Clinical Trials: What You Need To Know

Clinical Trials: What You Need To Know

Free Webinar: May 4 at 6:00pm EST

Clinical trials are an important part of research and care of women with ovarian cancer, but many people have misconceptions about what they are and how they work.

In this webinar, Dr. Oliver Dorigo gives a clinical trials overview, and discusses pros and cons of enrolling, things to think about, and questions to ask your doctor.

Sign up today to listen and ask questions live, or view the webinar post-event. All registrants will receive a link to the recorded presentation when it’s available.

To register for this event, hosted by the Ovarian Cancer Research Fund Alliance, click here.

Are YOU ‘too busy’ to spot the early warning signs?

Are YOU 'too busy' to spot the early warning signs?

Between family, career and a social life, most mothers struggle to find time in the day for themselves.

But being too busy to look after yourself could be fatal, health experts warn.

New research has found an increasing number of women are neglecting to go to the doctor with potentially life-threatening symptoms.

Why? Because they feel too busy with family or work commitments.

The study, by Ovarian Cancer Action, revealed more than a quarter of women place work above the doctor on their priorities list.

More than a third said looking after their family came before anything else.

Further, 14 per cent of women said that spending time with their partner is more important than seeking medical help.

Other reasons for foregoing a trip to the GP include feeling judged, being too embarrassed, or the belief that they won’t be taken seriously.

Chief Executive at Ovarian Cancer Action, Katherine taylor, said: “The reluctance for women to seek help and speak up about health issues is really worrying but it’s not hard to understand.

“From being too busy or feeling too shy, to prioritising the needs of our families or our jobs – every woman is different and there are myriad reasons that health issues may not take precedence in the busy lives we lead.

“However, in diseases like ovarian cancer – in which symptoms can be vague and diagnosis is tricky – we, as women, need to listen to our bodies, keep a close eye on our health and be persistent with doctors if we think something is wrong.”

In addition to being the most deadly gynaecological cancer, ovarian is the fifth most common cancer among women. The news follows a recent study that revealed screening for ovarian cancer can cut deaths by more than a quarter.

Symptoms include persistent stomach pain or bloating, finding it difficult to eat or feeling full quickly and needing to wee more often.

Back pain, changes in bowel habits and constantly feeling tired may also be warning signs.

Ovarian Cancer Action advise women to keep a diary to document their symptoms and present to your doctor as soon as possible.

Read this article, published online by Express, by clicking here.

Report Identifies Considerations for Alternative Payment Models for Cancer Care

Report Identifies Considerations for Alternative Payment Models for Cancer Care

A report recently published in the AACR journal Clinical Cancer Research describes five policy considerations critical to ensuring the delivery of high-quality oncology care while supporting innovation. These recommendations were put forth by a roundtable convened in July 2015 by the Turning the Tide Against Cancer Initiative, which is a collaboration between the AACR, the Personalized Medicine Coalition, and Feinstein Kean Healthcare.

The recommendations in the report, which was co-authored by Gilbert Omenn, MD, PhD, director, Center for Computational Medicine and Bioinformatics, University of Michigan; and chair of the AACR Health and Policy Subcommittee, were published in conjunction with the science policy session, “The Impact of the Affordable Care Act (ACA) on Cancer Research, Care, and Prevention,” which was held on April 17 at the AACR Annual Meeting 2016 in New Orleans.

The five recommendations specifically, which focused on the effects of alternative payment models (APMs) on oncology innovation and patient care, were as follows:

  • APMs should keep pace with rapidly emerging science by incentivizing the adoption of innovative medicines and technologies that have the potential to improve patient outcomes and make health care more efficient.
  • APMs should include mechanisms to encourage patient participation as appropriate in clinical trials as well as ongoing post-market clinical research.
  • Clinical pathways should be transparent and evidence-based, and updated regularly to reflect current scientific evidence and clinical advances within the overall continuum of care.
  • When providers and patients are making treatment decisions, patients should be given a clear, comprehensive picture of their treatment options, including cost information that is tailored to the specific patient’s insurance coverage and treatment plan.
  • APMs should require that clinical data be aggregated and integrated into providers’ workflows via electronic health records in order to support learning health care systems. Providers should have access to data that will support their shared decision-making with patients. Similarly, patients should have access to research results collected through a learning health care system.

To read the entire report as a PDF on AACR.org, click here.

