HIPEC Shows Survival Benefit for Advanced Ovarian Cancer

HIPEC Shows Survival Benefit for Advanced Ovarian CancerPatients with newly diagnosed advanced-stage ovarian cancer who were referred to receive three cycles of neoadjuvant chemotherapy experienced statistically significant improved recurrence-free survival and overall survival from hyperthermic intraperitoneal chemotherapy (HIPEC) during interval cytoreductive surgery, results of a phase 3 trial showed.

After 4.7 years’ median follow-up, 89% of patients who received surgery with no HIPEC had disease recurrence or death, compared with 81% of patients treated with HIPEC (hazard ratio, 0.66; P = .003). Patients in the HIPEC cohort experienced recurrence-free survival a median of 3.5 months longer than patients who received surgery alone (10.7 months vs. 14.2 months), Willemien J. van Driel, MD, PhD, of the Netherlands Cancer Institute, Amsterdam, and her colleagues reported in the New England Journal of Medicine.

Dr. van Driel and her coauthors also reported a median 11.8 months increased overall survival (33.9 months vs. 45.7 months) for HIPEC, compared with surgery alone.

Both recurrence-free survival and overall survival remained consistently beneficial for patients in the HIPEC group across prespecified stratification factors and subgroups, including age, histology type, regional involvement, and previous surgery, according to the researchers.

They also reported that no significant differences between the two groups were noted in the incidence of adverse events of any grade. In total, grade 3 or 4 adverse events were reported by 32 patients (27%) who received HIPEC and 30 patients (25%) who received surgery (P = .76); the most common were abdominal pain, infection, and ileus.

Combination treatment with intravenous and intraperitoneal chemotherapy has been shown to prolong overall survival after primary cytoreductive surgery, according to the authors.

“Catheter-related problems, increased demands on the patient, and gastrointestinal and renal side effects have hampered the adoption of this approach in most countries,” the researchers wrote. “Hyperthermia increases the penetration of chemotherapy at the peritoneal surface and increases the sensitivity of the cancer to chemotherapy by impairing DNA repair [and] … can circumvent most of these drawbacks while maintaining its advantages.”

This research was supported by the Dutch Cancer Society. Dr. van Driel reported no relevant financial disclosures. Two other researchers reported funding from various pharmaceutical companies as well as the KFW–Dutch Cancer Foundation.

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

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Blood Test To Detect 8 Cancers Early Gives Promising Results

Blood Test To Detect 8 Cancers Early Gives Promising ResultsScientists are reporting progress on a blood test to detect many types of cancer at an early stage, including some of the most deadly ones that lack screening tools now.

Many groups are working on liquid biopsy tests, which look for DNA and other things that tumors shed into blood, to try to find cancer before it spreads, when chances of cure are best.

In a study Thursday in the journal Science, Johns Hopkins University scientists looked to see how well their experimental test detected cancer in people already known to have the disease. The blood tests found about 70 percent of eight common types of cancer in the 1,005 patients. The rates varied depending on the type — lower for breast tumors but high for ovarian, liver and pancreatic ones.

In many cases, the test narrowed the possible origin of the cancer to one or two places, such as colon or lung, important for limiting how much follow-up testing a patient might need. It gave only seven false alarms when tried on 812 others without cancer.

The test is nowhere near ready for use yet; it needs to be validated in a larger study already underway in a general population, rather than cancer patients, to see if it truly works and helps save lives — the best measure of a screening test’s value.

“We’re very, very excited and see this as a first step,” said Nickolas Papadopoulos, one of the Hopkins study leaders. “But we don’t want people calling up” and asking for the test now, because it’s not available, he said.

Some independent experts saw great promise.

“It’s such a good first set of results” that it gives hope this approach will pan out, said Dr. Peter Bach, a health policy expert at Memorial Sloan Kettering Cancer Center who consults for a gene testing company. “Anything close to 50 percent or 40 percent detection is pretty exciting stuff,” and this one did better than that, he said.

Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, was encouraged that the test did well on cancers that lack screening tests now. If a blood test could find 98 percent of ovarian cancers at an early stage, as these early results suggest, “that would be a significant advance,” he said.

But he cautioned: “We have a long way to go to demonstrate its effectiveness as a screening test.”

TESTING THE TEST

The test detects mutations in 16 genes tied to cancer and measures eight proteins that often are elevated when cancer is present.

It covers breast, colon and lung and five kinds that don’t have screening tests for people at average risk: ovarian, liver, stomach, pancreatic and esophageal. Prostate cancer is not included. A blood test already is widely used — the PSA test — but its value for screening is controversial.

Researchers tried the new test on people whose cancers were still confined to where it started or had spread a little but not widely throughout the body. It detected 33 percent of breast cancers, about 60 percent of colon or lung cancers and nearly all of the ovarian and liver ones. It did better when tumors were larger or had spread. It did less well at the very earliest stage.

CAVEATS AND NEXT STEPS

The test probably will not work as well when tested in a general population rather than those already known to have cancer, researchers say. Hopkins and Geisinger Health System in Pennsylvania have started a study of it in 10,000 Geisinger patients who will be tracked for at least five years.

The work was financed by many foundations, the Mayo Clinic, the National Institutes of Health and Howard Hughes Medical Institute, which provides The Associated Press with funding for health and science coverage. Many study leaders have financial ties to gene testing companies, and some get royalties for patents on cancer detection methods.

Researchers say the test could cost around $500 based on current materials and methods, but the ultimate goal is to commercialize it, so what a company would charge is unknown.

OTHER LIQUID BIOPSY NEWS

Also this week, Taiwan-based CellMax Life gave results on its liquid biopsy test, which looks for whole tumor cells shed into blood, at an American Society of Clinical Oncology conference.

Researchers tested 620 people getting colonoscopies or with confirmed colon cancer at a hospital in Taiwan. The company said its test had an overall accuracy of 84 to 88 percent for detecting cancer or precancerous growths and a false alarm rate around 3 percent.

The company’s chief executive, Atul Sharan, said U.S. studies should start this year. The test is sold now in Taiwan for $500, but should cost around $150 in the U.S., he said.

Dr. Richard Schilsky, chief medical officer of the oncology society, said results are encouraging, but the test needs more study, especially to see if it gives too many false alarms.

“The last thing you’d want is a test that tells you you might have cancer if you don’t,” he said.

To read this full article on APNews.com, please click here.

BRCA1 Methylation Tied to Ovarian Cancer Risk

BRCA1 mutations are well-known to predispose to ovarian cancer risk. But now a new study, appearing in the Annals of Internal Medicine, suggests that methylation of normal BRCA1 genes might be a major ovarian cancer risk factor. In this 150-Second Analysis, F. Perry Wilson, MD, MSCE investigates the data.

BRCA1 Methylation Tied to Ovarian Cancer Risk

Testing for BRCA mutations in women with a compelling family history of breast or ovarian cancer has become relatively commonplace. The sequela of a positive test can be life-changing, with many women opting for prophylactic mastectomy and oophorectomy.

But what if the genetic test is normal? Well, according to a new paper appearing in the Annals of Internal Medicine, a “normal” BRCA test may not mean the gene is functioning properly.

BRCA1 is a DNA-repair protein. When it is inactivated by mutation, errors in DNA can build up over time, and eventually we see cancers develop – typically breast and ovarian cancers.

But there’s more than one way to inactivate a gene. Remember that a gene is transcribed when its promoter region is accessible to the transcription machinery.

BRCA1 Methylation Tied to Ovarian Cancer Risk

The promoter can be blocked by methylation, preventing transcription.

BRCA1 Methylation Tied to Ovarian Cancer Risk

And an untranscribed BRCA1 might as well be mutant – it can’t repair DNA if it isn’t there.

