More women could be spared death from ovarian cancer or developing the disease in the first place, according to new reports that suggest strategies for improved treatment and prevention.
An approach that employs aggressive surgery with subsequent intraperitoneal (IP) chemotherapy might cure up to half of women with advanced-stage ovarian cancer, wrote Steven Narod, MD, in an opinion article in Nature Reviews Clinical Oncology (2016 Jan 20. [Epub ahead of print], PMID: 26787282). A second report, study 262 by the Gynecologic Oncology Group (GOG), indicates that the standard front-line treatment for advanced ovarian cancer should be either every-three-week carboplatin, paclitaxel and bevacizumab (Avastin, Genentech) or every-three-week carboplatin and weekly dose-intense paclitaxel (N Engl J Med2016;374:738-748, PMID: 26933849).
Debulking Surgery and IP Therapy
“When I looked through all the data, it seemed very clear to me the maximum chance for survival was through primary debulking surgery, followed by intraperitoneal chemotherapy,” said Dr. Narod, a senior scientist at the Women’s College Research Institute, in Toronto. “This is not using any new drugs, but rather standard techniques that have been available for 20 years,” he added. “I think we could cure half the patients,” said Dr. Narod, emphasizing the importance of an initial surgery that removes all visible cancer cells. “That’s a big, big, big improvement from where we are now.”
Dr. Narod’s analysis of existing evidence led him to opine that an estimated 50% cure rate would be a great improvement over a 20% survival rate currently seen with conventional approaches—in which chemotherapy can come before or after surgery, and the extent of surgical removal of disease and the route of administration of the chemotherapy vary widely.
The treatment model he recommends is already fairly common practice in some parts of the United States and Canada. But outside of teaching hospitals and large cancer centers, it is less common. There, he suggested, one out of every three patients may receive IP chemotherapy.
“It’s not for everyone,” he said, noting that older, frailer women, for example, may not tolerate the targeted treatment. “But,” he added, it can “probably” be used “for 80%” of patients.
Jamie Bakkum-Gamez, MD, a gynecologic oncologist at Mayo Clinic in Rochester, Minn., noted that Dr. Narod’s recommendations generally reflect the beliefs and current practices at her institution. A cure rate of 50%, she said, is “definitely achievable.”
Although two recent clinical trials in Europe found that patients who underwent primary debulking surgery followed by chemotherapy showed no difference in overall survival compared with patients who got the treatments in the reverse order, Dr. Bakkum-Gamez noted that the surgeries performed were not nearly as aggressive or thorough as those done elsewhere, including at Mayo Clinic. “Not every surgeon is created equal,” she said.
Some surgeons, for example, may be less willing or able than others to remove tumors from inside the abdomen. She also noted that some debulking surgeries can take upward of eight to 12 hours. “Surgeons need to be prepared to dedicate that amount of time to the operation,” she said, suggesting that surgeons who are specialized in gynecology-oncology are best suited to thoroughly remove ovarian disease.
She highlighted one potential caveat to Dr. Narod’s recommendation: To get chemotherapy infused directly into the abdominal cavity, a port needs to be surgically placed, and that port is most safely placed during the debulking surgery. “If the decision is made three weeks later to do intraperitoneal chemotherapy, it can be [a] challenge to put that port in,” she said, noting that adhesions and scar tissue may have formed, increasing the risk for complications.
Dr. Bakkum-Gamez said her clinical practice opts more often for dose-dense IV chemotherapy, after prior attempts using the published combination regimen of IV and IP therapy showed that many patients are unable to tolerate the more-aggressive regimen. She and her colleagues had been awaiting results from another trial (GOG 252)
comparing IP and dose-dense chemotherapy to help inform their practice. But its initial results, unveiled at the annual meeting of the Society of Gynecologic Oncology (SGO) in March, she said, still don’t provide a clear answer.
Study Tempers Excitement Over IP Therapy
Presenting the results of the study at the SGO meeting, Joan Walker, MD, highlighted several potential explanations for the finding of no statistical difference in progression-free survival, which came as a surprise — even a disappointment — to many. It might be that too low of a dose of cisplatin was administered, noted Dr. Walker, a gynecologic oncologist at The University of Oklahoma’s Stephenson Cancer Center. This was actually by design. “If you look at the world, people aren’t using IP. Less than half of the patients that could have received IP chemo get it,” she said. “We looked at an alternative dosing schedule to overcome that barrier.”