Liquid Biopsies Predict Treatment Response and Survival in Gynecologic Cancers

Liquid Biopsies Predict Treatment Response and Survival in Gynecologic CancersA new study has demonstrated for the first time that personalized circulating tumor DNA (ctDNA) biomarkers in gynecologic cancers can detect the presence of residual tumor earlier than currently used serum and imaging studies.1,2 According to the data, undetectable levels of ctDNA at the completion of primary therapy were also an independent predictor of survival.

“Detection of residual disease represents a diagnostic dilemma and potential critical inflection point in precision medicine,” said John A. Martignetti, MD, PhD, of Icahn School of Medicine at Mount Sinai. “Ultimately, these studies open the door for future clinical investigations to further validate the usefulness of ctDNA as both a surveillance and prognostic tool in gynecologic cancers.”

Powerful Technology

As Dr. Martignetti reported at the 2016 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, the measurement of ctDNA—the so-called liquid biopsy—represents a powerful emerging technology capable of providing accurate assessment of both tumor behavior and disease burden. Moreover, a personalized test, unique to each patient, can be specifically designed for use.

“This is a noninvasive assessment,” said Dr. Martignetti. “It’s a blood draw. You can monitor patients throughout the disease course and in real time. And if you’re monitoring the mutations, you can monitor the evolution of tumor growth, response to treatment, acquired resistance to treatment, and development of tumor heterogeneity.”

For this single-institution study led by Dr. Martignetti, Peter Dottino, MD (Director of Gynecologic Oncology, Mount Sinai Health System), and Elena Pereira, MD, the team enrolled 44 cancer patients (24 ovarian, 17 uterine, 2 fallopian tube, and 1 peritoneal carcinoma). Serum and tumor samples were collected at the time of surgery and then throughout the treatment course. Tumor-specific mutations were identified for each patient using either whole-exome or targeted gene sequencing, and ctDNA levels were quantified using droplet digital polymerase chain reaction. These levels were then correlated with clinical disease status, CA-125 values, computed tomography (CT) scan results, surgical findings, and progression-free and overall survival

“We sought to explore the usefulness of ctDNA as both a surveillance and prognostic biomarker and to compare ctDNA efficiency, sensitivity, and lead time against serum CA-125 values and CT scans,” Dr. Martignetti explained. “To be enrolled in the study, each patient had to have blood samples drawn for ctDNA analysis within several weeks of either their CT scans or surgery. This allowed us to directly compare our ctDNA biomarker test results to useful and commonly accepted standards.”

Surveillance and Prognostic Biomarker

Researchers found that the sensitivity and specificity of ctDNA, detected in 93.8% of patients, were highly correlated with CA-125 and CT scanning, with a number of notable exceptions.

“We saw that ctDNA correlates with tumor presence and is in general as sensitive and specific as CA-125,” said Dr. Martignetti. “A powerful distinction in ctDNA as a biomarker was that, whereas only 60% of individuals at the time of surgery or recurrence had abnormal CA-125 levels, almost all patients under these same conditions had detectable ctDNA levels.”

More interesting to the researchers, however, were the six patients with negative CT scans, in whom circulating tumor DNA successfully identified the presence of cancer. “We had six individuals in our study population who had no evidence of disease on CT but positive traces of ctDNA,” said Dr. Martignetti. “All of these patients had disease progression as defined by tumor recurrence within 1 to 11 months of positive ctDNA and negative imaging. In other words, CT scan failed to detect the cancer that the ctDNA did.” On average, circulating tumor DNA had a predictive lead time of 7 months over CT imaging.

Dr. Martignetti also highlighted the potential for using ctDNA as a prognostic biomarker, as undetectable levels of ctDNA at the completion of primary therapy were associated with markedly improved progression-free survival and overall survival (P = .0048 and P = .0194, respectively).

“If we did not detect that patient’s unique ctDNA signature at the completion of primary chemotherapy,” said Dr. ­Martignetti, “the patients had an outstanding overall survival profile, whereas those with detectable ctDNA levels did not.”

He concluded, “These are relatively small studies. Ultimately, we need to demonstrate the clinical utility, but I think they’re a great starting point.”

Disclosure: Dr. Martignetti reported that RainDance Technologies, Inc, and Swift Biosciences provided technical and financial support for reagents used in these studies.

Read this entire article on The ASCO Post by clicking here.

