What’s the Best Chemotherapy Strategy in Ovarian Cancer?

 What's the Best Chemotherapy Strategy in Ovarian Cancer? Results from the Gynecologic Oncology Group (GOG) 252 trial, while highly anticipated in the oncology community, did not give any additional clarity for the use of intravenous (IV) versus intraperitoneal (IP) chemotherapy for patients with ovarian cancer, says Franco M. Muggia, M.D.

In the study, approximately 1,200 patients were randomized into three chemotherapy regimens. The reference arm consisted of IV paclitaxel at 80 mg/m2, IV carboplatin at AUC 6 and Avastin (bevacizumab) at 15 mg/kg. In the second arm, patients were treated with IV paclitaxel at 80 mg/m2, IP carboplatin at AUC 6, and 15 mg/kg of Avastin. Finally, the third arm included IV paclitaxel at 135 mg/m2, IP cisplatin at 75 mg/m2, IP paclitaxel at 60 mg/m2 and 15 mg/kg of Avastin.

Ninety percent of patients in both carboplatin arms completed a minimum of six cycles of platinum therapy, compared with 84 percent of patients in the cisplatin arm. Approximately 87 percent to 88 percent completed at least six cycles of the taxane in all three arms combined.

The primary endpoint of the study was progression-free survival (PFS). The analysis showed a median PFS of 26.8 months for patients in the IV carboplatin reference arm, 28.7 months among patients who received IP carboplatin and 27.8 months for patients who received IP cisplatin.

In an interview with CURE, Muggia, who is a professor of Oncology in the Department of Medicine at NYU Langone Medical Center, provided an in-depth overview of the GOG 252 trial and what the findings mean regarding IP therapy for patients with ovarian cancer.

Can you give an overview of the IP therapy and the GOG 252 trial?

This is a topic that is in transition because, since 2006, IP therapy for ovarian cancer has been standard. Unfortunately, it is associated with certain toxicities and a learning curve in terms of delivery of the treatment, so it was not applied across the board.

Some years ago, the GOG started to do pilot studies to see whether they could reduce the toxicity and retain the efficacy. Then, they devised this large study called GOG 252, for which the results of the study matured enough for PFS in March 2016. Low and behold, there is no difference between an IV arm — the former modified standard treatment — with IP cisplatin and IP paclitaxel, and a new arm to reduce toxicity of IP carboplatin with IV paclitaxel.

This trial, which accrued about 1,200 patients, led to the preliminary result that would indicate no actual difference between the three arms. This PFS is not overall survival (OS). Typically, the OS differences in these IP versus IV trials were even greater than the magnitude of effect in PFS.

This new study had a few variables. It introduced Avastin across all three arms and that may be the reason why the PFS was increased—even in the IV arm. It also dealt with weekly IV paclitaxel during the carboplatin and in the IV arm. In two of the arms, there was this new modification that may have made a difference.

What are the next steps, given these findings?

We should at least switch to IP carboplatin because there are some noteworthy features of the IP carboplatin therapy. It could be just as effective, but it certainly gets rid of the toxicity, in that it comes with the other analogue cisplatin. There are two trials, one in Canada and one in Japan, which will look at this comparison. Therefore, we have got to get the data. In the meantime, if you want to still leverage IP chemotherapy for ovarian cancer, you should be doing IP carboplatin.

What other possibilities are there from this IP therapy? One is to focus on a certain subset of patients. We know that patients with BRCA mutations are more sensitive to the platinum drugs. They may stand to benefit the most from IP therapy and, in fact, that has been in retrospective studies from prior protocol studies. It reflects that they are the ones who benefit from the IP administration.

There were patient-reported outcomes in the three arms that were very well done in this last study. It showed that IV or IP carboplatin has a better quality of life than IP cisplatin. This is no surprise to people who use the drugs but, in the IP studies in the past, the control was IV cisplatin.

Now, the control in this last study was IV carboplatin and so there is an even greater contrast that the quality of life for the IP chemotherapy may be impacted upon. Therefore, it’s incumbent that we make the proper modifications to make it just as effective, which it seems to be. It may be that the spotlight is on IP carboplatin. We’ll be in limbo for another year until these studies mature.

Are researchers looking at any other interesting combinations?

