New Study Offers Insight Into How to Improve Chemotherapy Strategies for Ovarian Cancer

New Study Offers Insight Into How to Improve Chemotherapy Strategies for Ovarian CancerMost women diagnosed with ovarian cancer undergo surgery to remove as many of the tumors as possible. However, it is usually impossible to eliminate all of the cancer cells because they have spread throughout the abdomen. Surgery is therefore followed by 18 weeks of chemotherapy.

Delivering chemotherapy drugs directly to the abdomen through a catheter offers better results than other methods, but this regimen suffers from significant complications, and many patients are unable to complete it.

MIT researchers who are working on an implantable device that could make intraperitoneal chemotherapy more bearable have published a new study that offers insight into how to improve chemotherapy strategies for ovarian cancer, and how to determine which patients would be most likely to benefit from this device.

“As we entered into this project, our question was how do we get the same beneficial outcomes and reduce all the side effects?” says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

The findings suggest that the outcome of initial surgery plays a key role in the effectiveness of subsequent intraperitoneal chemotherapy. Cisplatin, one of the most commonly used drugs, effectively treats very tiny tumor cell clusters when it is delivered continuously or as a single large dose. But the researchers found that for larger tumor cell clusters, continuous delivery of cisplatin, at higher doses than are tolerable with the current periodic chemotherapy method, was more effective. The device they are developing would make delivery of such higher, continuous doses possible.

Laura Tanenbaum, a recent MIT PhD recipient, is the lead author of the paper, which appears in the journal Gynecologic Oncology. Other authors are MIT graduate students Aikaterini Mantzavinou and Kriti Subramanyam, and Massachusetts General Hospital gynecologic oncologist Marcela del Carmen.

Targeting Residual Tumors

Ovarian cancer is usually not detected until the cancer has reached an advanced stage, with metastases covering organs throughout the peritoneal cavity, including the liver, bladder, and intestines. After surgery, known as “tumor debulking,” patients receive two types of chemotherapy to treat tumors left behind: intravenous delivery of paclitaxel and intravenous or intraperitoneal delivery of a platinum drug such as cisplatin.

Intraperitoneal chemotherapy is pumped directly into the abdomen through a catheter every three weeks for a total of six cycles. This allows cisplatin to come in direct contact with the residual tumors, which has been shown to be more effective than intravenous delivery but is not tolerable for many patients. “It’s painful and the catheter can be a site of local infections,” Cima says.

Several years ago, Cima and colleagues set out to develop an implantable device that could deliver cisplatin into the abdomen without all of the side effects produced by the catheter and the large, repeated cisplatin doses.

Their device is made of a drug-loaded polymer that could be inserted at the beginning of treatment and remain in place for the full treatment course, then removed with minimally invasive surgery. The researchers have tested proof-of-concept devices in mice and are now developing a version that could be tested in humans, though more animal studies are needed before human trials can begin.

In their new study, the researchers set out to investigate how the size of the residual tumors would affect their response to continuous, low-dose cisplatin delivery. They believed that size would play some role because once tumors reach a certain size, the drug may not be able to penetrate all the way into the inner core of the tumors.

To test this hypothesis, the researchers grew spherical ovarian cancer cell clusters 100 or 200 microns in diameter in a lab dish and exposed them to varying doses of cisplatin. Continuous, low-dose cisplatin delivery, similar to what tumors would receive from an implanted device, was as effective against 100-micron tumor spheroids as a single high dose, similar to that delivered by a catheter.

However, by increasing the continuous cisplatin dose, the researchers found that they could treat the larger 200-micron spheroids more effectively than they could with the single high dose. This increased dose could be delivered using an implantable device, but it would not be tolerable for patients if given through an abdominal catheter.

Better Treatment Strategies

Cima believes that the findings may also help to explain some of the preliminary results of a recent, large clinical trial in which doctors found that intraperitoneal cisplatin delivery was no more effective than intravenous chemotherapy alone. This contradicted previous findings from smaller studies, indicating that cisplatin delivery by catheter improved patient survival.

