor olaparib in platinum-sensitive relapsed ovarian cancer is well characterized,” wrote study authors led by Nicoletta Colombo, MD, of the University of Milan-Bicocca in Italy, in a poster presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract 5539).
SOLO1 was the first trial evaluating the agent’s use in women with newly diagnosed advanced ovarian cancer. Previously, it showed that maintenance olaparib provides a substantial progression-free survival benefit compared with placebo, and the new analysis examined the safety profile in this new setting.
The analysis included a total of 260 patients treated with olaparib and 130 treated with placebo, with a median follow-up duration of approximately 41 months. The median duration of treatment was 25 months with olaparib and 14 months with placebo.
The most common adverse events of any grade included nausea (77% of olaparib patients vs 38% of placebo patients), fatigue/asthenia (63% vs 42%), vomiting (40% vs 15%), anemia (39% vs 10%), and others. Most adverse events were grade 1/2, though grade 3 anemia occurred in 22% of patients receiving olaparib and only 2% of those receiving placebo.
The median time to first onset of those most commonly reported adverse events was under 3 months for all. The median duration of the first adverse event was also under 3 months for all; it was 1.87 months in the olaparib group for anemia, compared with 1.64 months with placebo.
Nausea, fatigue/asthenia, anemia, thrombocytopenia, and several other common adverse events were generally managed with supportive therapy, dose interruption, and/or dose reduction. Twenty-three percent of olaparib patients required at least one blood transfusion, compared with 2% of placebo patients.
Three patients developed acute myeloid leukemia (AML) during the trial in the olaparib group (1.2%). There were no cases of AML or myelodysplastic syndrome in the placebo group. The time to onset of AML in those 3 patients was 173 days, 49 days, and 52 days after stopping olaparib; AML was fatal in all 3 cases.
“The tolerability profile of olaparib in patients with newly diagnosed ovarian cancer was consistent with that reported in the relapsed-disease setting, with no new safety signals identified,” the authors concluded. “Given that anemia predominantly occurred early, stricter monitoring is required at the beginning of treatment.”
CA125 is a protein that both men and women have in their blood. The normal level of this is 35 units per millilitre (U/mL), or lower.
A CA125 blood test is used to check the level of the protein in the blood. It can be carried out at a local doctor’s surgery if they have the facilities, or the patient will be referred to their local hospital the same way they would for any other blood test.
When might a CA125 blood test be necessary?
A CA125 blood test should be requested if a doctor suspects a patient’s symptoms could be caused by ovarian cancer. A referral for this blood test should be made if a woman is presenting with any of the four main symptoms of ovarian cancer:
Persistent stomach pain
Persistent bloating
Needing to wee more frequently or urgently
Difficulty eating or feeling full more quickly
A referral for a CA125 blood test on presentation of these symptoms is particularly important if they are persistent, frequent and out of the ordinary with no other obvious explanation. A doctor would usually refer for a CA125 blood test following a physical abdominal or internal vaginal examination.
Does an increased CA125 level mean ovarian cancer?
An elevated CA125 level is not a diagnosis of ovarian cancer. More investigations are required to determine what is causing the elevated CA125 level. Patients will be referred for a pelvic or transvaginal ultrasound scan to gain a better internal picture and to identify any abnormal masses on or around the ovaries.
If abnormal masses are seen a patient would usually then require more scans, and some explorative surgery in order to make a certain diagnosis of ovarian cancer. For more information about how ovarian cancer is diagnosed visit the page on our website.
What else can cause a CA125 to be elevated?
There are a number of conditions that can cause a CA125 level to be elevated. They include the following:
It is also important to note that some women have naturally high CA125 levels in their blood.
Can a CA125 blood test be used as a screening tool for ovarian cancer?
Currently, it is not possible to use CA125 blood tests as a way of screening women for ovarian cancer for a number of reasons.
As previously discussed it is not just ovarian cancer that can cause an elevated reading, there are many other things that can cause this to be the case, along with the fact that some women will have a naturally elevated level with no cause for concern. So not all women with a raised CA125 level will have ovarian cancer, and it is also important to consider some women may have ovarian cancer but have a normal CA125 reading.
Annually screening all women with a CA125 blood test could lead to many being referred for further investigations that are unnecessary, causing needless worry and the possibility of having to undergo inappropriate surgery for no reason.
In 2015 the results of a long-term study looking at the effectiveness of annual CA125 blood tests and ultrasound scans found that in some instances more women were diagnosed with the disease earlier, and in some of these cases death rates from the disease were reduced. However, further analysis is required to determine if these results can be conclusive and cost-effective enough for CA125 blood tests and ultrasound scans to form part of a national screening programme.
What other research is happening in screening for ovarian cancer?
Ovarian Cancer Action funds the work of Professor Ahmed at the University of Oxford and so far, the team have made several exciting discoveries that have taken them closer to answering that question. They have found that the number of cells that have a protein called SOX2 is markedly increased in the fallopian tubes of women with or at high risk of ovarian cancer. Having a better understanding of how the disease develops is key to developing a screening tool.
Although they have made some exciting discoveries, there is still a lot more research to be done. Identifying the SOX2 protein is an important step forward but it’s very difficult to get to, meaning a screening tool centred around it would be quite invasive. They are now looking for other changes that take place in the body simultaneously to the SOX2 protein production and, by harnessing different markers, they hope to find another marker that is easier to test for.
They hope to complete their next stage of investigations within the next five years and then the next step would be to translate their findings into clinical research.
Maintenance therapy with the PARP inhibitor rucaparib offered improved post-progression outcomes in a phase III trial of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were in a complete or partial response to platinum-based chemotherapy, according to researchers.