There are a couple of studies going in that direction, where people have looked at various combinations. There is a study done by the GOG that is comprised of platinum-resistant patients receiving IP carboplatin with IP Velcade (bortezomib). Bortezomib is a proteasome inhibitor that interferes with the degradation of the transporter. When platinum therapy hits the transporter, it gets internalized and degraded, so no more platinum gets transported in. If you interfere with that transport degradation, you keep transporting platinum—and that was the hypothesis. Sure enough, in this small study of 20 patients or so, there were quite a few responses in this protocol.

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Study Explores Correlations Among Irregular Menstrual Cycles, PCOS, and Ovarian Cancer Risk

Study Explores Correlations Among Irregular Menstrual Cycles, PCOS, and Ovarian Cancer RiskLong or irregular menstrual cycles may be a marker of an increased risk for developing certain subtypes of ovarian cancer, according to the results of a recent study published in the International Journal of Cancer.

The study evaluated menstrual cycle characteristics and self-reported polycystic ovary syndrome (PCOS) in 2041 women with epithelial ovarian cancer to see if any of these characteristics were related to ovarian cancer occurrence.

The results showed no elevation in ovarian cancer risk for women who reported periods that were never regular or for those reporting a menstrual cycle length of >35 days with odds ratios of 0.87 (95% CI = 0.69-1.10) and 0.83 (95% CI = 0.44-1.54), respectively. The researchers in this study also observed no overall association between self-reported PCOS and ovarian cancer (OR = 0.97; 95% CI = 0.61-1.56). However, the authors did find significant differences in the association between menstrual cycle irregularities and risk of ovarian cancer subtypes (pheterogeneity  = 0.03) as well as by body mass index (BMI) and oral contraceptive (OC) use (pinteraction  < 0.01).

Menstrual cycle irregularity was also found to be associated with a decreased risk of high grade serous tumors, and at the same time, correlated with an increased risk of serous borderline tumors among women who had never used OCs and those who were overweight.

However, the association between irregular menstrual cycles and serous borderline subtype was only shown to be statistically significant in patients with irregular cycles who have never used OCs or were overweight, with a BMI >25.

“Hormonal abnormalities among women with PCOS or menstrual cycle irregularity could be an explanation for the association observed in some studies,” Holly Harris, ScD, a researcher with the Fred Hutchinson Cancer Research Center in Seattle, said in an interview with OncLive. “Conversely, there is also evidence that women who ovulate less frequently, which would be expected among women with long/irregular cycles, might have protection against ovarian cancer.”

Harris explained that this study was meant to examine multiple subtypes of ovarian cancer because the term “ovarian cancer” actually encompasses what is thought to be multiple tumor types involving the ovary. Moreover, risk factors for each subtype can vary.

This research was not able to determine why risk levels differ when patients are stratified by BMI or OC use. Thus, the study authors noted that their findings highlight the need for further research in the field.

“This observation may help us learn more about the different mechanisms that lead to the development of specific types of ovarian cancer,” Harris said. “Ovarian cancer is a rare cancer, so this study should not cause women to be overly concerned about their individual risk.” While most irregular menstrual cycles may not lead to cancer, it is important that a woman who is concerned about her periods see her healthcare provider, Harris explained.

Harris went on to say that a larger collaborative study that includes more cases of ovarian cancer would help to clarify these associations, and that research is currently underway.

To read this full article by OncLive, please click here.

Murine Study Finds Potential Boost For Ovarian Cancer Drug Olaparib

Murine Study Finds Potential Boost For Ovarian Cancer Drug OlaparibResearchers from the Chinese Academy of Sciences have discovered that the metabolic enzyme phosphoglycerate mutase 1 (PGAM1) helps cancer cells repair their DNA and found that inhibiting PGAM1 sensitizes tumors to the cancer drug Olaparib (Lynparza). Their findings in the study “Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells,” which has been published in The Journal of Cell Biology, suggest that this FDA-approved ovarian cancer medicine has the potential to treat a wider range of cancer types than currently indicated.

Cancer cells often alter their metabolic pathways in order to synthesize the materials they need for rapid growth. By producing the metabolite 2-phosphoglycerate, PGAM1 regulates several different metabolic pathways, and the levels of this enzyme are abnormally elevated in various human cancers, including breast cancer, lung cancer, and prostate cancer.