In the newer trial, conducted at about 500 treatment centers, surgeons admitted patients to the study based on size estimates of the tumors remaining after surgery. However, Cima says, this subjective evaluation may have resulted in patients entering the study whose tumors were too large to be helped by the current intraperitoneal therapy.

This points to the importance of both developing a good method for screening patients before future trials begin, to make sure they are likely to benefit from the treatment, and devising new strategies to help surgeons remove as many tumors as possible, Cima says.

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

Bringing Ovarian Cancer Research Into This Century

By: Marcella Lee, CBS 8 Anchor/Reporter

Bringing Ovarian Cancer Research Into This CenturyA local non-profit is working to improve ovarian cancer survival rates by guiding patients into a new frontier.

Ovarian cancer is known as a silent killer because symptoms are vague like: bloating, abdominal or back pain, frequent urination – and symptoms are often misdiagnosed until it is too late.

An emergency room physician for more than 30 years, doctor Tania Homochuk has helped save countless lives. Now, she is a patient in the fight of her own life and taking part in a clinical trial out of Boston

Doctor Homochuk is battling her third recurrence of stage three ovarian cancer – originally diagnosed in 2010.

Surprised and scared Dr. Homochuk’s life flashed before her eyes. Despite her extensive training in emergency medicine, she had little experience in oncology.

“I immediately went back to what I learned in the late 70s, early 80s which is that ovarian cancer is the kiss of death and I was going to die,” said Dr. Homochuk.

Hillary Theakston is executive director of the Clearity Foundation in San Diego. It’s the only non-profit of its kind in the nation, using precision medicine to help ovarian cancer patients get individualized care.

“About 22,000 women every year are diagnosed with ovarian cancer and we lose 14,000 women every year to the disease. We help women understand their tumor biology. We often identify some out of the box treatment options that their physicians might not have thought about,” said Theakston.

One challenge in treating ovarian cancer is that each tumor is unique. By studying the cells and learning how they are mutating, the Clearity Foundation helps each patient understand how best to tackle her tumor.

“Sometimes ovarian tumors behave more like a lung cancer tumor or colon cancer tumor or breast cancer tumor, so some of the drugs that have been developed specifically to target those genetic mutations, might also work in ovarian cancer,” said Theakston.

The startling reality is that many ovarian cancer patients are treated with drugs developed more than four decades ago.

Only one, out of every three women survive ten years after being diagnosed.

The Clearity Foundation helps patients, free of charge, find the best treatment options and clinical trials.

Visit the Clearity Foundation website to learn more about its work and symptoms of ovarian cancer.

Video of Foundation Medicine Lab provided by James Guardino/Bluedeeno.

To watch the full video interview, please click the link: CBS News 8 – San Diego, CA News Station – KFMB Channel 8

Avastin Benefit Varies By Ovarian Cancer Subtype

Avastin Benefit Varies By Ovarian Cancer SubtypeSuperior progression-free survival (PFS) was seen for patients with proliferative or mesenchymal ovarian tumors who were treated with Avastin (bevacizumab), compared with patients with  immunoreactive or differentiated tumors. Further, Avastin was setting a trend toward improved overall survival (OS) for this group, according to results from a study published in Clinical Cancer Research.

In univariate analysis, adding Avastin to standard chemotherapy with carboplatin and paclitaxel was associated with a median PFS of 21.9 months versus 11.8 months for standard chemotherapy alone in patients with the proliferative subtype of ovarian tumors. That represents an improvement of 10.1 months.

Avastin was associated with a nonsignificant improvement in PFS of 8.2 months in patients with mesenchymal subtype tumors.

“We demonstrate that molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment which includes bevacizumab,” the researchers wrote. “Taken together, these data indicate that stratifying patients by molecular subtype could be an effective therapeutic strategy for ovarian cancer.”

