CE lesson worth 1.0 contact hours that is intended for advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients.
STATEMENT OF NEED
This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.
Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may articipate in this CE activity.
Upon completion, participants should be able to:
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METHOD OF PARTICIPATION
This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.
Olanzapine is an FDA-approved antipsychotic agent that blocks multiple neurotransmitters. Some of the receptors that olanzapine blocks may be involved in nausea and vomiting, suggesting it might have clinically significant properties for prevention of chemotherapy-induced nausea and vomiting.
A phase III trial enrolled 380 chemotherapy-naïve patients being treated with HEC (either cisplatin or cyclophosphamide-doxorubicin). They were randomized to 2 groups, with 190 patients given 10 mg of olanzapine orally and 188 a matching placebo on days 1 through 4 of chemotherapy. All patients in both cohorts were also treated with an antiemetic regimen of dexamethasone, aprepitant or fosaprepitant, and a 5-HT3—receptor antagonist.
The study’s primary endpoint of no nausea was assessed at 3 time points: early assessment (0-24 hours), later assessment (25-120 hours), and over-all (0-120 hours) after chemotherapy. Researchers were also interested in comparing complete response (no emesis and no use of rescue medication) in the 2 study arms over the 3 phases, as well as determine any toxicities related to olanzapine.
Patients were asked to keep daily records of episodes of vomiting or retching, the use of rescue therapy, and daily levels of nausea from the first day of chemotherapy through day 5. A study nurse also contacted each patient on days 2 through 5 to ask about and record any side effects related to the regimen.
In the olanzapine arm, 73.8% of patients experienced no nausea during the early assessment period versus 45.3% of patients with placebo. During later assessment, nausea was prevented in 42.4% of patients with olanzapine versus 25.4% in the control arm, and during the overall period, no nausea was reported in 37.3% of patients receiving olanzapine compared with 21.9% with placebo.
The complete response rate also was better with olanzapine compared with placebo during the early assessment phase (85.7% vs 64.6%, respectively), the later assessment phase (66.9% vs 52.4), and over the entire period (63.6% vs 40.6%).
“We’ve long known the nausea and vomiting that come along with chemotherapy are a major problem and affect the quality of life of our patients,” said study author Steven Powell, MD. Powell is an oncologist at Sanford Health in Sioux Falls, South Dakota, and a community co-chair of the study. “The findings of this study, fortunately, provide physicians with a tool to better address the needs of those they are treating for cancer.”
In keeping with olanzapine’s known side effect profile, drowsiness was significantly increased on day 2 in the experimental arm and was severe in 5% of patients, the researchers reported; however, no patients stopped taking olanzapine as a result, and the sedation effect resolved after day 1.
The researchers suggested that lower dosing of olanzapine (eg, 5 mg) represents an area for further study, adding that evaluating the agent only at the 10-mg dose is 1 limitation of this trial. In addition, they reported no significant differences between the 2 arms on the side effect of undesired increase in appetite on days 2 through 5 after chemotherapy.
Three grade 4 adverse events (AEs)—including 2 hematologic—were seen in the olanzapine arm and none in the placebo arm. Two grade 3 AEs occurred in the experimental arm—hyperglycemia and fatigue; in the placebo arm, 2 grade 3 AEs (diarrhea and abdominal pain) were observed. Notably, however, treating clinicians did not attribute any of the grade 3/4 AEs to the study drug.
The authors explained that although previous research has shown that NK-1 receptor antagonists (aprepitant, fosaprepitant, netupitant, and rolapitant) provide significant control of early and later emesis in patients receiving HEC, “they appear to have been less effective in controlling nausea”—an unmet need. Based on the findings of this trial, they wrote, “Patients who received olanzapine were more likely than those who received placebo to be free of nausea and emesis in the early, later, and overall assessment periods.”
Nausea Prevention After Chemotherapy
Assessment Period (hours)
Olanzapine Arm (% of patients reporting no nausea)
Placebo Arm (% of patients reporting no nausea)
Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375(2):134-142.