Min Huang, Jian Ding, and colleagues at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, discovered that inhibiting PGAM1 made cancer cells more sensitive to drugs that induce breaks in both strands of the cells’ DNA. This was because the cells were unable to activate a pathway called homologous recombination that repairs this type of DNA damage. The researchers found that cells synthesized fewer deoxyribonucleotide triphosphates (dNTPs)—the building blocks of DNA—when PGAM1 was inhibited. This, in turn, activated a cellular stress response pathway that culminated in the degradation of a protein called CtIP that is required for homologous recombination repair.

Cancers carrying mutations in the BRCA1 and BRCA2 tumor suppressor genes are unable to undergo homologous recombination and therefore rely on a different pathway to repair their DNA and continue growing. Olaparib blocks this second repair pathway by inhibiting an enzyme called poly ADP ribose polymerase (PARP). Olaparib was approved by the FDA in 2014 to treat ovarian cancers with BRCA mutations.

In this study, the researchers tested the effects of Olaparib on the tumors formed by human breast cancer cells injected into mice. Olaparib had no effect on tumors formed by breast cancer cells containing functional BRCA1 and BRCA2 genes. But by combining the drug with a PGAM1 inhibitor to impair both homologous recombination and PARP-dependent DNA repair, the researchers were able to significantly suppress tumor growth.

“This suggests that PGAM1 inhibitors can sensitize cancers to PARP inhibitors such as Olaparib, thereby expanding the benefits of PARP inhibitors to BRCA1/2-proficient cancers, particularly triple-negative breast cancers that currently lack effective therapies,” says author Min Huang.

To read this full article on Medical Xpress, please click here.

More Chemo May Not Equal Better Outcomes in Ovarian Cancer

More Chemo May Not Equal Better Outcomes in Ovarian CancerIncreasing, the number of cycles of chemotherapy doesn’t appear to significantly influence recurrence rates or survival in patients with early stage ovarian clear cell carcinoma (OCCC), according to researchers.

The retrospective cohort study of 201 patients showed that recurrence and survival rates were comparable whether patients received 3 or 6 cycles of platinum chemotherapy, with or without taxane adjuvant chemotherapy, reported Emily N. Prendergast, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.

Patients who received 3 cycles of adjuvant chemotherapy had a recurrence rate of 18.4% versus 27.3% for those who received 6 cycles (P= 0.4). Similarly, there was no difference in the impact of 3 cycles of chemotherapy versus 6 on progression-free survival (PFS) or overall survival (OS), even in surgically staged patients, they wrote online in Gynecologic Oncology.

“These findings add to the literature suggesting that the number of chemotherapy cycles may not impact survival in this rare histologic subtype and that the optimal treatment regimen has yet to be identified,” the authors stated.

The study also showed that advancing stage (from IA/IB to IC to II) was associated with worse PFS and OS outcomes. However, after accounting for the potential impact of stage on survival, and the effect of full surgical staging on outcomes, “we still did not observe an advantage to 6 over 3 cycles of adjuvant chemotherapy,” they said. “Thus, the question of whether or not there is an added benefit with more cycles of chemotherapy in this relatively chemo-resistant histology is an ongoing clinical question.”

More clinical trials that include the use of novel agents are needed, the authors added, noting that the current was underpowered to definitively determine whether the standard of care should be 3 or 6 cycles.

“Still, we feel our study provides an important contribution as we found no separation in survival curves to favor the administration of more chemotherapy,” they wrote. A prospective trial with 80% power would need at least 4,000 patients diagnosed with this rare histologic subtype of cancer, they said.

But “given the rarity of this particular type of ovarian cancer, it is unlikely that a clinical trial would be possible to fully address this question,” commented Victoria Bae-Jump, MD, PhD, of the University of North Carolina at Chapel Hill.

“This is a strong study, and the largest of its kind to address this important question for early-stage clear cell cancers of the ovary,” Bae-Jump wrote in an email to MedPage Today. “However we need to remember that it is retrospective, and the findings do not carry the weight of a randomized prospective clinical trial.”

While the study could not determine standard of care, the findings can still can be part of the discussion when talking with patients, suggested Bae-Jump, who was not involved in the study. “It is certainly reasonable for gynecologic oncologists to discuss these new findings with their patients with early-stage clear cell ovarian cancer as part of treatment counseling and decision making.”

