I&rsquo;d like to present a 54-year-old woman with newly diagnosed advanced epithelial ovarian cancer. She represents sort of the typical scenario: 54 years old, comes to her gynecologist, thinks that she has some symptoms in her pelvisurinary frequency, a little early satiety, kind of bloated&mdash;and it&rsquo;s been gradual over the last handful of months. So she goes to see her gynecologist. Her gynecologist does a physical examination and feels a mass. The gynecologist notes her past medical history of obesity, prediabetes&mdash;so diabetes that&rsquo;s controlled with diet&mdash;and also some controlled single-medication hypertension. A CT [computed tomography] scan confirms there is an 11-cm pelvic mass. Interestingly, there is some ascites and some carcinomatosis on the CT scan, and, as is routine, the physician does a CA-125 [cancer antigen 125 test], which is elevated at 785 U/mL.

So what&rsquo;s the right step? Well, the right step is a referral to a gynecologic oncologist. She&rsquo;s evaluated by the gynecologic oncologist. The gynecologic oncologist recommends that she have a midline laparotomy with a surgery, planning a hysterectomy with the preemptive diagnosis of ovarian cancer and, ultimately, likely a debulking surgery and maybe even a bowel resection. So she undergoes an exploratory laparotomy, a full abdominal hysterectomy, a bilateral salpingo-oophorectomy, an omentectomy, and debulking; and indeed, the pathology shows a high-grade serous ovarian cancer.

Interestingly, the entire debulking was not successful. There was just over a centimeter of residual diseasewhat we would call large-volume residual disease. And the reason that it was not completely resected is because it involved the porta hepatis right there next to the gallbladder, next to the portal vein, or peritoneal disease if you will. And so she had large-volume residual disease and is sent for the evaluation of adjuvant chemotherapy. At that time, she undergoes genetic counseling and has germline

testing, and she is found to be negative for deleterious or suspected deleterious

So the patient under consideration again is 54 years old, and is prediabetic, hypertensive, mildly obese, and recovering from a midline laparotomy debulking surgery. The first thing we do is we look at histologic subtype. Her histology is a high-grade serous ovarian cancer. That represents about 85% of newly diagnosed cases. Secondly, we look at the molecular signature. She does not have a germline

mutation, and I could just add that she should have had somatic

negative. And then finally we look at the residual disease, and she has large-volume residual disease just over a centimeter.

The consideration now is to consider adjuvant therapy. But first I want to comment that the most difficult decision that we make when confronted with a woman who is suspected to have an advanced ovarian cancer is whether to begin with chemotherapy or to begin with an operation. When we begin with chemotherapy, that&rsquo;s called neoadjuvant chemotherapy. Then the surgery is interdigitated between the third and the fourth doses, typically with the plan ultimately of either 6 continuous doses of chemotherapy or 3 doses, surgery, and 3 doses.

So how do you figure out whether a patient should have neoadjuvant chemotherapy or primary debulking? Again, that&rsquo;s the hardest decision that we make. In this particular patient, she had large-volume residual disease, so one could argue that she should have had neoadjuvant therapy. It&rsquo;s a tough decision. More and more, the surgeon is looking in with a laparoscope to get an assessment. This particular patient did not have a laparoscopic assessment. The decision was made to go directly to debulking surgery. You really can&rsquo;t be critical that the surgeon tried, and it&rsquo;s understood that occasionally there is unresectable residual disease.

Newly Diagnosed Advanced Ovarian Cancer: Case Reactions

Many patients with newly diagnosed advanced ovarian cancer are treated by medical oncologists, and that&rsquo;s OK. Many gynecologic oncologists do not give chemotherapy, and as such, they collaborate with a medical oncologist. There are others, like me, gynecologic oncologists who are surgeons but also give chemotherapy. This patient though has to, in combination with the provider, make some critical decisions as to what the appropriate chemotherapy should be. And there are 3 questions. Number 1, Should she receive intraperitoneal chemotherapy? Number 2, Should the paclitaxel be given weekly, perhaps even in a dosage-dense fashion, which would be 80 mg/m

every week without a break. Third is deciding whether targeted therapy should be giveneither bevacizumab given with the chemotherapy and then in maintenance, or olaparib, a PARP inhibitor, just in maintenance.