“Hematopoietic stem cell transplantation is an intensive potentially curative therapy for patients with hematologic malignancies,” said lead author Areej El-Jawahri, MD. “However, patients who undergo the procedure experience physical and psychological symptoms that can negatively affect quality of life and mood.”
In the study, 160 patients with hematologic malignancies admitted for autologous or allogeneic HCT were randomized into two groups: 81 patients received the inpatient palliative care intervention integrated with transplant care, and 79 received transplant care alone. Most participants were white, female, and over age 50.
During integrated palliative and transplant care, patients had at least 2 weekly visits during hospitalization. For those patients getting only transplant care, palliative care was available upon request. Patients were accessed for quality of life, symptom burden, and mood during week 2 after transplant, then again at 3 months post-HCT.
The research team, led by El-Jawahri, an oncologist specializing in hematologic malignancies at Massachusetts General Hospital Cancer Center, used the Functional Assessment of Cancer Therapy-Bone Marrow Transplant to assess quality of life; the Hospital Anxiety and Depression Scale and Patient Health Questionnaire to assess mood; and the Edmonton Symptom Assessment Scale to measure symptoms at baseline, week 2 and 3 months post-HCT.
Posttraumatic stress disorder (PTSD) symptoms were measured using the PTSD checklist at baseline and 3 months post-HCT.
At week 2, improvements were seen in quality of life, depression, anxiety, and symptom burden in the intervention group. At 3 months, the intervention led to improvements in quality of life, depression, and PTSD. “Predominantly, palliative care physicians focused on symptoms, establishing rapport with patients and families, as well as coping,” during their palliative care and initial consultation visits, El-Jawahri explained. When it came to specific symptoms, they focused on pain, nausea, constipation, and diarrhea.”
“This is important because this is really the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing curative therapy,” El-Jawahri said.
El-Jawahri urged more multisite randomized controlled trials to demonstrate the efficacy of the care model for patients hospitalized for HCT. Future studies are needed to evaluate the impact of early palliative care for this population.
Mary E. DiLorenzo, MSN, RN-C, NP-C
Mary E. DiLorenzo, MSN, RN-C, NP-CBlood and Marrow Stem Cell Transplantation ProgramsJohn Theurer Cancer CenterHackensack, NJ
As clinical providers, the ability to connect the science of medicine with the physical, emotional, spiritual, and financial impact it has on patients, is often unintentionally overlooked or, at the very least, minimized during the active treatment phase of care; therefore, the purpose and potential benefits that result from integrating palliative care early on in the process is missed.
According to a randomized control study led by Areej El-Jawahri, MD, of Massachusetts General Hospital Cancer Center in Boston, 160 patients with hematologic malignancies admitted for autologous or allogeneic hematopoietic stem cell transplant (HCT) noted improvement in quality of life as evidenced by increased understanding of illness, lower rates of depression, anxiety, and symptom burden during hospitalization as a result of receiving palliative care services.
Logically, the next question becomes why haven’t we been more proactive in setting into motion these services, which seemingly only benefit this patient population? In my opinion, it is the historical stigma that surrounds “palliative care” that detracts both providers from implementing it early on in the care plan, as well as patients from embracing the resources inherently connected to it.
Palliative care is wrongly thought of as only “end of life” care and consequently often implemented as such. As the ability to transplant older patients with higher risk comorbidities continues to grow, we need to acknowledge that the net result is a patient population with greater needs both emotionally and financially. What happens to the 70-year-old man who has limited financial means because he is not actively working, and then is forced to cope with chronic graft-versus-host disease—an all-too-common and potentially debilitating complication associated with allogeneic stem cell transplantation?
It is this scenario, as well as a multitude of others, that must empower providers to truly understand what palliative care is, what it does, who it can benefit, and how to convey it to their patients in an appropriate and timely fashion so that the patient is willing to accept the services that palliative care can provide for them.