The ARIEL3 trial previously found that rucaparib maintenance therapy significantly improved progression-free survival (PFS) compared with placebo in this setting; the agent was granted approval by the US Food and Drug Administration based on these results. “Evaluation of overall survival may require extended follow-up and may be confounded by subsequent treatments,” wrote study authors led by Robert L. Coleman, MD, of the University of Texas MD Anderson Cancer Center in Houston, in a poster presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract 5522). “Therefore, additional post-progression assessments are needed to help demonstrate the clinical benefit of maintenance therapy.”
The study included a total of 564 patients randomized to receive either rucaparib maintenance therapy (375 patients) or placebo (189 patients). Most of the cohort had epithelial ovarian cancer (83.2%), and most had BRCA wild-type disease (65.3%).
The median chemotherapy-free interval, measured as the time from the last dose of prior chemotherapy to initiation of subsequent chemotherapy, was 15.0 months with rucaparib compared with 9.2 months with placebo, for a hazard ratio (HR) of 0.44 (95% CI, 0.36–0.55; P < .0001). That benefit was seen both in BRCA-mutant and BRCA wild-type patients.
The same was seen for the time from randomization to the start of second subsequent therapy, at 22.2 months with the study drug and 18.6 months with placebo, for an HR of 0.70 (95% CI, 0.54–0.91; P = .0064).
The median PFS2, defined as the time from randomization to disease progression on the subsequent line of therapy or death, was also better with rucaparib, at 21.1 months compared with 16.5 months, for an HR of 0.62 (95% CI, 0.48–0.79; P = .0001). The median time from randomization to the start of first subsequent therapy was 12.5 months with rucaparib and 7.4 months with placebo, for an HR of 0.43 (95% CI, 0.35–0.53; P < .0001). BRCA mutation status did not change any of these outcomes. No new safety signals were identified in the analysis.
“Prior rucaparib treatment did not adversely impact the possibility for patients to benefit from subsequent therapy,” the authors wrote.
In a poster discussion session at ASCO, Iain A. McNeish, MD, PhD, of Imperial College London, said the continued separation of survival curves between rucaparib and placebo is reassuring. The improvement in post-progression outcomes, he said, “does suggest that rucaparib does not blunt the effect of post-progression chemotherapy.” Still, it is only with longer follow-up that the agent’s efficacy will be best understood. “Clearly the hardest of all hard endpoints in these trials is overall survival, and those data are awaited with great interest,” McNeish said.
Patients with BRCA-mutated, platinum-sensitive relapsed ovarian cancer derived significant clinical benefit from treatment with olaparib monotherapy compared with treatment of physician’s choice, according to the results of the SOLO3 trial, a US Food and Drug Administration (FDA) confirmatory phase III study (abstract 5506). The data were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Olaparib gained FDA accelerated approval based on the results of a pooled analysis of phase I and II data in patients with advanced BRCA-mutated ovarian cancer who had received 3 or more prior lines of therapy. In this early data, patients had a 34% overall response rate. Accelerated approvals are supposed to be contingent on results of confirmatory trials showing clinical benefit of the treatment.
“SOLO3 provides important prospective data on the efficacy of these treatment options for women with heavily pre-treated platinum sensitive recurrent BRCA-mutated ovarian cancer,” said Richard T. Penson, MD, of Massachusetts General Hospital, who presented the updated results at the meeting.
The study randomly assigned patients 2:1 to olaparib (n = 178) or treatment of physician’s choice, which included paclitaxel, topotecan, gemcitabine, or pegylated liposomal doxorubicin. The primary endpoint was overall response rate.
Overall response rate for olaparib was 72% as measured by blinded Independent Review Committee, with 9% of patients achieving complete remission. In the chemotherapy arm, the overall response rate was 51%, with 3% of patients achieving complete remission (odds ratio, 2.53; 95% CI, 1.40–4.58; P = .002).
In addition to a significantly improved overall response rate, assignment to olaparib resulted in a 38% decreased risk for progression as assessed by blinded independent ventral review compared with physician’s choice (hazard ratio, 0.62; 95% CI, 0.43–0.91).
Median progression-free survival improved by about 4 months among patients assigned to olaparib (median 13.4 vs 9.2 months; P = .013) compared with physician’s choice. Investigator review yielded a similar difference (13.2 vs 8.5 months; P < .001).
Overall survival data are still immature.
“Subsequent therapies clearly are important and likely to dilute out any overall survival advantage for effective biological therapies,” Penson said. “Seventy participants in the olaparib arm (39%) and 29 in the chemotherapy arm—a third—received platinum immediately or as a subsequent line of therapy.”
Additionally, 3% of patients in olaparib group and 27% in the chemotherapy arm received a PARP inhibitor as part of their first or second subsequent therapy.
There was no clinically or statistically significant difference in health-related quality of life between the olaparib and chemotherapy arms. Serious adverse events were reported in 24% of patients assigned to olaparib and 18% of patients assigned to physician’s choice. However, there were half as many adverse events leading to treatment discontinuation in the olaparib arm.
In total, 4 participants (2%) assigned to olaparib and 3 assigned to chemotherapy (4%) developed myelodysplastic syndrome/acute myeloid leukemia. Also, 3 patients in the olaparib arm were diagnosed with new primary malignancy: BRCA2-mutated lung cancer, BRCA1-mutated gastric cancer, and BRCA1-mutated breast cancer.
Abstract discussant Don S. Dizon, MD, FACP, FASCO, of Lifespan Cancer Institute, said that a question posed by many looking at these results might be, “Do we need chemotherapy to treat recurrence?” The answer is, “Probably not,” he said.
However, he did point out that in SOLO3, women with platinum-sensitive disease were not treated with a platinum regimen in the control arm. Additionally, toxicities seen here were not ones commonly seen in previous randomized trials, with a higher serious adverse event rate.
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