PARP inhibitors have probably been the biggest boon in our field in the past 5 years.— Thomas Herzog, MD
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AT THE 12TH ANNUAL New Orleans Summer Cancer Meeting, Thomas Herzog, MD, Deputy Director of the University of Cincinnati Cancer Institute and Professor of the Division of Gynecologic Oncology at the University of Cincinnati College of Medicine, delivered an update on nonimmunotherapy advances in the management of endometrial, cervical, and ovarian cancers.1
SURGICAL STAGING is increasingly being performed with minimally invasive techniques (robotics or laparoscopy), and the role of sentinel lymph node mapping is evolving. “We find even in women with a BMI [body mass index] of 50 kg/m2 and above, these techniques are wonderful in terms of decreasing procedure-related morbidity,” he said.
Patients with early-stage endometrial cancer can generally be observed after surgery with the option for brachytherapy either adjuvantly or upon local recurrence. Intermediate-risk endometrial cancer is divided into high or low categories, but according to Dr. Herzog, the question of whether or not to add chemotherapy or hormones to radiation adjuvantly in the high/intermediate-risk category has not been answered. In patients with high-risk or recurrent endometrial cancer, chemotherapy is increasingly being used with or without radiation, and hormones are being used selectively.
Looking to the future, he predicted a focus on biologics and targeted therapies, the combined use of more precise radiation therapy and chemotherapy, the application of molecular genetic profiling, and microsatellite instability testing.
“WE STILL SEE HOTSPOTS around the world, and it’s important to understand that cervical cancer is devastating in terms of the number of years of life lost,” Dr. Herzog noted. Although most cases of cervical cancer occur in underdeveloped countries among women in their mid 30s, “we still have a significant incidence in our country of a disease that’s almost completely preventable.”
Early-stage cervical cancer is still usually treated with surgery and/or radiation therapy with concomitant chemotherapy, but in the advanced stage, persistent, or recurrent disease, the standard is a platinum/paclitaxel regimen with bevacizumab (Avastin), a drug that has conveyed significant improvements in metastatic disease.
Vaccine approaches are also used in this disease on a number of different platforms, one of which is the Listeria platform. Based on a successful phase II program, a phase III global study is enrolling that will evaluate a Listeria-based vaccine in patients with advanced disease at presentation and a high risk of recurrence (AIM2CERV; ClinicalTrials.gov identifier NCT02853604).
Ovarian Cancer: Surgery, Staging, and Cytoreduction
“THE MAJORITY OF GYNECOLOGIC CANCERS are endometrial in terms of incidence, but more deaths still occur from ovarian cancer,” revealed Dr. Herzog.
According to Dr. Herzog, for front-line treatment, the question is when to treat with chemotherapy, and a number of different approaches exist. One option is primary surgery followed by chemotherapy, and another is neoadjuvant chemotherapy followed by cytoreduction, then additional chemotherapy. “A number of factors go into decision-making, but there are differing opinions among thought leaders,” he said.
Two large phase III trials have supported the neoadjuvant approach: EORTC 559712 and CHORUS.3 “There were a lot of people who thought neoadjuvant chemotherapy was inferior in most cases and not as good as upfront surgery,” he said. “But if you look at the data, achieving small volume of residual disease is more likely with interval cytoreduction than with primary cytoreduction.” Procedure-related mortality and morbidity were also significantly lower with the interval approach.
“So why wouldn’t we use that as our primary approach?” asked Dr. Herzog. The answer lies in the survival curves. Survival times were not decreased with the neoadjuvant approach in the two phase III trials, but these overall survival times were inferior to contemporary single-institution data where primary cytoreduction was utilized. Although the best approach is still debatable, Dr. Herzog advised clinicians to consider multiple factors: if the patient is elderly, has a poor performance status, or has disease distribution that raises concerns of significant residual disease, then opt for the neoadjuvant approach. If the patient is expected to tolerate aggressive cytoreduction upfront, and imaging suggests the tumor is resectable, then consider primary cytoreduction where a precise diagnosis of cancer origin is confirmed upfront.
Defining Current Standards for Front-Line Therapy
WHEN CONSIDERING FRONT-LINE chemotherapy for ovarian cancer, consider the dose-dense approach: giving paclitaxel as a weekly therapy instead of every 3 weeks, Dr. Herzog suggested. In a Japanese study,4 dose-dense chemotherapy led to significant improvements in progression-free and overall survival, and numerous clinicians who treat front-line ovarian cancer have since adopted it. The results were negative in another study (GOG 262) that attempted to recapitulate these findings,5 but according to Dr. Herzog, the introduction of optional bevacizumab to that study likely skewed the results in that 84% of patients received bevacizumab. Furthermore, in the small cohort who did not receive bevacizumab, an advantage to the dose-dense schedule was observed.