In the paper, Stefan Kommoss, M.D., with the department of women’s health at Tuebingen University Hospital in Tuebingen, Germany, and his colleagues noted that antiangiogenic treatment is crucial to treating in ovarian cancer, but there is no biomarker identifying which patients are most likely to benefit. They designed this study to determine whether there was a correlation between ovarian cancer molecular subtypes and outcomes after treatment with Avastin.

Researchers reviewed gene expression array data from patients enrolled in the AGO-OVAR11 trial, the German cohort from the ICON7 multicenter phase III trial. In that trial, women with peritoneal, tubal, or ovarian carcinoma were randomly assigned to carboplatin and paclitaxel with or without Avastin.

Of the 359 patients included in this analysis, 73 (20 percent) had differentiated tumors, 122 (34 percent) tumors were immunoreactive, 68 (19 percent) were mesenchymal, and 96 were proliferative (27 percent). Patients were separated into Avastin (189 patients) and standard chemotherapy alone (170 patients) cohorts.

For all patients, there was a 6.5-month improvement in median PFS for the Avastin arm compared with the standard arm (21.1 vs 14.6). When adjusted for high risk of progression, age, grade, and histology, Cox regression analysis showed that Avastin significantly improved. Improvement in OS was only borderline significant.

In univariate analysis of the immunoreactive and differentiated subtypes, Avastin produced nonsignificant PFS improvements of 3.8 months and 3.7 months, respectively. Improvements in PFS for the mesenchymal, immunoreactive, and differentiated groups remained nonsignificant in multivariate analysis. In preliminary OS results, only the proliferative subtype showed a statistically significant trend toward improved OS. Multivariate analysis showed that any improvements in OS in the mesenchymal, immunoreactive, and differentiated groups were nonsignificant.

“The present investigation is the first to examine the correlation of ovarian cancer molecular subtypes with outcome after treatment with bevacizumab in a randomized controlled phase III trial of primary ovarian cancer,” wrote Kommoss et al. “We show that the proliferative and mesenchymal molecular subtypes appear to benefit most, with a prolongation in PFS and a trend toward greater OS.”

Brian Slomovitz, M.D., director of the division of gynecologic oncology at the University of Miami Sylvester Comprehensive Cancer Center, reviewed the results. While he said the findings had “great promise,” it’s impossible to draw any conclusions until the results are validated in a prospective study.

“This study reflects great potential,” he said. “Why do we want to identify patients who respond to different therapies? One, so patients can be directed toward that therapy. But perhaps more importantly, to prevent a patient from receiving a noneffective therapy, one in which they’d only be receiving side effects without the potential benefit.

“It’s an interesting idea. It’s a great idea. In order for us to get better at treating patients with cancer, we need to do a better job identifying different subgroups of patients who will respond to different therapies.”

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

Bevacizumab Benefit Varies Among Ovarian Cancer Subtypes

Bevacizumab Benefit Varies Among Ovarian Cancer SubtypesPatients with proliferative or mesenchymal ovarian tumors treated with bevacizumab (Avastin) had superior progression-free survival (PFS) and a trend toward improved overall survival (OS) compared with patients with immunoreactive or differentiated tumors, according to results published in Clinical Cancer Research.

In univariate analysis, adding bevacizumab to standard chemotherapy with carboplatin and paclitaxel was associated with a median PFS of 21.9 months versus 11.8 months for standard chemotherapy alone in patients with the proliferative subtype of ovarian tumors. That represents an improvement of 10.1 months (HR, 0.55; 95% CI, 0.34-0.90; P = .016).

Bevacizumab was associated with a nonsignificant improvement in PFS of 8.2 months (HR, 0.78; 95% CI, 0.44-1.40; P = .41) in patients with mesenchymal subtype tumors.

“We demonstrate that molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment which includes bevacizumab,” the researchers wrote. “Taken together, these data indicate that stratifying patients by molecular subtype could be an effective therapeutic strategy for ovarian cancer.”