Study Supports Initial Attempt at Debulking Surgery in Stage IIIC Ovarian, Fallopian Tube, and Peritoneal Carcinoma

Study Supports Initial Attempt at Debulking Surgery in Stage IIIC Ovarian, Fallopian Tube, and Peritoneal Carcinoma

In a study exploring the effect of primary debulking surgery in women with bulky stage IIIC ovarian, fallopian tube, and primary peritoneal cancers, cytoreduction to no gross residual disease was associated with the best survival outcomes.1 Cytoreduction to 1 to 10 mm of residual disease was also associated with survival benefit as compared to residual disease greater than 10 mm.

“Although primary debulking surgery to no gross residual disease was associated with the longest progression-free survival and overall survival, cytoreduction to 1 to 10 mm of residual disease was also associated with significantly prolonged progression-free survival and overall survival compared with more than 10 mm of residual disease,” said Vasileios Sioulas, MD, Fellow in Gynecologic Oncology at Memorial Sloan Kettering Cancer Center, New York.

Despite the lower survival rates for patients with more than 10 mm of residual disease, Dr. Sioulas noted that they were “very similar” to those reported in the literature for patients treated with neoadjuvant chemotherapy.

“The administration of neoadjuvant chemotherapy should not automatically be the option chosen for patients who cannot undergo primary cytoreduction to no gross residual disease,” he said, “especially if intraperitoneal chemotherapy can be given after the primary debulking surgery.”

As Dr. Sioulas reported at the 2016 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, primary debulking surgery followed by platinum- and taxane-based chemotherapy is a cornerstone of management of advanced ovarian cancer. However, two recently published, randomized, controlled trials have found the use of platinum-based primary chemotherapy followed by delayed surgery to be an effective and safe alternative treatment regimen.2,3 In addition, it has been suggested that neoadjuvant chemotherapy and interval debulking surgery to allow for no gross residual disease might be superior to primary debulking surgery after which the patient is left with gross residual disease.

Study Design and Results

Dennis Chi, MD, Head of Ovarian Cancer Surgery at Memorial Sloan Kettering Cancer Center, along with Dr. Sioulas, and colleagues retrospectively reviewed 496 patients with stage IIIC ovarian, fallopian tube, or primary peritoneal carcinoma who underwent primary debulking surgery at Memorial Sloan Kettering between January 2001 and December 2010. Patients with borderline tumors or nonepithelial histology were excluded from the study. The median follow-up was 53 months, and the median age of the study population at the time of primary debulking surgery was 62 years.

The greatest diameter of the residual tumor was noted at the end of the surgery and obtained from these respective reports. According to the reported residual disease, participants were classified into four groups: group 1 (0 mm); group 2 (1–5 mm); group 3 (6–10 mm); group 4 (> 10 mm).

As Dr. Sioulas reported, no gross residual disease at the end of primary debulking surgery was achieved in 37% of patients, and 26% of study participants were suboptimally debulked. Significant differences in progression-free survival were observed among the four patient groups, said Dr. Sioulas (Table 1). The median progression-free survival for the entire cohort was 18.6 months (95% confidence interval [CI] = 16.7–20.4 months).

Dr. Sioulas also noted statistically significant differences between patient groups with respect to overall survival (Table 2). The median overall survival for the entire cohort was 54.7 months (95% CI = 50.8–58.7 months).

Given the relatively small number of patients with residual disease measuring 6 to 10 mm and to be consistent with the cutoff of 10 mm that is used in the vast majority of the existing literature to define optimal residual disease, patients with residual disease of 1 to 5 mm and 6 to 10 mm were combined into one group for the remaining analysis. The median overall survival for this combined group was 52.6 months.

“Importantly,” said Dr. Sioulas, “patients with residual disease between 1 and 10 mm had significantly better overall survival compared to those with residual disease greater than 10 mm [38.9 months].”

Role of Intraperitoneal Chemotherapy

In addition, 42% of patients with either no gross residual disease or residual disease between 1 and 10 mm at the end of the primary debulking surgery received at least one cycle of primary intravenous/intraperitoneal chemotherapy.

“Similar to the results of the retrospective analysis of the GOG 114 and 172 studies, the addition of intraperitoneal chemotherapy to the primary treatment regimen was associated with significantly improved overall survival in patients with residual disease between 1 and 10 mm,” Dr. Sioulas reported (65.1 vs 40.6 months). Finally, the survival outcomes of the suboptimally debulked patients with greater than 10 mm of residual disease were comparable to those treated with neoadjuvant chemotherapy, as reported in the EORTC 55971 and CHORUS trials.