The concept of maintenance therapy in the upfront setting was popularized by GOG-178,6 and GOG-0212 examined overall survival in this setting. The results, released this year, were negative.7 “We were optimistic that paclitaxel or Xyotax [paclitaxel poliglumex] given for an additional year or more would result in an overall survival difference, and it didn’t,” he noted.
Dr. Herzog concluded that for front-line therapy, the critical components include surgery with comprehensive staging and/or maximal cytoreduction along with platinum and taxane chemotherapy (carboplatin and paclitaxel). Beyond this, decisions are individualized regarding the use of dose-dense chemotherapy, maintenance strategy, use of intraperitoneal chemotherapy (which is being used less often), and incorporation of biologics.
Treatment for Recurrence
IN THE SETTING of recurrence, treatment is patient-centric. “It depends on her current symptoms, her performance status and comorbid conditions, her response to front-line treatment, and the toxicities she has incurred,” said Dr. Herzog. Drug efficacy, toxicity, and dosing schedule should be considered, as well as logistics (ie, travel time). Finally, clinicians should consider tumor characteristics such as resistance status and resistance mechanisms at play as well as treatment-free intervals. “These are the things we need to be mindful of in terms of selection of subsequent therapy,” he noted.
Categorization of patients with recurrent disease has become slightly more complicated, and now it takes into consideration such factors as BRCA status, biomarkers, and histology, but the terms “platinum-resistant” and “platinum-sensitive” are still relevant. For platinum-resistant disease, many novel agents are being evaluated.
Bevacizumab has outperformed other drugs in this setting, but contrary to predictions, it has not improved overall survival in most settings. “Since ovarian cancer is a disease very much driven by VEGF [vascular endothelial growth factor], we thought if we position bevacizumab in the front-line setting, we’d see an improvement in overall survival. That hasn’t been the case,” admitted Dr. Herzog. This may be because post–disease progression intervals are so long in ovarian cancer that showing a survival advantage is extremely difficult, he suggested.
Bevacizumab has, however, been associated with consistent improvements in response rates and progression-free survival in the front-line, platinum-sensitive, and platinum-resistant settings. “I use bevacizumab in these settings, and I treat until disease progression,” he said.
To treat platinum-sensitive disease, Dr. Herzog recommends a combination of platinum-based therapy with either a poly (ADP-ribose) polymerase (PARP) inhibitor if a response to the platinum-based therapy is observed or bevacizumab. For resistant disease, he suggests a single agent with or without bevacizumab, depending on prior exposure and specific patient characteristics. “PARP inhibitors have probably been the biggest boon in our field in the past 5 years,” he added. “These agents are highly effective in the treatment setting for recurrent disease, including in platinum-resistant patients, with response rates that outperform chemotherapy significantly.”
PARP inhibitors are now being evaluated in the front-line setting and in combination with antiangiogenesis and immunotherapies. And in the maintenance setting, phase III trials of PARP inhibitors have resulted in hazard ratios under 0.3. “I think this is really a game changer in terms of the treatment of ovarian cancer, but we need to determine how we optimize their use in terms of treatment vs maintenance settings and the importance of BRCA and homologous recombination–deficient mutations vs platinum responders.”
Finally, as for genetic testing in ovarian cancer, oncology societies recommend testing all patients with epithelial tumors and so does Dr. Herzog. “We can’t distinguish based on family history, age, histology, and so forth,” he pointed out. “Furthermore, the opportunity for cascade testing in family members of carriers can be lifesaving.” ■
DISCLOSURE: Dr. Herzog is on advisory boards for AstraZeneca, Clovis, Genentech, J&J, and Tesaro.
1. Herzog T: Novel advances in the management of ovarian, uterus and cervical cancer: PARP inhibitors and others (except immunotherapy). 12th Annual New Orleans Summer Cancer Meeting. Presented July 22, 2017.
2. Vergote I, Tropé CG, Amant F, et al: Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943-953, 2010.
3. Kehoe S, Hook J, Nankivell M, et al: Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): An open-label, randomised, controlled, non-inferiority trial. Lancet 386:249-257, 2015.
4. Katsumata N, Yasuda M, Isonishi S, et al: Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): A randomised, controlled, open-label trial. Lancet Oncol 14:1020-1026, 2013.
5. Chan JK, Brady MF, Penson RT, et al: Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med 374:738-748, 2016.
6. Markman M, Liu PY, Moon J, et al: Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: Follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. Gynecol Oncol 114:195-198, 2009.
7. Copeland LJ, Brady MF, Burger RA, et al: A phase III trial of maintenance therapy in women with advanced ovarian/fallopian tube/peritoneal cancer after a complete clinical response to first-line therapy: An NRG Oncology study. 2017 Society of Gynecologic Oncology Annual Meeting. Abstract 1. Presented March 14, 2017.