“Clear cell ovarian cancers tend to be inherently more chemo-resistant to the agents typically used in the treatment of other epithelial ovarian cancers, including the typical frontline treatment of carboplatin/paclitaxel,” she noted.

Previous studies such as ICON1, EORTC-ACTION, and GOG 157 have also evaluated the impact of adjuvant chemotherapy on all histologic subtypes of early-stage ovarian cancer. In particular, GOG 157 found no statistical difference in survival with 3 versus 6 cycles of chemotherapy, the study authors pointed out.

For the current study conducted from January 1994 to December 2011, the investigators identified 259 cases of International Federation of Gynecology and Obstetrics (FIGO) stage I and II OCCC from five institutions.

Patients were divided into those who received 3 cycles of adjuvant chemotherapy and those who received 6 cycles. The final cohort consisted of 210 patients with stage IA-II disease. Of this group, 116 underwent full surgical staging.

All cases were reviewed by independent gynecologic pathologists.

Median age of the cohort was 53 and 83.3% of the patients were Caucasian. All had received adjuvant chemotherapy with 90% receiving adjuvant carboplatin and paclitaxel (Taxol).

Only 1% of patients received cisplatin and paclitaxel, 2% received single-agent carboplatin, and 7% received alternative platinum-based chemotherapy regimens. These included neoadjuvant carboplatin and paclitaxel, intraperitoneal chemotherapy, and carboplatin and gemcitabine (Gemzar).

A total of 38 patients received 3 cycles of adjuvant chemo and 172 patients received 6 cycles. There were 54 recurrences and 40 deaths.

Many clinicians opt for g chemo cycles because of the aggressive nature of the disease, the researchers noted. Studies have suggested OCCC carries a poor prognosis compared to its histologic counterparts and that in Asian patients in particular, it appears to associated with chemo-resistance.

Paradoxically, the researchers observed a trend towards worse outcomes in patients receiving 6 versus 3 cycles of chemotherapy. “This suggests a potential selection bias in clinical practice, with patients with worse prognostic features being selected to receive more aggressive therapy,” they said.

Worse prognostic features can cause concern, Bae-Jump acknowledged, probably resulting in “a tendency to recommend more aggressive treatment.” But she reiterated that the study was not powered to provide definitive answers.

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

Endometrioid Ovarian Cancer Presents Earlier, Offers Better Survival Than Serous Carcinoma

Endometrioid Ovarian Cancer Presents Earlier, Offers Better Survival Than Serous CarcinomaWomen with endometrioid ovarian cancer present at a younger age and with earlier stage disease than those with serous ovarian cancer, according to a new analysis. The earlier presentation resulted in better 5- and 10-year overall survival rates as well.

Endometrioid carcinoma accounts for about 20% of all epithelial ovarian cancers. “The prognostic significance of histologic subtype is controversial, given the relative rarity of histologic subtypes other than serous,” wrote study authors led by Lilian T. Gien, MD, MSc, of the University of Toronto.

The new study was a retrospective analysis of 533 women with ovarian cancer diagnosed at a single center between 1988 and 2006. Of those, 98 women (18.4%) had endometrioid histology, and 435 women (81.6%) had serous histology. Researchers compared these cohorts with regard to presentation, treatment, and survival; the results were published online ahead of print in the Journal of Obstetrics and Gynaecology Canada.

At the time of diagnosis, endometrioid patients were a median age of 50 years, compared with 58 years for serous patients (P < .001). They also presented at an earlier stage of disease, with 83.7% of endometrioid patients presenting with stage I or II vs only 13.8% of serous patients (P < .001).

Almost all endometrioid histology patients (98%) underwent surgery as their primary treatment, compared with 69% of serous patients (P < .001). Most serous patients (97.2%) received adjuvant chemotherapy, compared with 57.1% of endometrioid patients.

Recurrences were more common in serous patients, with 70.1% experiencing a recurrence during the study period compared with 31.6% of endometrioid patients. Among those who did recur, 48.4% of endometrioid patients had the recurrence within the pelvis alone, compared to only 17.9% of serous patients, in whom abdominal recurrences were more likely.