The study of interest examined 1,541 women with ovarian cancer and no BRCA mutations. They matched these cases with 3,682 controls. Most of the women in both groups had normal BRCA1, but roughly 9% of those with cancer had abnormal methylation in the BRCA1 promoter – compared to only around 4% of control participants. After adjustment for other factors, having methylated BRCA1 conferred almost a threefold higher risk of ovarian cancer.

BRCA1 Methylation Tied to Ovarian Cancer Risk

These findings, which were replicated across two cohorts, make abnormal BRCA1methylation the second strongest risk factor for ovarian cancer beyond an out-and-out BRCA1 mutation.

One thing I want to point out here – these methylation results did not come from breast tissue – these were the results in white blood cells. It’s already pretty clear that abnormal methylation at the tissue level can promote cancer in that tissue – this is one of the best studies yet to demonstrate that the methylation problem may be global.

But how does this abnormal methylation happen? Is it some environmental exposure that we could potentially avoid? The researchers believe the relevant exposure happens in utero or early in life, based on data from a cohort of newborns.

What that exposure is, though, remains in the mists of science’s undiscovered country.

Aside from identifying a new risk factor for ovarian cancer, there is something more compelling about this study. Because the BRCA1 gene in these women is normal, one can imagine a therapy that would reduce methylation allowing the gene to be properly transcribed. Would this open the door to a novel treatment in a subset of women with ovarian cancer? Or perhaps a therapy that would help prevent ovarian cancer in the first place? I’m sure that’s something we would all promote.

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

Markman Proposes Shift in Ovarian Cancer Clinical Trial Paradigm

Markman Proposes Shift in Ovarian Cancer Clinical Trial ParadigmHistorically, FDA approvals of oncologic agents have occurred as a result of positive phase III trial results. However, Maurie Markman, MD, proposes that in this era of precision medicine, phase III trials with the endpoint of overall survival (OS) should not be the be-all and end-all in respect to drug approvals—particularly in ovarian cancer.

“There is a risk that we might discard potentially valuable drugs because of this irrational endpoint,” says Markman, president of medicine and science, Cancer Treatment Centers of America, and editor-in-chief of OncologyLive. Instead, he suggests allowing other endpoints and earlier-phase or basket studies as the basis for future regulatory decisions.

In a lecture during the 35th annual CFS®, Markman discussed the need to change the paradigm of clinical trials and FDA approvals for ovarian cancer.

OncLive: Can you discuss your presentation on the treatment paradigm of ovarian cancer?

Markman: My talk at this meeting was to basically challenge the existing paradigm in clinical trials in the United States and worldwide in ovarian cancer. There has been so much progress with new drugs and new strategies, and as a result, phase III randomized trials looking at OS as a primary endpoint is simply no longer rational.

The reason for that is if you conduct a trial with “regimen A” versus “regimen B,” patients progress, then go off of the trial, that would be progression-free survival (PFS) or disease-free survival as an endpoint—which was what the trial endpoints have to be now. However, if you looked at OS as an endpoint, that would assume that what happens to a patient after they go on that trial is going to be the same on either arm of the trial—and that is a completely irrational endpoint.

We are not talking about patients who might live 2 or 3 months after they finish a trial; we have patients who are living 1 to 3 years or longer after they finish a trial. Therefore, holding that drug or combination—which a patient would have received 2 or 3 years ago—hostage to a survival endpoint when all of the things that might have happened to the patient population during the interim is not controlled simply makes no sense. Stating that doesn’t mean that an individual drug or strategy can’t improve OS—that is not what I am saying. If we had this wonderful new drug or strategy and we do a trial and hit a “grand slam” with survival, that would be wonderful. That is not the point. The point is that we could see an enormously positive outcome.