In the study, GOG 252, the regimen was changed in an effort to make it more tolerable and feasible in the outpatient setting. The dose of cisplatin was trimmed to 75 mg from the 100 mg used in GOG 172, which had found IP chemotherapy actually did improve survival. Meanwhile, pacilitaxel was given in a 3-hour infusion as opposed to the 24-hour infusion. “Those two things may have compromised our results,” said Dr. Walker. “I’m afraid that my attempt to help people get IP chemotherapy may have done the opposite — not because this is a definitive study, but because of its design.”
What’s more, she added, the addition to the arms of bevacizumab may have further blurred the results.
Dr. Walker noted that she still plans to review all of the operative reports and CT scans to categorize patients more precisely into their stage of disease and how much tumor was removed, as she did previously for GOG 172. And then there’s the waiting game. “As Dr. Narod pointed out, progression-free survival doesn’t always translate into cure,” added Dr. Walker. “We treated our last patient in 2009. We won’t have long-term survival for a while.”
Just how IP chemotherapy works is still largely unknown. But hints are emerging about the roles of immunology and genetics. Putting something in the abdominal cavity, for example, might stimulate the immune system better than an IV. And, as Dr. Walker and her team reported from GOG 172, cancer patients whose tissues expressed the BRCA1 mutation did better with IP chemotherapy than those who did not express it.
“If we can find the patients most likely to benefit from IP chemotherapy then we can direct chemotherapy to the right patients,” she said.
“Everybody would be joyous if they could get rid of IP chemo because it is so hard to do. But, at same time, if it is truly better, we need to know,” added Dr. Walker. “This is not a final answer. So we don’t want to eliminate enthusiasm for maximizing surgery and treatments.”
Dr. Bakkum-Gamez agreed, also expressing concerns with the differences in the treatment regimen of GOG 252 compared to GOG 172. While the regimen used in GOG 172 is “very toxic,” and can be hard for many patients to tolerate due to a variety of side effects including renal insufficiency and dehydration, she said, “supplementary and supportive measures” can be taken to ameliorate some of those effects.
“The reason that the doses were changed in GOG 252 was so that patients could tolerate it better,” she added. “This is a good lesson in making the false assumption that different doses are going to give you the same effect just because the drug is administered the same way.”
Meanwhile, “unknown interactions” with bevacizumab may have “negated some of the benefits of IP therapy,” said Dr. Bakkum-Gamez.
She noted that her opinion remains the same: “The best survival outcomes we have are in patients who receive IP chemotherapy.” But she added that the regimen should be administered in the same way as it was in GOG 172 — cisplatin dosed at 100 mg/m2 and IV paclitaxel infused over 24 hours—and “probably only in fit patients, who are best-suited to receive it.”
“There’s still a lot of work to be done,” said Dr. Walker, adding that greater attention also needs to be directed towards prevention.”That’s where the most money needs to be spent. It’s more productive in long run.”
Study Proposes Standard Chemotherapy Regimen
In the meantime, although the GOG 262 study did not evaluate IP therapy, the regimen of dose-intense weekly chemotherapy used in the study makes use of key aspects of IP chemotherapy—higher doses and weekly administration. However, the IV regimen used in the study did not show the adverse effects that have been seen with IP treatments.
During the study, which was supported by the National Cancer Institute and Genentech, Bradley Monk, MD, and his co-investigators evaluated 692 patients at 12 centers throughout the United States. They stratified patients based on whether they chose to receive bevacizumab (84% elected to receive it), and then randomly assigned them to receive six cycles of carboplatin (at a dose equivalent to an area under the curve of 6) plus either 175 mg/m2 of paclitaxel IV every three weeks or 80 mg/m2 of paclitaxel IV every week. The primary end point was progression-free survival (PFS).
In the intention-to-treat analysis, weekly paclitaxel was not associated with longer PFS than every-three-week paclitaxel (14.7 and 14.0 months, respectively; hazard ratio [HR] for disease progression or death, 0.89; 95% CI, 0.74-1.06;P=0.18). However, among patients who did not receive bevacizumab, PFS was 3.9 months longer among those given weekly paclitaxel than among those given every-three-week paclitaxel (14.2 vs. 10.3 months; HR, 0.62; 95% CI, 0.40-0.95;P=0.03), whereas among patients who received bevacizumab, weekly paclitaxel did not significantly prolong PFS compared with every-three-week paclitaxel (14.9 and 14.7 months, respectively; HR, 0.99; 95% CI, 0.83-1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with and without bevacizumab (P=0.047). The rates of grade 3 or 4 anemia (36% vs. 16%) and grade 2 to 4 sensory neuropathy (26% vs. 18%) were higher among patients given weekly paclitaxel than those given every-three-week paclitaxel, but the rate of grade 3 or 4 neutropenia was lower (72% vs. 83%).
