Clinical Insights: February 2016

Wednesday, February 24, 2016

Release Date: February 25, 2016
Expiration Date: February 25, 2017


This activity is provided free of charge.

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.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may articipate in this CE activity.
 

EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:

  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with  cancer
  • Assess new evidence to facilitate survivorship and supportive care for patientswith cancer

ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing,Provider #16669 for 1.0 Contact Hour.
 

DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION

  1. Read the articles in this section in its entirety.
  2. Go to www.gotoper.com/go/ONN16Feb
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your Certificate of Credit.

OFF-LABEL DISCLOSURE/DISCLAIMER

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®.

Hematologic Malignancies

Benefits of Elotuzumab Sustained in 3-Year Multiple Myeloma Data

Silas Inman

The combination of elotuzumab, lenalidomide, and dexamethasone showed sustained improvements in progression-free survival (PFS) and overall survival (OS) for patients with relapsed/refractory multiple myeloma, according to a 3-year analysis of the ELOQUENT-2 trial presented at the 2015 Annual Meeting of the American Society of Hematology. (Abstract 28) 

In updated data from the phase III study, the additionof elotuzumab reduced the risk of progressionor death by 27%, and overall survival (OS) was improved by 4.1 months versus lenalidomide anddexamethasone alone. Additionally, the minimal incremental toxicity observed with elotuzumab remained consistent.

“Elotuzumab, a novel first-in-class immunostimulatory monoclonal antibody, in combination with enalidomide and examethasone demonstrated a durable and clinically relevant improvement in both progression-free survival and overall response rate,” senior investigator Paul G. Richardson, MD, from the Dana-Farber Cancer Institute, said during a presentation of the data. “I’m very pleased to see that this benefit was sustained. Very importantly, we see a delay in next therapy, which is very relevant.”

On November 30, 2015, the FDA approved elotuzumab in combination with lenalidomide and dexamethasone for patients with multiple myeloma following progression on 1 to 3 prior therapies. This decision was based on a 2-year analysis of the ELOQUENT-2 trial, which showed a 30% improvement in PFS with the addition of elotuzumab compared with lenalidomide/dexamethasone alone.

In the study, 646 patients at a median age of 66 years were randomized in a 1:1 ratio to elotuzumab plus lenalidomide and dexamethasone (n = 321) or lenalidomide and dexamethasone alone (n = 325). Patients had received a median of 2 prior therapiesbefore entering the trial and 35% were refractory to their last therapy.

The dual primary endpoints of the study were PFS and objective response rate (ORR). Key secondary endpoints focused on OS and safety. Additionally, post-hoc analyses were conducted for pain assessment using the Brief Pain Inventory-Short Form (BPI-SF). A sustained improvement in pain was defined as a ≥3-point decline for ≥2 consecutive 28-day treatment cycles.

In the elotuzumab arm, the antibody was administered intravenously at 10 mg/kg once a week for the first 2 cycles followed by biweekly. Dexamethasone was administered intravenously at 8 mg prior to infusion of elotuzumab and orally at 28 mg. In
the control arm and for weeks without elotuzumab, dexamethasone was administered orally at 40 mg. Lenalidomide was administered at 25 mg orally on days 1 to 21 of each cycle for both groups.

Median PFS with elotuzumab was 19.4 versus 14.9 months with lenalidomide and dexamethasone alone. The 3-year PFS rate was 26% with elotuzumab versus 18% with the doublet alone, representing a relative improvement of 44% at 3 years.

The ORR with elotuzumab was 75% compared with 66% in the control arm. The complete response (CR) and very good complete response rate with elotuzumab was 34% versus 29% for lenalidomide and dexamethasone alone. The CR rate was 5% versus 9%, with and without elotuzumab, respectively.

The time to next treatment was 12 months longer with elotuzumab (33 vs 21 months). Overall, 38% fewer patients started subsequent therapy during the follow-up period with elotuzumab, representing a substantial clinical benefit for patients,according to Richardson.

In patients who experienced a response, there was a sustained improvement in BPI-SF scores that favored the elotuzumab arm. An improvement in patient-reported pain was experienced by 74 patients treated with elotuzumab and for 56 patients in the lenalidomide/dexamethasone arm.

At the analysis, 26% of patients continued to receive elotuzumab versus 14% in the control arm. Treatment discontinuation was primarily due to progression in both arms. The most frequently reported grade 3/4 adverse events (AEs) with and without elotuzumab, respectively, were anemia (15% vs 16%) and neutropenia (15% vs 16%).