The other very important issue that I want to comment on is not just the issue of PFS in phase III trials, but in fact the new paradigm that we have, which is basically precision cancer medicine. When you have a situation where you are dealing with a relatively uncommon cancer, such as ovarian cancer, the likelihood of completing a phase III randomized trial is low. Therefore, we have to come up with other strategies to evaluate efficacy. We don’t have to do clinical trials, but is it the only way to move a drug forward into the non-research domain with phase III randomized trial in the era of precision cancer medicine?

We need to come up with a novel approach. That could be looking at high objective response rates (ORRs), or time to disease progression compared with a well-categorized historical control. It could potentially be having patients’ own natural history of disease characterize their time to progression. For example, [they could go] on this novel therapy and the time to progression was 50% to 100%. There are a variety of ways we could look at this, but the point is that we need to come up with strategies that are acceptable to the regulatory agencies, insurers, and ultimately, the patients.

OncLive: Are there any steps being taken toward this?

There is no question that what I am describing and advocating for is happening. The extraordinary poster child for that is the approval of a checkpoint inhibitor [pembrolizumab (Keytruda)] based on robust phase II trial data with microsatellite instability-high (MSI-H) tumors, and I applaud the FDA for this. What they have done is extraordinary important for patients.

Obviously, it is my hope that we see many more examples of this in ovarian cancer. For example, MSI-H occurs in 2% of patients with ovarian cancer. It would take 20, 30, or 40 years to do a trial only in ovarian cancer where one looked at this. The response rates in [the FDA approval] were more than 40%, with many of these responses lasting more than 6 months or a year. If a patient has ovarian cancer and their tumor is MSI-H, they now have the potential to benefit from this therapy because of the FDA’s action. The FDA needs to be encouraged for these kinds of events.

OncLive: Other than OS, what other endpoints might be worth exploring?

You can take ORRs, as they are measurable, and the duration of responses in combination with that. One can make a very valid argument that the tumor shrank, but how valuable is that? The duration of response as well as percentage of response could be a composite.

What about a situation where you didn’t have easily measurable disease? This is common in ovarian cancer. There, you might not be able to use measurable response, but you could use time to disease progression or time to stable disease. These are some objectively measured endpoints, but then you will want to combine it with some other parameter.

Again, it could be the patient’s own time to progression on their prior therapy. You can add to that the toxicities, of course, symptoms of the patients—if they subsided. Symptom improvement is critically important, but sometimes the measurement of symptoms is difficult. We talk about quality of life (QoL) and that is very important; however, the QoL related to the improvement of the symptoms versus the QoL related to the toxicities of the therapies, sometimes get mixed. Therefore, in a setting where one tries to be objective and measure, measurement is hard. It is not a question of importance of symptoms or QoL, it’s a question of measuring objectively.

My concern is not rigorous research or measurable outcomes; it is the classic reliance on phase III randomized trials. These have done as well in the past, but we must come up with other ways to measure benefit so we can take the enormous knowledge that we are gaining and convert that into therapies of benefit.

OncLive: Is there anything happening in ovarian cancer that is resembling this?

There are a lot of trials ongoing. We are seeing basket trials, which are one of the very exciting strategies that are ongoing. These include different drugs for varying tumor types. For example, ASCO’s TAPUR trial is an extraordinary trial; in fact, it is a paradigm-changing trial. A patient with ovarian cancer could be on that trial if they had a particular mutation and they would be included in that basket. If it turns out that a particular target with a particular drug meets satisfaction, hopefully, there will be an approval and ovarian cancer will potentially be included in that. This is similar to what happened with MSI-H and checkpoint inhibitors.

We have to figure out this trial issue, we have to learn how to do trials, gather information, and decide whether these strategies are of value or not. There are opportunities today in terms of understanding the biology; there are hundreds of drugs out there and we have to test them and find their impact.

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

Combinations May Be The Future Of Immunotherapy In Ovarian Cancer

Combinations May Be The Future Of Immunotherapy In Ovarian CancerTo date, trials testing the use of immunotherapy in the treatment of ovarian cancer yielded disappointing results. However, researchers are not giving up. Instead, they’re investigating to see if immunotherapy drugs – such as PD1 and PDL-1 inhibitors – can be combined with other agents to benefit patients.