This discussion would be remiss if we did not acknowledge, however, that the “end of life” aspect of palliative care does exist, and it, too, is often not discussed until a patient is actively passing or in the immediate days prior to his or her death. Thus, neither the patient nor the patient’s family members truly benefit from the variety of services available to them. Once again, it is the responsibility of the provider and healthcare team
to become knowledgeable and comfortable speaking about what is truly important—the quality of life of the patient and how best to optimize it.
The emotional and physical “roller coaster ride” that each of our patients face as they undergo HCT should guarantee them a holistic care approach that includes the input and expertise of physicians, nurses, mental health experts, social workers, allied health professionals, and ancillary services—all working in partnership as a team. It is there that the “missing link” in the care provided for these patients is found.
Anita T. Shaffer
The objective response rate (ORR) was 16% among 214 patients who participated in an expansion cohort of the CheckMate-040 study, Bruno Sangro, MD, PhD, reported at the 2016 International Liver Cancer Association conference. Among the 35 patients who responded, 33 had partial responses and 2 experienced a complete response. Another 111 patients had stable disease.
The interim findings are similar to efficacy and safety observations from the dose-escalation portion of the study reported at the 2016 ASCO Annual Meeting (J Clin Oncol. 2016;34[suppl; abstr 4012]), although the follow-up period is much shorter than the 3-year timeframe in the first phase, said Sangro, director of the Liver Unit at Clinica Universidad de Navarra in Pamplona, Spain. The overall survival (OS) rate for all patients was 82.5% at 6 months and 70.8% at 9 months. “While these results are preliminary, the 9-month overall survival rate of 71% is certainly encouraging.”
In all, the expansion phase of the trial consisted of 4 groups of patients, all of whom received nivolumab at 3 mg/kg every 2 weeks: patients without hepatitis who had not received or were intolerant to sorafenib (n = 54); participants who had progressed after receiving sorafenib (n = 58); patients who were infected with hepatitis C (n = 51); and individuals who were infected with hepatitis B (n = 51).
During the study, patients received a median of 10 doses of nivolumab (range, 1-27) over a median time on treatment of 20 weeks, Sangro said.
“Most of the patients who discontinued treatment did so because of progression,” he said. “Only a minority of 7% of the total population had to discontinue treatment because of study drug toxicity. Treatment was, by and large, very well tolerated.” The most frequent symptomatic treatment-related adverse events (AEs) of any grades included fatigue (21%), pruritus (15%), and rash (12%). Treatment-related grade 3/4 AEs were reported in 39 patients (18%).
In terms of durability, Sangro indicated that responses were ongoing in 30 of 35 responders at the time of analysis in March 2016, and the median duration of response had not yet been reached. He also said 29 of the patients responded within 3 months of beginning treatment.
As analysis continues on this group of patients, a phase III randomized trial of nivolumab versus sorafenib has been launched in the front- line setting (NCT02576509). The trial, which is seeking to enroll 726 patients, has an estimated primary completion date of July 2017.
Laura Metcalfe, MSN, RN, APN-C, AOCNS
Laura Metcalfe, MSN, RN, APN-C, AOCNSJohn Theurer Cancer CenterHackensack, NJ
To date, the majority of the patients diagnosed with hepatocellular carcinoma (HCC) have been hepatitis C, B, or both, positive. The American Cancer Society reports that worldwide, the most common risk factor for HCC is chronic infection with hepatitis B (HBV) or hepatitis C (HCV) virus. These infections can lead to cirrhosis, a disease in which damaged liver cells are replaced by scar tissue (fibrosis).
It has been well-established that those with cirrhosis have an increased risk of HCC. Non-alcoholic fatty liver disease (NAFLD) is a condition in which people who consume little or no alcohol develop a fatty liver and is more common in the obese. Patients with non-alcoholic steatohepatitis (NASH), a form of NAFLD, often develop cirrhosis, thus increasing their risk for HCC.