The most common all-grade nonhematologic AEs with and without elotuzumab, respectively, were fatigue (48% vs 40%), diarrhea (48% vs 37%), pyrexia (38% vs 28%), constipation (36% vs 28%), cough (33% vs 19%), and muscle spasms (30% vs 27%).

Infections of any grade were seen in 83% of patients in the elotuzumab arm compared with 75% with lenalidomide and dexamethasone alone. Once adjusting for treatment exposure, the rates were similar between the two arms. Infusion reactions, which were mostly grade 1/2, occurred in 10% of patients in the elotuzumab arm

“Updated safety and tolerability data are consistent with previous findings, confirming that there is minimal incremental toxicity associated with the addition of elotuzumab to lenalidomide/dexamethasone,” said Richardson.

Carfilzomib Bests Bortezomib Across Multiple Myeloma Subgroups

Silas Inman

Treatment with carfilzomib reduced the risk of progression or death by 47% compared with bortezomib for patients with relapsed multiple myeloma, according to findings from the phase III ENDEAVOR trial reported at the 2015 Annual Meeting of the American Society of Hematology (Lancet Oncol. 2016;17(1):27-38).

In the study, the median progression-free survival (PFS) with carfilzomib was 18.7 versus 9.4 months with bortezomib. Median overall survival was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib group.

“The randomized, open-label phase III ENDEAVOR study demonstrated that carfilzomib in combination with dexamethasone led to a significant reduction in the risk of progression or death when compared with bortezomib and dexamethasone in patients with relapsed multiple myeloma,” said lead author Meletios A. Dimopoulos, MD, of the School of Medicine at the National and Kapodistrian University of Athens.

“Higher response rates, a greater depth of response, and longer duration of response were also observed with carfilzomib versus bortezomib across cytogenetic subgroups.”

In the phase III study, 929 patients were randomized to receive carfilzomib as a 30-minute  infusion along with dexamethasone (n = 464) or bortezomib and dexamethasone (n = 465). The median age of patients enrolled in the trial was 65 years. All but 7% of patients had ECOG performance status of 0 or 1 (about 50% ECOG 0), and about 20% of the patients had high-risk cytogenetics by fluorescence in situ hybridization.

Carfilzomib was administered at a starting dose of 20 mg/m2 on days 1 and 2 of the first cycle. If tolerated, the dose was escalated to 56 mg/m2 on day 8 of the first cycle. After this point, the 56-mg/m2–dose was maintained on days 9, 15, and 16 then throughout subsequent cycles. In the control arm, patients received bortezomib at 1.3 mg/m2. The majority of patients received bortezomib subcutaneously (75%).In a subgroup analysis, those with high-risk cytogenetics had a median PFS of 8.8 months with carfilzomib (n = 97) versus 6.0 months with bortezomib (n = 113). In patients with standard-risk cytogenetics, the median PFS was not evaluable for carfilzomib (n = 284) versus 10.2 months for bortezomib (n = 291).

Those with high-risk cytogenetics who received one prior therapy had a median PFS of 11.1 versus 7.4 months, for carfilzomib and bortezomib, respectively. With more than two prior lines of therapy, median PFS was 7.6 months with carfilzomib versus 5.6 months for bortezomib.

The largest margin of benefit for carfilzomib was seen for patients at standard risk who received just one prior therapy. In this group, the median PFS with carfilzomib was not yet reached compared with 12.1 months with bortezomib.

“Carfilzomib had a favorable benefit–risk profile in patients with high-risk relapsed multiple myeloma, and was superior to bortezomib, regardless of baseline cytogenetic risk status,” explained Dimopoulos.

Across the full population of the study, the objective response rate was 76.9% with carfilzomib versus 62.6% with bortezomib. The complete response rate with carfilzomib was 12.5% versus 6.2% with bortezomib. The rate of very good partial response or better with carfilzomib was 54.3% compared with 28.6% with bortezomib.

Grade 3 adverse events (AEs) occurred more frequently in the carfilzomib arm compared with bortezomib (73% vs 67%). Additionally, serious AEs were more common with carfilzomib (48% vs 36%). However, dose reductions associated with AEs were more frequent with bortezomib versus carfilzomib (48% vs 23%). Treatment discontinuation due to AEs and on-study deaths were comparable between the two arms.