Although the dose-intense paclitaxel regimen did not extend PFS, the findings support “the use of weekly chemotherapy without bevacizumab in treating advanced ovarian cancer,” according to Dr. Monk, the director of the Division of Gynecologic Oncology and vice chair of the Department of Obstetrics and Gynecology, the University of Arizona Cancer Center at St. Joseph’s Hospital, in Phoenix. He and his co-investigators noted that although the every-three-week paclitaxel plus carboplatin regimen combined with bevacizumab “may be more convenient than weekly paclitaxel and carboplatin without bevacizumab, the every-three-week regimen is also associated with higher costs.” They referred to an incremental cost-effectiveness ratio calculated by other investigators of “$401,088 versus $5,809 per progression-free life-year saved” (Oncologist2014;19:523-527, PMID: 24721817; J Clin Oncol 2011;29:1247-1251, PMID: 21383297; Gynecol Oncol 2012;124:199-204, PMID: 22055763).
New Recommendations Released
Dr. Narod underscored the need for more research, including the “systematic collection of information on a large series of patients in several hospitals.” That would enable adequate statistical power for survival data to be broken down by age, disease stage, timing and route of chemotherapy, and the extent of residual disease. He also suggested that a standard for ovarian cancer treatment should be the subject of a “professional debate within the OB-GYN community.”
A recent congressionally mandated report by a committee of the National Academy of Sciences (NAS) might spur such debate (http://nas.edu/OvarianCancers). Noting that the quality of care given to women with ovarian cancer varies throughout the United States, the NAS committee wrote, “Being treated by a gynecologic oncologist and having treatment in a high-volume hospital or cancer center are the two most significant predictors of whether a woman with ovarian cancer will receive the appropriate standard of care, and both are associated with better outcomes.”
The NAS committee made several recommendations, including one urging that strategies be developed and put into place “to increase genetic counseling and testing” and to assess the “clinical utility of testing for other germline mutations beyond BRCA1 and BRCA2.” A recent report from the GOG uncovered nine such additional mutations associated with increased risk for ovarian cancer.
The committee also recommended that researchers and funding organizations focus on research evaluating the different subtypes of ovarian cancer, the cellular origins of ovarian cancer and the mechanisms of ovarian cancer pathogenesis.
They noted, for example, that recent evidence indicates that many ovarian cancers arise in other tissues, such as the fallopian tubes, and there are suggestions that surgical removal of the fallopian tubes could have a beneficial effect.
In 2015, the American College of Obstetricians and Gynecologists (ACOG) published recommendations for the removal of the fallopian tubes and preservation of the ovaries during hysterectomy for women at low risk for ovarian cancer (Obstet Gynecol 2015;125:279-281, PMID: 25560145).
It remains to be seen how the ACOG recommendation has influenced practice, but a recent cross-sectional study examining practice patterns before the 2015 ACOG recommendation indicated that the rate of bilateral salpingectomy with ovarian conservation was relatively low, with substantial variation among hospitals (Obstet Gynecol 2016;127:297-305, PMID: 26942357). Xiao Xu, PhD, an assistant professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine, in New Haven, Conn., and her colleagues evaluated women at low risk for ovarian cancer or subsequent ovarian surgery from the 2012 National Inpatient Sample, a large inpatient care database. Based on more than 20,000 hospitalizations for benign hysterectomy, they found that the rate of bilateral salpingectomy with ovarian conservation was 5.9% (95% CI, 5.4%-6.5%), with rates ranging from 0% to 72.2%. Larger-volume hospitals, as well as those with higher rates of laparoscopic hysterectomies, tended to perform more bilateral salpingectomies.
Dr. Xu noted that she and others are eagerly awaiting data to see how practice might have changed since ACOG’s recommendations. Meanwhile, she offered advice to providers: “When consulting patients, provide them with comprehensive information about the options available so that they can make an informed decision.”
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