A new analysis has confirmed that even those NASH patients without cirrhosis are still at risk for the development of HCC. Given the obesity epidemic, along with concomitant risk factors of diabetes and hypertension, it follows that NASH-associated HCC will also increase, as Ju Dong Yang, MD, noted at the International Liver Cancer Association Annual Conference. This realization is very disappointing especially given the fact that the newer therapies for hepatitis C (eg, simeprevir, sofosbuvir), which can achieve sustained virologic response, are expected to decrease the incidence of HCC.
Healthcare professionals can play an important role in reducing the risk of developing NASH-related HCC. Yang proposes screening patients with known risk factors, which should be done, but I would hope we could do more. Patient education is a large part of my role as a clinical nurse specialist, but it is essential for all nurses. Educating patients on ways to maintain a BMI within the healthy range and underscoring the importance of not smoking, eating a healthy diet, and getting the recommended 30 minutes daily of aerobic exercise could go a long way toward decreasing the incidence of NASH in the first place.
Prevention is key, since unfortunately, patients with HCC currently have limited treatment options. Liver transplant is the only curable option, but few patients qualify for transplant, and even if they do, livers are not always available. Liver-directed therapies offer another option for selected patients. These therapies include transarterial chemoem-bolization and Yttrium-90 radioembolization. Again, not all patients are candidates for these treatments.
Sorafenib is approved as first-line systemic therapy for HCC, but as Jordi Bruix, MD, points out, no agents are currently approved in the second-line setting. Based on the survival benefit shown in the phase III RESORCE study, however, regorafenib will be submitted for approval. Yet as far as cancer treatments go, having only 2 lines of therapy available is not encouraging. As any oncology nurse knows, patients always want to know that there is “another option if the current one doesn’t work or stops working.”
Now the good news! Immunotherapy, specifically nivolumab, appears to be showing promise in HCC, even for those patients who have failed prior therapies. This PD-1 inhibitor activates the immune system to effect antitumor activity and has shown “highly encouraging and durable responses in patients with advanced HCC,” according to Bruno Sangro, MD, and pembrolizumab, another PD-1 inhibitor, is also being studied in this setting.
Thus, the message at this time to patients with HCC and their healthcare providers alike should be: “There’s hope on the horizon, so don’t give up the fight.”
Andrew J. Roth
In a multivariate analysis of retrospective data for 4734 patients, hypertension and cigarette smoking were independently associated with non-cirrhotic NASH-related HCC. The odds ratio for non-cirrhotic NASH HCC was 2.52 for those with hypertension and 2.27 for those who smoked; diabetes was inversely related with having non-cirrhotic NASH HCC.
“We identified potential risk factors for the development of HCC in the absence of cirrhotic liver disease in patients with NASH,” said Yang, an associate faculty member, Division of Gastroenterology and Hematology, at the Mayo Clinic College of Medicine in Rochester, Minnesota. “Our data proposed that potentially we can put liver cancer surveillance [in place], for example, for a patient who has smoked in the past or is currently smoking, because they may be at high risk of developing liver cancer, even in the absence of cirrhotic liver disease.”
NASH, a form of non-alcoholic fatty liver disease, is one of the major causes of HCC in western countries. In the United States, NASH is the most rapidly growing etiology of HCC and second leading cause of liver transplantation.
The idea that cirrhosis is not present in all patients with NASH-associated HCC has been shown previously; however, Yang and his colleagues set out to confirm these findings in a larger analysis. For this study, researchers looked at data from patients who were part of the longitudinal BRIDGE study (Liver Int. 2015 Sep;35(9):2155-66).
This study found that males had a 1.61-fold increased risk of non-cirrhotic HCC, whereas Hepatitis B was associated with a 3.15-fold increased risk, and hypertension was associated with a 1.60-fold increased risk. Most importantly, Yang pointed out, NASH was associated with a 3.57-fold increased risk of non-cirrhotic HCC.
To identify risk factors associated with non-cirrhotic HCC in patients with NASH, investigators analyzed data from 312 patients from the BRIDGE study with NASH—82 did not have cirrhosis and 230 did. A number of factors were significantly different between arms, namely male gender (78% non-cirrhotic vs 65% cirrhotic), diabetes (65% vs 83%, respectively), hypertension (78% vs 65%), smoking (67% vs 50%), albumin (4.0 vs 3.6), platelets (248 vs 132), and tumor size in centimeters (6.5 vs 4.0).