A number of grade ≥3 AEs occurred in a similar proportion of patients in both groups, including anemia, thrombocytopenia, and neutropenia. upper respiratory infection, and pneumonia. However, there was an increase in the incidenceof hypertension and dyspnea with carfilzomib versus bortezomib. The most frequent nonhematologic grade ≥3 AEs were diarrhea, fatigue, dyspnea, pyrexia, constipation, and insomnia.

Peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% vs 6%).

On January 21, 2016, the FDA approved carfilzomib in combination with dexamethasone or with lenalidomide plus dexamethasone for patients with relapsed/refractory multiple myeloma, following treatment with 1 to 3 lines of therapy. In addition to the combination approvals, this decision also converts carfilzomib’s single-agent accelerated approval in this setting to a full approval. Carfilzomib is now approved as a monotherapy for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy.

 Nurse Perspective  

Melissa Baker Melissa Baker, RN, MSN, OCN, APN-C
Adult Blood & Marrow Stem Cell Transplantation Program
John Theurer Cancer Center
Hackensack, NJ
Multiple myeloma has seen dramatic changes over the past year leading to improved quality of life and improved overall survival. The ENDEAVOR trial is the first head-to-head study comparing two proteasome inhibitors in the treatment of relapsed multiple myeloma. Carfilzomib in combination with dexamethasone has shown superiority over the standard of care, bortezomib plus dexamethasone. This randomized, phase III study demonstrated that the carfilzomib regimen led to a significant two-fold reduction in risk of progression to death compared with the standard combination using bortezomib (patients lived twice as long without progressive disease).

While the incidence of cardiac and renal failure was higher in the carfilzomib arm at this dose, the incidence of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% vs 6%). Peripheral neuropathy is often under-recognized and likely underreported, and can be especially problematic in patients with relapsed and/or refractory multiple myeloma. As an oncology nurse, the ability to offer patients therapy that will not significantly increase the risk of peripheral neuropathy is appealing, as it promotes improved quality of life and increases the possibility that they will remain on treatment.

Oncology nurses play a pivotal role in optimizing patient outcomes through patient education, advocacy, and management. Ongoing therapy is indicated for most myeloma patients, and the nurse needs to reinforce the rationale for the ongoing treatment plan. Nurses encourage selfadvocacy through education, discussion, and goal setting. They provide tools for side effect awareness and management of symptoms. This can be accomplished through active participation in symptom management and by use of a symptom diary. Engaging in open communication improves therapy adherence, and this influences patient outcomes. Specific to carfilzomib, nurses teach patients about common side effects such as: dyspnea, fatigue, cytopenias, risk of infection (including the use of antiviral prophylaxis), and tumor lysis syndrome.

As treatment options for patients with myeloma become increasingly more complex, clinicians must consider both the disease and patient-related factors in order to choose appropriate therapy. The goal is to improve efficacy without increasing toxicity. The carfilzomib regimen is promising and well tolerated without the neurotoxicity or challenging side effects of other proteasome inhibitors, and has become the drug of choice for patients with relapsed and/or refractory multiple myeloma.


Frontline ibrutinib Significantly Improves Survival in CLL

Beth Fand Incollingo

Ibrutinib reduced the risk of death by 84% versus chlorambucil in treatment-naïve elderly patients with chronic lymphocytic leukemia (CLL) or smalllymphocytic lymphoma (SLL), accordingto results from the phase III RESONATE-2 study presented at the 2015 ASH Annual Meeting. The results also showed a 2-year overall survival (OS) rate of 98% with ibrutinib.1,2

“The ibrutinib data represent some of the most compelling results I’ve seen during my career. These data may change how we clinicians treat patients with CLL or SLL in the frontline setting,” noted lead study investigator Jan Burger, MD, PhD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “Theresults showcase the clinical utility of ibrutinib in this setting and the value it may bring as an appropriate treatment option for these patients.”

RESONATE-2 included 269 treatment-naïve patients aged ≥65 years with CLL or SLL. The median age was 73 years. Investigators studied ibrutinib in this population because they thought it “should be highly effective, easy to deliver and safe, and could be a promising treatment for these elderly patients,” one of the study’s authors, Alessandra Tedeschi, MD, of the Azienda Ospedaliera Niguarda Cà Granda in Milan, Italy, said when presenting the data at ASH.