“Ovarian cancer is a highly unmet medical need. Most cases are diagnosed in advanced stages, and most cases recur,” Bradley J. Monk, M.D., professor and director of the Division of Gynecologic Oncology at Creighton University at St. Joseph’s Hospital and Medical Center in Phoenix, told OncLive, a sister publication of CURE. “We need agents such as immuno-oncology agents to help patients live better and longer.”

Aside from microsatellite instability-high (MSI-H) or mismatch-repair deficient endometrial cancers, there are currently no FDA-approved immunotherapy agents in this space. Previous studies have evaluated a variety of monotherapies for this patient population – including Opdivo (nivolumab), Keytruda (pembrolizumab), Bavencio (avelumab), Imfinzi (durvalumab) and Tecentriq (atezolizumab) – however, they induced insignificant clinical outcomes.

“I am sorry to say that the single-agent activity of these PD-1/PD-L1 molecules is only between 10 to 15 percent,” Monk said. “Therefore, we are now studying combinations. The idea is to enhance the activity of these checkpoint inhibitors.”

There are five phase 3 clinical trials that are testing combination regimens that include at least one checkpoint blockade drug. Of the five trials, two are investigating combination regimens that include Bavencio and three are looking into Tecentriq.

“The idea is to enhance the activity of these checkpoint inhibitors – converting what we call cold tumors to hot tumors, and there are two strategies,” said Monk. “The first is to add immunogenic chemotherapy and an anthracycline, such as pegylated liposomal doxorubicin, or carboplatin/paclitaxel. The other strategy is adding a PARP inhibitor.”

The JAVELIN Ovarian 200 trial, which has enrolled 550 patients with platinum-resistant, recurrent ovarian cancer, will be the first randomized trial to have its results reported. This study is investigating outcomes in patients treated with Bavencio alone compared with Bavencio plus Pegylated Liposomal Doxorubicin and with Pegylated Liposomal Doxorubicin alone.

In the JAVELIN Ovarian 100 trial, 950 patients with untreated, epithelial ovarian cancer are expected to enroll. Patients will be randomized to receive either Bavencio plus carboplatin and paclitaxel or chemotherapy alone in the frontline setting.

The other three trials will be looking into triplet combinations using chemotherapy, Avastin (bevacizumab) – an anti-VEGF therapy – and Tecentriq.

“It’s a very exciting time, and very ambitious,” Monk said.

For now, there are no safety contradictions that researchers are concerned about, though investigation is still in the early stages. More research is needed not only to figure out the potential safety and side effect profile, but also the best ways, in general, to use immunotherapy agents in ovarian cancer treatment.

“It is exciting, but it will only be personally satisfying if we can bring these medicines to patients and prove that they are both efficacious and safe,” Monk said.

To read this entire article on Cure Today, please click here.

Study Aims to Identify Women with Ovarian Cancer Who May Benefit from Maintenance Treatment

Study Aims to Identify Women with Ovarian Cancer Who May Benefit from Maintenance TreatmentMyriad Genetics and AstraZeneca have expanded their collaboration to conduct a study to identify women with advanced ovarian cancer who may benefit from maintenance treatment with Lynparza (olaparib) and Avastin (bevacizumab).

Myriad’s myChoice HRD Plus is a test for BRCA1 and BRCA2 tumor status, as well as tumor genomic instability status – the frequency at which mutations are found within the genome. Genome instability is thought to be central for the development of cancer in humans.

Cells have several DNA repair mechanisms. When one is impaired, as happens when BRCA genes are mutated, they rely on other enzymes, like poly ADP ribose polymerase (PARP), to have their DNA repaired. Therefore, tumors with BRCA mutations are highly susceptible to PARP inhibitors, such as Lynparza.