How do you make those decisions? Personally, I think the most recent intraperitoneal chemotherapy study, which isolated the role of the intraperitoneal administration, did not confirm the value of intraperitoneal chemotherapy. As such, intraperitoneal chemotherapy is practiced less and less. Secondly, dosage-dense weekly paclitaxel used to be very common based on a Japanese trial. However, as that trial has become clear and tried to be confirmed in the more European sort of ethnicity, it cannot be confirmed with bevacizumab as in GOG-0262 with Dr John Chan in the

So again, the pendulum has shifted away from intraperitoneal chemotherapy and also away from dosage-dense weekly chemotherapy, making the most common chemotherapy backbone intravenous, every 3 weeks, carboplatin, generally at an AUC [area under the concentration time curve] of 6, although some use 5, and paclitaxel delivered over 3 hours at 175 mg/m

. Every 3 weeks, intravenous carboplatin and paclitaxel. Again, that&rsquo;s the most common regimen.

What are the nuances? The nuances are targeted therapy. On June 13, 2018, bevacizumab was added to intravenous chemotherapy as an FDA-approved option, again given with chemotherapy after surgery for a total of 15 months. And then on December 19, 2018, only in

-mutated patients, whether there was a germline mutation or a somatic mutation, giving olaparib, an oral PARP inhibitor, for 2 years in maintenance.

How would an oncologist decide whether to add targeted therapy to the frontline treatment of advanced newly diagnosed ovarian cancer? I think it&rsquo;s easy because the use of olaparib is restricted and indicated based on germline and somatic

mutations. Obviously ASCO [the American Society of Clinical Oncology], NCCN [the National Comprehensive Cancer Network], and the Society of Gynecologic Oncology recommends germline testing in all patients. We have to operationalize the somatic testing of the tumor because that&rsquo;s an opportunity in about 5% to 10% of patients. So if you take that 5% to 10% of the somatic patients and the 15% to 20% of the germline patients, that&rsquo;s a quarter of patients with a

mutation who can receive frontline olaparib in maintenance for 2 years and can increase the progression-free survival by almost 36 monthsSOLO-1,

What about bevacizumab in the frontline? Bevacizumab in frontline newly diagnosed advanced ovarian cancer is based on 2 studies: GOG-0218 published by Dr Robert Burger in the

in December 2011, and ICON7, which was published by Dr Timothy Perren in the same issue of the

. The Burger trial, GOG-0218, was placebo controlled. It used bevacizumab, again with chemotherapy, started on the second dose at 15 mg/kg and in maintenance.

How do you decide when to use bevacizumab? Well, again, it&rsquo;s indicated after surgery for all comers with advanced disease. But in order to enroll on GOG-0218, you had to have residual disease. Many individuals would think that the most exaggerated benefit would be in patients with large-volume residual disease or stage IV disease. And that&rsquo;s supported both in the Dr Burger, GOG-0218 trial and in the Dr Perren, ICON7 trial. So in this particular patient who had large-volume residual disease, many practitioners would again begin carboplatin-paclitaxel with the first dose, add bevacizumab at 15 mg/kg on the second dose, continuing it in cycles 2 through 6, and then continuing single-agent bevacizumab in maintenance for a total of 15 months or 22 cycles.

Newly Diagnosed Advanced Ovarian Cancer: Treatment Overview

One of the evolving areas of the treatment of advanced ovarian cancer is maintenance therapy. We have 3 PARP inhibitorsolaparib, rucaparib, and niraparib in maintenance, all comers, second and beyond-line therapy if a patient has a complete or partial response to a platinum. All comers: second-line oral niraparib, rucaparib, and olaparib. Now we have frontline maintenance PARP inhibitor olaparib but only in

patients. And then we have frontline maintenance bevacizumab with chemotherapy, again up to 15 months.

The point is, we have 5 maintenance-targeted therapies. We have 3 PARP inhibitors in the second-line setting, 1 PARP inhibitor in the frontline, and bevacizumab. Maintenance is here to stay, and the reason it&rsquo;s here to stay is for 3 reasons. One, it works. All those studies show important statistically significant and clinically important delays in progression-free survival. And, two, they&rsquo;re relatively well tolerated. And, three, it&rsquo;s convenient. So that&rsquo;s the nuance of maintenance-targeted therapy in ovarian cancer. It works, it&rsquo;s tolerable, and it&rsquo;s convenient.