There were some differences between the groups in regard to treatment: patients with non-cirrhotic NASH HCC more commonly re- ceived surgical resection compared with their cirrhotic NASH HCC counterparts (36% vs 9%), though they were less likely to receive liver transplantation (0% vs 18%). The groups were treated with curative intent at the same rate (49% for non-cirrhotic patients vs 45% for cirrhotic patients) and overall survival was similar.
With the increasing prevalence of NASH in the general population, NASH-associated HCC will increase too, Yang noted, so researchers should have some sense of urgency. “The associations seen in the current study between cigarette smoking, hypertension, and non-cirrhotic HCC may help to guide HCC risk stratification, but they should be further validated in a future study,” Yang concluded.
Anita T. Shaffer
Regorafenib’s success is set against a background of continued development of novel agents that may widen the treatment options
for patients with advanced disease in the near future, researchers reported at the 2016 International Liver Cancer Association (ILCA) Annual Conference.
The near-term potential includes a head-to-head comparison between lenvatinib (Lenvima) and sorafenib (Nexavar) in a first-line setting (NCT01761266), and separate phase III studies versus placebo of cabozantinib (Cabometyx; Cometriq; NCT01908426) and tivantinib in second-line settings (NCT01755767), noted Ann-Lii Cheng, MD, PhD.
He also pointed to phase III trials of 2 PD-1 inhibitors, nivolumab (NCT02576509) and pembrolizumab (NCT02702401), as possible practice-changers in the next several years. Nivolumab is being tested against sorafenib in patients with advanced HCC who have not received systemic therapy, while pembrolizumab is being compared with placebo in previously treated patients.
Also presenting was Jordi Bruix, MD, PhD, a professor of Medicine at the University of Barcelona and director of the Barcelona Clinic Liver Cancer Group, and the lead investigator for the pivotal RESORCE trial on regorafenib.
As it stands now, sorafenib is the only choice of systemic therapy for patients with advanced-stage HCC. Bruix said sorafenib is most effective for patients with stage C disease with symptoms including portal invasion and extrahepatic spread and Child-Pugh A-B scores, according to the BCLC algorithm, the most widely used staging system in the field.
However, in the phase III RESORCE trial, initially presented at the 2016 World Congress on Gastrointestinal Cancer, regorafenib improved overall survival (OS) by 2.8 months compared with placebo as a second-line therapy for patients with HCC. Median OS was 10.6 months with regorafenib versus 7.8 months for placebo.
Progression-free survival was 3.1 months with regorafenib compared with 1.5 months for placebo. Similarly, the time to progression (TTP) was 3.2 months for regorafenib compared with 1.5 months for placebo. The drug’s manufacturer has submitted the RESORCE findings to the FDA and the European Medicines Agency for approval.
This observational study found that patients with stage IIIC disease treated with NACT had significantly decreased overall survival (OS) compared with those treated with PCS (median, 33 vs 43 months). Among patients with stage IV disease, however, there was no significant difference in OS (median, 31 vs 36 months).
“Our results suggest that primary cytoreductive surgery may improve survival for patients with stage IIIC ovarian cancer who are likely to achieve an optimal cytoreduction, while neoadjuvant chemotherapy may be the preferred option for many women with stage IV ovarian cancer,” explained Larissa A. Meyer, MD, assistant professor, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center.
The current study examined the use of NACT, as well as outcomes associated with it, at 6 National Cancer Institute—designated cancer centers between 2003 and 2012. Patients were assigned to a treatment arm (NACT or PCS) on the basis of whether they received chemotherapy or surgery.
In the first cohort of patients, the authors examined NACT use over time among 1538 patients diagnosed between 2003 and 2012 and treated within 12 weeks of diagnosis. In the second cohort, the goal was to examine factors and outcomes associated with NACT versus PCS within a subset of 1158 patients from the first cohort. This subset excluded patients who had received intraperitoneal and intravenous (IP/IV) chemotherapy.