Similarly, tumors with high genomic instability require a functioning PARP pathway. Blocking this enzyme causes cancer cells to accumulate too much DNA errors and die.

Under the agreement, Myriad will use its myChoice test as a potential addition to other diagnostic tools in an ongoing Phase 3 clinical trial to help identify patients with faulty DNA repair.

Myriad’s myChoice is designed to detect when a tumor has lost the ability to repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging drugs such as platinum chemotherapy or PARP inhibitors.

The newest formulation of Lynparza tablets was approved by the U.S. Food and Drug Administration (FDA) in August 2017 as a maintenance therapy for ovarian cancer. The new tablet allowed patients previously taking the drug in capsule form to reduce their daily intake from eight capsules per day to two tablets per day.

“As the pioneer in companion diagnostics for PARP inhibitors, we are excited to continue our collaboration with AstraZeneca and to apply innovative new technologies like myChoice HRD Plus to increase the number of patients who may benefit from Lynparza,” Jerry Lanchbury, PhD, the chief scientific officer of Myriad, said in a press release.

“myChoice HRD Plus is the most comprehensive test for identifying defects in DNA repair pathways,” he said. “We are optimistic that myChoice HRD Plus will identify more women with ovarian cancer who could benefit from therapy with Lynparza than previous tests that only identify germline BRCA1/2 mutations.”

Myriad and AstraZeneca’s collaboration began in 2007, when the two partners joined forces to develop a new companion diagnostic test to identify candidates for treatment with Lynparza.

In December 2014, one of the first outcomes of the collaboration was the FDA approval of Myriad’s BRACAnalysis CDx, created to help identify ovarian cancer patients who are eligible for fourth-line treatment with Lynparza.

To read this full article on Ovarian Cancer News Today, please click here.

Researchers Describe Key Cellular Receptor Involved In Ovarian Cancer Metastasis

Researchers Describe Key Cellular Receptor Involved In Ovarian Cancer MetastasisResearchers of the Molecular Signaling in Cancer group of the Oncobell program (Bellvitge Biomedical Research Institute – IDIBELL) – proCURE Program (Catalan Institute of Oncology – ICO) have described a key cellular receptor in the processes of metastasis in ovarian cancer. The finding, published in Molecular Cancer Therapeutics, might lead to the use of inhibitors of this receptor as a therapeutic target in the most aggressive variants of the disease, in which a differential expression has been found.

The IDIBELL-ICO research team has succeeded in associating the expression of the CXCR4 receptor in ovarian tumor cells to their dissemination potential through the bloodstream. CXCR4 is a receptor involved in blood cell movement, which had previously been related to processes of dissemination in breast cancer.

In studies in orthotopic models, the researchers proved that administration of CXCR4 inhibitors in cancers where high expression of this receptor had previously been detected greatly decreased the propagation of the tumor cells at the blood level and within the peritoneum. At the same time, they have also observed that the genetic elimination of CXCR4 in cell culture gives rise to tumors with slower growth and a lower percentage of dissemination.

The diagnosis of ovarian cancer usually comes late; in 80% of cases, patients already show metastases or peritoneal disseminations that can affect vital organs of the digestive, circulatory or renal systems. On the other hand, although it is true that the combination of surgery and chemotherapy with platinum derivatives works very well, the percentage of recurrence of the disease at two years is 70%.

The IDIBELL-ICO researchers believe that studying the dissemination patterns of tumor cells is essential in order to understand and improve the prognosis of the disease. Their line of research focuses on identifying the molecules involved in this dissemination, which usually presents itself together with an abnormal buildup of fluid in the abdomen (ascites). “If we identify the factors that drive movement and implantation of tumor cells in new organs, we can try to block them in order to minimize the chances of metastasis; CXCR4 is not the only factor, but we have proved that it is one of them”, says Dr. Agnès Figueras, first author of the study.

To read this entire article on News Medical Life Sciences, please click here.