“Taken together, if primary de­bulking surgery to no gross residual disease is not feasible, the administration of neoadjuvant chemotherapy should not automatically be the chosen option, especially if intraperitoneal chemotherapy can be given after cytoreduction to residual disease of 1 to 10 mm,” Dr. Sioulas concluded.

Disclosure: Dr. Sioulas reported no potential conflicts of interest.

Read this full article on The ASCO Post by clicking here.

Genetic Testing in Women With Ovarian Cancer Helps to Determine Prognosis

Genetic Testing in Women With Ovarian Cancer Helps to Determine Prognosis

A new study suggests that homologous recombination deficiency may have significant prognostic implications for patients with ovarian cancer, highlighting the importance of genetic testing in this population.1

According to the data, patients with ovarian cancer who have mutations in genes affecting homologous recombination had significantly longer progression-free survival and overall survival than did those with no mutations. In addition, these mutations were found in all histologic subtypes of ovarian cancer, not just high-grade serous tumors.

“This is important prognostic information for our patients,” said lead author Barbara Norquist, MD, a gynecologic oncologist at the University of Washington in Seattle. “Given how striking the effect is, mutation status should be incorporated into clinical trial design.”

Study Details

As Dr. Norquist reported at the 2016 Society of Gynecologic Oncology Annual Meeting, the original study, a phase III clinical trial (GOG 218), was intended to examine the impact of adding bevacizumab (Avastin) to standard chemotherapy for advanced ovarian cancer. Patients with advanced primary ovarian cancer were randomized to one of three arms: standard chemotherapy with carboplatin/paclitaxel; chemotherapy with concurrent bevacizumab; or chemotherapy with bevacizumab and bevacizumab maintenance.

“The primary finding in this study was a difference of 3.8 months in median progression-free survival when comparing arms 1 and 3,” said Dr. Norquist. “Due to this relatively modest benefit, there’s interest in determining which patients are most likely to benefit from this treatment.”

In this new analysis, researchers sought to determine whether having mutations in DNA repair genes, called homologous recombination genes, affected the response to the combined treatment.

Of the 1,873 patients enrolled in GOG 218, Dr. Norquist and colleagues sequenced DNA from blood and/or tumors from 1,195 (63.8%) using a gene panel test. A total of 307 patients (25.6%) had a mutation in a gene predicted to affect homologous recombination. Of those with mutations, 148 (48.2%) had mutations in BRCA1, 78 (25.4%) had mutations in BRCA2, and 81 (26.5%) had mutations in one of the other homologous recombination genes.

Impact of Mutation Status on Treatment Response

Proportional hazards models were used to provide estimates of relative hazards for progression-free survival and overall survival by genotype, adjusted for clinical characteristics. As Dr. Norquist reported, all three mutation-carrier groups had significantly better progression-free and overall survival when compared with those who had no mutations.

Median progression-free survival and overall survival for women with no mutations were 12.6 and 42.1 months, respectively. For women with BRCA1 mutations, progression-free survival and overall survival were longer, at 15.7 and 55.3 months. For women with BRCA2 mutations, median progression-free survival and overall survival were even longer still, at 21.6 and 75.2 months. Finally, for patients with mutations in non-BRCA genes, median progression-free survival and overall survival were 16 and 56 months, similar to outcomes seen for those with BRCA1 mutations.

Researchers also found that these mutations were present in all histologic types of ovarian cancer, not just high-grade serous tumors. In fact, said Dr. Norquist, the mutation rate in high-grade serous tumors was not significantly different from the rate in unspecified carcinomas, endometrioid, or clear cell carcinomas. The only subtype that had a significantly lower mutation rate was low-grade serous tumors, at 11%.

“These findings underscore the importance of genetic testing in all women with ovarian cancer,” said Dr. Norquist. “Clinical trials that focus only on high-grade serous histology are likely to be missing a significant fraction of homologous recombination–deficient carcinomas.”

The relationship between mutation status and bevacizumab effect was also assessed with a test of interaction. Researchers had hypothesized that patients with ovarian cancer who had homologous recombination deficiency may derive less benefit from extended bevacizumab because of their positive response to platinum, but mutational status did not significantly modify the effect.

“If a clinician feels their patient is a candidate for bevacizumab, we don’t have sufficient evidence at this time that mutation status should impact that decision,” Dr. Norquist concluded.

Disclosure: Dr. Norquist reported no potential conflicts of interest.

To read this article, published online by The ASCO Post, click here.