In the paper, Stefan Kommoss, MD, with the department of women’s health at Tuebingen University Hospital in Tuebingen, Germany, and his colleagues noted that antiangiogenic treatment is crucial to treating in ovarian cancer, but there is no biomarker identifying which patients are most likely to benefit. They designed this study to determine whether there was a correlation between ovarian cancer molecular subtypes and outcomes after treatment with bevacizumab.

Researchers reviewed gene expression array data from patients enrolled in the AGO-OVAR11 trial, the German cohort from the ICON7 multicenter phase III trial. In that trial, women with peritoneal, tubal, or ovarian carcinoma were randomly assigned to carboplatin and paclitaxel with or without bevacizumab.

Of the 359 patients included in this analysis, 73 (20%) had differentiated tumors, 122 (34%) tumors were immunoreactive, 68 (19%) were mesenchymal, and 96 were proliferative (27%). Patients were separated into bevacizumab (n = 189) and standard chemotherapy alone (n = 170) cohorts.

For all patients, there was a 6.5-month improvement in median PFS for the bevacizumab arm compared with the standard arm (21.1 vs 14.6; HR, 0.68; 95% CI, 0.53-0.89; P = .005). When adjusted for high risk of progression, age, grade, and histology, Cox regression analysis showed that bevacizumab significantly improved PFS (HR, 0.64; 95% CI, 0.49-0.83; P = .0008). Improvement in OS was only borderline significant (HR, 0.66; 95% CI, 0.44-1.00; P = .05).

In univariate analysis of the immunoreactive and differentiated subtypes, bevacizumab produced nonsignificant PFS improvements of 3.8 months (P = .08) and 3.7 months (P = .61), respectively. Improvements in PFS for the mesenchymal, immunoreactive, and differentiated groups remained nonsignificant in multivariate analysis.

In preliminary OS results, only the proliferative subtype showed a statistically significant trend toward improved OS (HR, 0.50; 95% CI, 0.24-1.03; P = .06). Multivariate analysis showed that any improvements in OS in the mesenchymal, immunoreactive, and differentiated groups were nonsignificant.

“The present investigation is the first to examine the correlation of ovarian cancer molecular subtypes with outcome after treatment with bevacizumab in a randomized controlled phase III trial of primary ovarian cancer,” wrote Kommoss et al. “We show that the proliferative and mesenchymal molecular subtypes appear to benefit most, with a prolongation in PFS and a trend toward greater OS.”

Brian Slomovitz, MD, director of the division of gynecologic oncology at the University of Miami Sylvester Comprehensive Cancer Center, reviewed the results for OncLive. While he said the findings had “great promise,” it’s impossible to draw any conclusions until the results are validated in a prospective study.

“This study reflects great potential,” he said. “Why do we want to identify patients who respond to different therapies? One, so patients can be directed toward that therapy. But perhaps more importantly, to prevent a patient from receiving a noneffective therapy, one in which they’d only be receiving side effects without the potential benefit.

“It’s an interesting idea. It’s a great idea. In order for us to get better at treating patients with cancer, we need to do a better job identifying different subgroups of patients who will respond to different therapies.”

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

ImmunoGen Drug Moving Ahead In Single-Agent, Combination Trials

ImmunoGen Drug Moving Ahead In Single-Agent, Combination TrialsLatest results from a mid-stage trial of ImmunoGen Inc’s experimental antibody-drug conjugate show that it shrinks or stabilizes tumors in nearly half of advanced ovarian cancer patients with at least medium levels of a key biomarker whose disease has become resistant to standard chemotherapy.

Looking at all 113 patients so far evaluated in the trial, 30 percent responded to the drug and patients lived for a median of 4.3 months without their disease progressing.