Results showed that, between 2003 and 2011, the use of NACT increased steadily over time from 16% to 34% among patients with stage IIIC ovarian cancer, and from 41% to 62% among patients with stage IV disease. PCS was found to be associated with significantly improved survival in women with stage IIIC, but not stage IV disease, compared with NACT.
Patients with stage IIIC and IV disease treated with NACT were more likely to achieve <1 cm or microscopic residual disease after interval cytoreductive surgery (ICS) compared with PCS. However, few differences were found in complexity, aggressiveness, or complications of surgery.
The authors wrote that it was important to note that, although patients with stage IIIC disease who received NACT were significantly more likely to have <1 cm or R0 microscopic residual disease after ICS, this finding was not associated with a survival benefit. In contrast, patients who achieved <1 cm of residual disease after PCS, rather than NACT and ICS, had significantly longer survival. Future research should prospectively compare the survival outcomes of patients treated with PCS versus NACT stratified by residual disease after surgery, according to the authors.
These results come shortly after the publication of ASCO’s new NACT ovarian cancer guideline, which recommends NACT as the optimal first-line treatment for some women with newly diagnosed, advanced ovarian cancer.2
“The findings in our study are aligned with the recently issued ASCO/SGO guideline for neoadjuvant chemotherapy,” said Meyer.
One of the guideline recommendations states that NACT is favored over PCS for women who are fit for PCS, but are also deemed unlikely to achieve cytoreduction to <1 cm (ideally to no visible disease) by a gynecologic oncologist. Meyer says the findings of the current study support that recommendation.
“The bottom line is a one-size-fits-all strategy no longer works for treatment of ovarian cancer,” said Meyer.
1. Meyer LA, Cronin AM, Sun CC, et al. Use and effectiveness of neoadjuvant chemotherapy for treatment of ovarian cancer [published online September 6, 2016]. J Clin Oncol.
2. Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer: Society of Gynecological Oncology and American Society of Clinical Oncology clinical practice guideline [published online August 8, 2016]. J Clin Oncol.
Marieta Branis, DNP, ANP, NP-C
Marieta Branis, DNP, ANP, NP-CWomen's Oncology DivisionJohn Theurer Cancer CenterHackensack, NJ
Using neoadjuvant chemotherapy (NACT) for the treatment of some women diagnosed with advanced-stage ovarian cancer is the optimal treatment choice according to the 2016 SGO/ASCO Practice Guidelines. The recently published guidelines address the use of neoadjuvant chemotherapy versus primary cytoreductive surgery (PCS) for women newly diagnosed with stage IIIC or IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. For this patient population the use of neoadjuvant chemotherapy is can be beneficial in decreasing the incidence of perioperative and postoperative morbidity and mortality.
The guidelines developed by an expert panel after a systematic review of current medical literature provide direction to the oncology clinical team members and patients regarding deciding which patients are likely to derive the most benefit from NACT. It is recommended that prior to initiation of therapy, all advanced ovarian cancer patients stage IIIC or IV be evaluated by the gynecologic oncology team. In addition to extensive imaging evaluation (CT scan of chest, abdomen, pelvis), patients need to be assessed if they present a high perioperative risk, or if surgery will result in less than 1 cm of residual disease.
For those women that fit the criteria, NACT would be an appropriate choice of treatment. Women with potentially resectable disease, who are fit for surgery which will result in less than 1-cm residual disease, could either proceed with surgery first, followed by adjuvant chemotherapy, or NACT followed by surgery. The choice will be determined by the gynecologic oncology team, which now has additional evidence to ascertain the right treatment approach fit for each individual patient.
This is great news for the gynecologic medical and surgical oncology community and for our patients diagnosed with advanced-stage ovarian cancer. We now can move one step closer to providing individualized care—customized and carefully selected—using the approach proven most effective for each individual patient.