The use of targeted therapies in newly diagnosed advanced ovarian cancer has to be understood in the context of adverse effects. All anti-cancer therapies have toxicities. So let&rsquo;s talk about the 2 categories: anti-angiogenics, or bevacizumab, and PARP inhibitorsin this case, olaparib for

-mutated patients. The most common adverse event associated with bevacizumab is hypertension. Certainly, they can have proteinuria and other adverse effects, and we worry about GI [gastrointestinal] perforation. GI perforations can be mitigated and reduced if you start the second or even third cycle and if you avoid treatment or the use of bevacizumab in patients who have inflammatory bowel disease.

The adverse effects of olaparib and other PARP inhibitors are threefold: fatigue, and that can be managed with dose delays and dose reductions; bone marrow suppression, and sometimes even anemia and thrombocytopenia; and GI toxicities, particularly nausea, vomiting, and diarrhea. Again, they can be managed with supportive care, dose delays, and dose reductions. So we have to have a healthy respect for these targeted therapies. But with dose reductions, dose delays, and supportive care, and by managing the hypertension, if you will, with bevacizumab, or by managing the nausea and fatigue and bone marrow suppression with PARP inhibitors, these medications can be used with patients without a decrement in quality of life. All these studies have had questionnaires, or patient-reported outcome assessments, and there was no decrement.

There&rsquo;s a lot of discussion about contraindications to bevacizumab. The easy ones are nonhealing wounds, deep venous thrombosis [DVT] that is not well controlled. Patients who have stable DVT are eligible for bevacizumab treatment but also, in our particular patient, hypertension. Because the most common serious adverse event is hypertension. So what we do is we certainly start it only if the hypertension is well controlled, and we ask the patient to monitor her blood pressure at home. And ultimately if she starts to have elevated blood pressure or hypertension, if you will, then we manage it. And it can be managed without altering the dosing regimen, frequently.

Targeted Therapy in Newly Diagnosed Advanced Ovarian Cancer

I&rsquo;m happy to report that the era of targeted in gynecologic oncology has arrived. It is part of the frontline treatment of newly diagnosed advanced ovarian cancer with 2 options. In the molecular signature-positive patientin germline

mutations or somatic mutationsthose patients can begin maintenance olaparib for 2 years with a 36-month improvement in progression-free survival. And in the molecular signature-negative patients, those patients can have bevacizumab added to the chemotherapy regimen in cycle 2, and it can be continued in maintenance for 15 months with a very dramatic benefit in those with large-volume residual disease, which also includes stage IV patients.

And the beauty of it is that we understand the toxicities. We can manage them. We can manage the olaparib-related toxicities, which include fatigue, bone marrow suppression, and GI [gastrointestinal] toxicities with supportive-care dose reductions and dose delays. We can manage the adverse events associated with anti-angiogenic therapy, which is generally hypertension, and it can be managed without altering the dosing regimen. So the era of targeted therapy is here. I challenge you to understand it. I challenge you to offer it to your patients so that your patients can live longer and live better.

My personal experience with newly diagnosed advanced ovarian cancer is that almost all patients respond and recover. But the opposite is also true. Almost all patients recur and ultimately die. So the best place to improve those outcomes is in the frontline, and the best opportunity is through a maintenance strategy. So we have to get it right in the beginning. Once a patient recurs, she&rsquo;s destined to serial recurrences, shorter and shorter times to progression, and ultimately, succumbing to her advanced cancer. So let&rsquo;s get it right in the frontline. Let&rsquo;s give her the best option to survive or, hopefully, even be cured. With these new targeted therapies and with good surgery, cure rates are approaching as high as 40%.

Patients frequently ask what they can do to improve their outcome. There&rsquo;s no question that patients who have a more global healthy lifestyleexercise, diet, low stress, sleep, alcohol in moderation, balanced diet&mdash;do better. So we try to coach our patients in this survivorship mode to do their part to try to live the healthiest lifestyle possible.

Advanced Ovarian Cancer

Newly Diagnosed Advanced Ovarian Cancer: Case Reactions

Newly Diagnosed Advanced Ovarian Cancer: Treatment Overview

Targeted Therapy in Newly Diagnosed Advanced Ovarian Cancer

Experience Managing Newly Diagnosed Advanced Ovarian Cancer