PARP/AKT Inhibitor Combination Active in Multiple Tumor Types

PARP/AKT Inhibitor Combination Active in Multiple Tumor TypesThe combination of the PARP inhibitor olaparib and the investigational AKT inhibitor AZD5363 resulted in durable responses in patients with solid tumors, with and without BRCA mutations, according to a phase I trial reported at the 2016 AACR Annual Meeting.

Overall, 27% of evaluable patients across multiple tumor types had complete or partial responses to two different schedules of the combination of olaparib and AZD5363. Duration of response approached 2 years in some cases.

“The combination of olaparib and AZD5363 is feasible and well tolerated,” said Vasiliki Michalarea, MBBS, a researcher in the drug development unit at the Royal Marsden Hospital in London, who presented the data at AACR.  “Antitumor activity has been observed in BRCA-mutated and non-BRCA-mutated tumors as well as in patients who previously received PARP inhibitors, as well as AKT-pathway inhibitors.”

The trial included 53 patients, including 21 patients with germline BRCA mutations. The BRCA representation in the trial consisted of nine of 19 patients with ovarian cancer, eight of 16 with breast cancer, three of four patients with prostate cancer, and one of two patients with bile duct cancer.

All patients received olaparib at 300 mg twice daily and AZD5363 by one of two administration schedules.  Twenty-three patients received AZD5363 at a dose of 400 mg twice daily for 4 days, followed by 3 days off treatment (4/3), and 30 patients received AZD5363 at 640 mg twice daily for two days, followed by 5 days off treatment (2/5).

The 37 patients evaluable for response included 15 patients with BRCA mutations. The results showed 10 objective responses by RECIST criteria: four patients with BRCA-mutated breast cancer; two patients with platinum-resistant, BRCA-mutated ovarian cancer; one patient with BRCA wild-type triple-negative breast cancer; two patients with BRCA wild-type ovarian cancer; and one patient with BRCA-unknown.

In general, the combination was well tolerated, as a single case of grade 3 rash was the only dose-limiting toxicity associated with either AZD5363 administration schedule.

Some patients had stable diseases or responses that did not conform to RECIST criteria, Michalarea noted. As an example, she described a 78-year-old man with BRCA-mutated, castration-resistant prostate cancer who had received two prior lines of therapy and was treated with the 4/3 AZD5363 schedule. He had an ongoing MRI and PSA response at 23 months of follow-up.

Other examples of patients that had promising response included a patient with PI3K/mTOR-resistant peritoneal mesothelioma, who had a significant, persistent reduction in levels of the CA125 antigen and stable disease by RECIST criteria that lasted for 21 months.

One of the responding patients had BRCA-mutated high-grade serous ovarian cancer and previously had a partial response by RECIST criteria to olaparib monotherapy, persisting for 11 months. Treated again with olaparib in combination with the 4/3 AZD5363 schedule, the 72-year-old woman had another RECIST partial response that was ongoing at 18 weeks.

The one dose-limiting toxicity occurred in a patient on the 4/3 schedule. Other non-dose limiting toxicities associated with the schedule were three cases of grade 3 anemia, and one case each of grade 3 diarrhea, vomiting, and proteinuria. Grade 3 toxicities associated with the 2/5 schedule consisted of two cases each of transaminitis, nausea, fatigue, and anemia; and one case each of rash, hyperglycemia, and diarrhea. With both of the dosing schedules, common grade I/II toxicities included nausea, fatigue, anemia, diarrhea, anorexia, mucositis, and vomiting.

A phase I dose-escalation trial had previously demonstrated the safety of daily olaparib in combination with two different schedules of AZD5363: 4 days on, 3 days off; or 2 days on, 5 days off. The trial demonstrated the feasibility and safety of the combination and the dose-escalation schedules, leading to the follow-up study reported by Michalarea.

Preclinical studies had suggested therapeutic synergy between PARP-inhibitors and agents that inhibit the PI3K pathway, including AKT. Robust activity was observed in both BRCA-mutated tumors and sporadic cancers.

Investigators performed next-generation sequencing of 160 cell-free DNA samples obtained from 38 of the 53 patients. Driver mutations were identified and tracked from baseline in 28 of the 38 patients, and Michalarea and colleagues found 100% concordance in mutation status between tumor and cell-free DNA. Changes in cell-free DNA concentrations appeared to correlate with treatment response in 72% of patients.

Read this article on OncLive by clicking here.