Patients were randomized 1:1 to receive either 420 mg of ibrutinib daily until progression or 0.5 to 0.8 mg/kg of chlorambucil on days 1 and 15 of each 28-day cycle, for a total of 12 cycles. Patients in the chlorambucil arm were allowed to switch over to an extension study that offered ibrutinib if such treatment was indicated, and 43 patients did so.

The median duration of treatment was 17.4 months with ibrutinib and 7.1 months with chlorambucil. At the time of study completion, 87% of patients in the ibrutinib arm remained on therapy. 

The study’s primary endpoint was progression-free survival (PFS) as evaluated by an independent review committee (IRC). Overall survival and overall response rate (ORR) were secondary outcome measures.

The IRC found that, compared with chlorambucil, ibrutinib led to an 84% reduction in the risk of progression or death; investigators calculated that risk reduction as 91%. At a median follow-up of 18.4 months, the median PFS was not yet reached with ibrutinib versus 19 months with chlorambucil. The median 18-month PFS rates were 94% and 45%, respectively.

As per IRC review, ORR was 86% with ibrutinib, with 4.4% of those being complete responses, versus 35.3% with chlorambucil, 1.5% of them complete responses.

Investigator-assessed ORR was 90.4%, with 9.6% of those being complete responses, versus 35.3%, with 4.5% of those being complete responses, respectively.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets. This is important because, in the elderly, bone marrow failure is a common cause of morbidity, Tedeschi said.

A reduction of 50% or more in lymph node burden was observed in 91.2% versus 36.8% of patients (P <.0001) who took ibrutinib and chlorambucil, respectively, and a reduction in spleen enlargement was seen in 75.7% versus 39.1% of patients (P <.0001).

Rates of sustained hematologic improvements were 84% with ibrutinib versus 45% with chlorambucil in patients with baseline anemia (P <.0001), and were, respectively, 77% versus 43% in patients with thrombocytopenia (P = .0054).

Adverse events, most of which were grade 1 and did not result in treatment discontinuation, included diarrhea, fatigue, cough, nausea, peripheral edema, dry eye, arthralgia and vomiting. Neutropenia also occurred in both arms, and was typically more severe than grade 1.

Fatigue, nausea, vomiting and cytopenias were more frequent with chlorambucil, as wereside effects that led to treatment discontinuation. Hypertension was noted more frequently on ibrutinib, but was limited to grades 1 through 3 and managed without dose modification or discontinuation.

Over a median follow-up of approximately 1.5 years, major hemorrhage occurred in 4% of patients with ibrutinib and in 2% with chlorambucil. There were 3 deaths in the ibrutinib arm and 17 in the chlorambucil arm.

References
1. Tedeschi A, Barr PM, Robak T, et al. Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naïve CLL/SLL (RESONATE-2). Presented at: the 57th Annual Meeting of the American Society of Hematology; Orlando, Florida; December 5-8, 2015.Abstract 495.
2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia [published online December 6, 2015]. N Engl J Med.


Breast Cancer

Patient-Reported Symptoms Can Inform Advice on Tamoxifen Versus Anastrozole

Lauren M. Green

A new study has shown that overall quality of life is similar among patients taking tamoxifen or anastrozole, but patient reports on their hot flashes, night sweats, vaginal dryness, and joint pain can help illuminate which therapy may be right for a particular woman. And, the analysis shows, age matters.

The findings, based on a secondary analysis of the phase III NSABP B-35 trial, mark an important step toward the goal of “personalizing medicine for the whole patient,” remarked Patricia A. Ganz, MD, presenting the findings during a press conference at the San Antonio Breast Cancer Symposium (SABCS).1 The results were also published online December 10 in the Lancet.

NSABP B-35 was a double-blind, placebo-controlled trial that compared the efficacy of 5 years of tamoxifen versus anastrozole in reducing breast cancer recurrence in women treated with lumpectomy and radiation for their HR-positive DCIS. The study enrolled 3104 women, and results reported at the 2015 ASCO Annual Meeting showed that although both agents proved effective on the study’s primary outcome measure of time to any breast cancer event, anastrozole was found to be slightly better than tamoxifenin terms of breast cancer–free interval and most beneficial in women younger than 60 years.2

At SABCS, Ganz, director of the UCLA Jonsson Comprehensive Cancer Center’s Prevention and Control Research program, reported findings on patient-reported outcomes (PROs), a secondary endpoint of NSABP B-35. The findings are based on the responses of 1193 participants to validated measures of PROs used in prior breast cancer prevention trials. In addition to assessing their overall quality of life, women taking tamoxifen (n = 601) or anastrozole (n = 592) were asked to report on specific symptoms, such as hot flashes, vaginal dryness, and muscle and joint pain.