For its pivotal trial, ImmunoGen is enrolling only patients with platinum-resistant disease and medium or high levels of a biomarker known as folate receptor alpha who have received up to three prior lines of therapy. Of the 36 trial earlier-stage trial patients meeting those criteria, 47 percent responded to the drug and median progression-free survival was 6.7 months, the company said on Wednesday. The full research will be presented next month at a meeting of the American Society of Clinical Oncology.

“We are looking to get on the market as quickly as possible in the single agent setting,” ImmunoGen Chief Executive Mark Enyedy told Reuters. The company expects to have final data from the pivotal trial in 2019.

About 22,400 American women are diagnosed with ovarian cancer each year and about 14,000 will die from the disease, according to the American Cancer Society.

Mirvetuximab soravtansine combines an antibody targeting a receptor, anti-folate alpha, associated with certain types of cancer cells with an anti-tumor agent to kill the targeted cells.

ImmunoGen is also studying the drug in combination with other treatments for earlier-stage ovarian cancer, and said it will move forward with more advanced combination trials involving Roche Holding AG’s Avastin and Merck & Co Inc’s Keytruda. It is also evaluating future studies with carboplatin chemotherapy combinations.

Early-stage trial results showed that for advanced ovarian cancer patients treated with Avastin and the ImmunoGen antibody-drug conjugate, 29 percent responded to the treatment with a median progression-free survival of 9.5 months.

Side effects in the Avastin group included excess protein in the urine for 36 percent of patients and hypertension in 21 percent of patients.

ImmunoGen said it was too early to assess results for the Keytruda arm of the trial.

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

B.C. Scientists Uncover 7 New Subtypes of Ovarian Cancer

B.C. Scientists Uncover 7 New Subtypes of Ovarian CancerScientists in Vancouver have found seven new subtypes of ovarian cancer based on genetic changes, a finding that can help guide treatment and new drug discovery.

“We use an entire pattern of alterations in the genome and can read the genomes of these cancers and the mutations reflect the changes in these cancers,” Dr. Sohrab Shah, who led the research, said in a telephone interview with CTV News.

“It helps us understand the processes in the development of the cancer…like a forensics of the biology,” said Dr. Shah, a senior scientist at the BC Cancer Agency.

The discovery, published in Nature Genetics, analyzed the genetic information of more than 100 ovarian cancer patients in order to identify abnormalities in the DNA of ovarian cancer cells.

Seven cancer subtypes were discovered. Two belong to a very common and deadly form of ovarian cancer called high grade serous carcinoma (HGSC).

Scientists think the structural changes in the cancer DNA can identify which patients won’t respond to current chemotherapy. And when a test becomes available, it will spare women from “futile and toxic therapy.”

The DNA changes may also help scientists design and test new experimental medications.

“This study demonstrates that patterns of changes across the DNA inside cancer cells can help direct drug development efforts for the hardest-to-treat subtypes of ovarian cancer,” said Dr. Shah.

The other five subtypes uncovered were found by analyzing clear cell, endometriod and adult granulosa cell ovarian cancers. The results from this work suggest that some of these subtypes may be susceptible to existing treatments.

Scientists are now moving forward, trying to turn the DNA patterns discovered into tests that could be used by doctors, in a bid to separate those who will respond to current treatments and those who need to try experimental therapies.

To read this entire article on CTV News, please click here.

Ovarian Cancer: Clot Risk High in All Phases of Treatment

Ovarian Cancer: Clot Risk High in All Phases of TreatmentOne in four women with ovarian cancer develop blood clots, and over 10% develop clots during neoadjuvant chemotherapy given before surgery, according to a study published online May 5 in Obstetrics & Gynecology.

Past efforts at preventing blood clots in patients with cancer have focused on the period after surgery. But the new study suggests that women with ovarian cancer are at high risk for blood clots during all phases of treatment and highlights clot risk during neoadjuvant chemotherapy.

The study is the first to put a number on the risk for blood clots specifically in ovarian cancer, although physicians who care for such patients have long recognized the problem, the authors write. The study grew out of clinical observations that patients receiving neoadjuvant chemotherapy for ovarian cancer often develop blood clots.