There were 361 total deaths over the median follow-up period of 9.1 years; 26 of the endometrioid patients died (29.6%), and 355 of the serous patients died (77%). The 5-year overall survival rate was 80.6% in women with endometrioid carcinoma, compared with 35% in those with serous disease. At 10 years, these rates were 68.4% and 18.4%, respectively.

On a multivariate analysis that adjusted for age at diagnosis, tumor grade, and treatment variables, the hazard ratio (HR) for death from endometrioid carcinoma compared to serous carcinoma was 0.41 (95% CI, 0.26–0.66; P < .001). When tumor stage was added to that model, the HR was no longer significant, at 0.74 (95% CI, 0.45–1.24; P = 0.26). Adding tumor stage to a model for recurrence risk also attenuated the result.

“This demonstrates that stage of disease at presentation has a profound effect on overall survival and disease-free survival,” the authors wrote, though they noted that it remains unknown exactly why the two histologies tend to present at different stages. “There is a need for further exploration of molecular markers and biologic pathways to better characterize the behavior of these rare histologic subtypes. This will allow us to develop targeted therapies, improve treatment strategies, and improve survival rates and control recurrences.”

To read this full article on Cancer Network, please click here.

Latest Medical Advances in Gynecologic Cancers Released Report Highlights Need for Research Dollars

Latest Medical Advances in Gynecologic Cancers Released Report Highlights Need for Research DollarsToday in celebration of its 25th anniversary, the Foundation for Women’s Cancer with the Society of Gynecologic Oncology released a comprehensive report on the most recent advances in the detection and treatment of gynecologic cancers.

The 2016 State of the State of Gynecologic Cancers: Report to the Women of America details the progress in the field of gynecologic oncology, but it also calls for the need for more research funding.

“While much has been accomplished in the last 25 years, much more research is required to lessen the burden of these cancers unique to women,” wrote Anil Sood, MD, chair of the Research and Awards Committee of the Foundation for Women’s Cancer.

It is estimated in 2016 more than 105,890 new cases of gynecologic cancers occurred with 38,890 estimated deaths compared to 2015, which estimated 98,280 new cases and 30,440 deaths, according to the American Cancer Society.

The report also highlights the symptoms, risk factors, screening/prevention methods of gynecologic cancers such as: cervical cancer, ovarian cancer, uterine cancer, vaginal cancer and vulvar cancer. The report which is available online, was composed by practicing gynecologist oncologists from leading academic institutions.

Read the full report online by clicking here.

Program Opens to Expand Patient Access to Niraparib for Ovarian Cancer

Program Opens to Expand Patient Access to Niraparib for Ovarian CancerFollowing niraparib’s priority review for the treatment of ovarian cancer last month, TESARO, the manufacturer of the oral, once-daily PARP inhibitor, is opening an expanded access program (EAP) for women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer following a complete or partial response to platinum-based chemotherapy.

The FDA granted niraparib’s new drug application a priority review in December based on the phase 3 ENGOT-OV16/NOVA trial, where niraparib, when used as a maintenance therapy, reduced the risk of progression or death by 73 percent compared with placebo in patients who had germline BRCA-positive, platinum-sensitive, recurrent ovarian cancer. The median progression-free survival (PFS) after 16.9 months was 21 months with niraparib, compared with 5.5 months in patients treated with a placebo.

Expanded access programs offer patients who may not otherwise qualify for clinical trials access to investigational medicines. These patients typically have serious illnesses and are at a loss for alternate therapies.

“The niraparib EAP will provide a mechanism by which eligible women with ovarian cancer may benefit from access to this investigation therapy, which has been accepted for priority review by the U.S. FDA,” Mary Lynne Hedley, Ph.D., president and TESARO’s chief operating officer, said in a statement.

Other ongoing studies of niraparib include the phase 3 PRIMA trial for women who have received first-line treatment for ovarian cancer, the phase 2 QUADRA trial for women with ovarian cancer who have received multiple lines of therapy, and the phase 3 BRAVO trial, for patients with germline BRCA-mutated, metastatic breast cancer. Niraparib is also being investigated in combination studies investigating the agent in combination with other therapies, such as Keytruda (pembrolizumab) and Avastin (bevacizumab).

Patients interested in enrolling in the US EAP should first speak with their health care providers to determine if niraparib is a viable treatment option for them. Then, they can call Idis Managed Access at 1-877-768-4303 or email niraparibUSEAP@clinigengroup.com.

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