Ambulatory patients receiving neoadjuvant chemotherapy do not routinely receive anticoagulation in current clinical practice.  That may need to change, suggests the study authors.

“[I]n ovarian cancer patients, where the incidence is in double digits, I think intervention is warranted,” lead author, Shitanshu Uppal, MBBS, University of Michigan, Ann Arbor, said in an online interview with Obstetrics & Gynecologyeditors.

Jamie Bakkum-Gamez, MD, and Sean Dowdy, MD, Mayo Clinic, Rochester, Minnesota, authors of a linked editorial, seemed to agree.

The findings are “startling” and point to a potential “crisis in undertreatment” in ovarian cancer care, Dr Bakkum-Gamez told Medscape Medical News.

In their editorial, Dr Bakkum-Gamez and Dr Dowdy highlighted the serious and life-threatening nature of blood clots in ovarian cancer. Three percent of women with ovarian cancer have a clot at initial diagnosis. And, without prophylaxis, almost 17% who undergo primary surgery develop a clot within 30 days of surgery.  Blood clots can also interfere with cancer care and drive up healthcare costs.

While intervention may be warranted, that may not happen without additional research to support guideline development.

“It’s tough to say what approach I would suggest physicians take in their patients on neoadjuvant chemotherapy. When we don’t have consensus expert guidelines to support an intervention, oftentimes it’s difficult for a third party payor to be willing to cover it even if we feel it’s the right thing to do,” she said.

Women with operable tumors often receive surgery first, followed by chemotherapy, during which time they usually receive blood clot prophylaxis. Current National Comprehensive Cancer Network guidelines for blood clot prophylaxis reflect this approach.

However, a patient who is not a good candidate for surgery — because of comorbidities or advanced disease — often receives neoadjuvant chemotherapy first. No national guidelines exist for blood clot prophylaxis in such patients.

One problem is that good-quality evidence has yet to accumulate showing benefit for prophylaxis in patients like these, Dr Uppal explained.

At the University of Michigan, his team has begun a quality improvement project in which patients receiving neoadjuvant chemotherapy are given prophylactic enoxaparin (Lovenox, Sanofi). Results over the next couple of years should indicate whether the intervention makes a difference.

Dr Uppal also hopes for a randomized trial using newer oral anticoagulants, like rivaroxaban (Xarelto, Janssen), which may improve patient adherence.

Also, at the Mayo Clinic centers, a large multi-institutional phase 3 randomized controlled trial is evaluating prophylactic rivaroxaban vs placebo in patients receiving solid-tumor chemotherapy. However, because the trial includes patients with tumors that pose a lower risk for blood clots, Dr Bakkum-Gamez predicts results will dilute clot risk in ovarian cancer. A trial looking only at ovarian cancer may be necessary to fully estimate this risk.

Study Details

In the study, researchers did retrospectively reviewed electronic medical records of women diagnosed with ovarian, fallopian tube, and primary peritoneal cancer at the University of Michigan between January 2009 and May 2014.  They categorized blood clots according to presenting symptom and timing (during neoadjuvant chemotherapy, after surgery, and during adjuvant chemotherapy after surgery).

The analysis included 125 women who received neoadjuvant chemotherapy primarily at the University of Michigan. After exclusion of 13 patients (10.4%) with blood clots at initial diagnosis, results showed that 30 women (26.8%) developed blood clots at some point during treatment.

During neoadjuvant therapy, 13 women developed clots (11.6%), 1 of whom died as a result of the clot. Six women (5.4%) developed clots after surgery, and 11 (9.9%) did so during adjuvant chemotherapy.

The authors mentioned several limitations of their study, including the retrospective design and its small sample size. Also, the study took place at a single, tertiary referral center, where patients may have more advanced disease, so the results may overestimate the risk for blood clots in this population.

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