These data were collected over 5 years, with questionnaires issued at baseline and every 6 months thereafter. Data for an additional 12 months have not yet been analyzed, Ganz noted. The women across both treatment arms were divided fairly evenly by age, with slightly more women aged ≥60 years (n = 633); 12% of participants were nonwhite.

On the measure of overall quality of life, investigators found no difference between women in the tamoxifen and anastrozole groups on either their physical or mental component scores using the SF-12 tool over the 5 years of analysis. “There was no change in either physical functioning or mental functioning as women took either of these two drugs,” said Ganz.

Results on specific bothersome symptomsrevealed some difference in PROs for the two medications, however. After 6 months of therapy,the frequency of hot flashes increased with both drugs in both older and younger women, and was “a tad worse” in the tamoxifen group, Ganz reported. Vaginal dryness also went up with both tamoxifen and anastrozole, but more significantly with anastrozole.

“Over 60% of the women entering the trial at baseline had musculoskeletal complaints and joint pain,” Ganz noted. “This is very common in postmenopausal women.” These complaints did rise after 6 months of adjuvant therapy—by 10% in the tamoxifen group and about 20% with anastrozole.

Ganz also discussed severity of symptoms, which she said provides a better picture of women’s experience with both of the drugs. On a 1-5 severity scale, with 5 being the most severe, Ganz stressed that vasomotor and musculoskeletal symptoms remain between 1 and 2 on average after treatment with either of the twotherapies. “We’re talking about modest severity of symptoms. Even though they may be frequent,they’re not that severe.”

Shortly after starting the drugs, a composite of hot flash and night sweat scores did go up (P = .0105), but also iminished over time in both treatment arms, Ganz explained. The musculoskeletal pain composite score (joint pain, muscle aches, and general aches and pains) went up in both treatment groups, but more so with anastrozole (P = .0006), and Ganz said, “[these complaints] do not really subside significantly; they stay up over time.”

Investigators had expected sexual functioning would be worse with anastrozole, but the results did not bear this out. Although sexual functioning was worse than average in both groups, there was no difference in sexual functioning scores between the two arms, a finding which was sustained over the 5 years of the trial (P = .56).

Stratifying results by age may help clinicians to advise their patients on which adjuvant approach may be better for them, Ganz said. For example, “not only are vasomotor symptoms worse in patients treated with tamoxifen, they are significantly greater in younger women [<60 years]…This might be a symptom that would be important to think about in younger women with tamoxifen.”

Although no difference overall was seen between the two therapies with respect to worry over weight (something Ganz noted was a concern among menopausal women generally, and not just breast cancer survivors), “younger women significantly reported greater difficulty with weight gain and being unhappy with their appearance”; however, no difference was reported between the two treatment arms, Ganz said. This trend was also true across both arms with regard to vaginal symptoms in younger women, but these were worse with anastrozole, Ganz noted. Likewise, gynecologic problems (eg, discharge, itching) were worse in younger women in both arms, “but again, very low severity,” Ganz added.

“With this kind of information on patient-reported outcomes…physicians and patients can now make much more personalized decisions about which of these two effective agents they should select,” Ganz concluded.

References
1. Ganz PA, Cecchini RS, Julian TB, et al. Patient-reported outcome (PRO) results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole vs tamoxifen in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX.
2. Margolese RG, Cecchini R, Julian TB, et al. Primary results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole versus tamoxifen in postmenopausal patients with DCIS undergoing lumpectomy with radiation. J Clin Oncol. 2015;33 (suppl; abstr LBA500).

 Nurse Perspective  
 
Janice Famorca Tran, RN,MS, AOCNP, CBCN, ANP-C Janice Famorca Tran, RN,MS, AOCNP, CBCN, ANP-C
Texas Oncology
Houston, TX
The secondary analysis of the phase III NSABP B-35 trial reported symptom variation between women taking either tamoxifen or anastrazole,shedding light on the appropriate therapy basedon the individual. The side effects addressed were vasomotor symptoms, vaginal dryness, and musculoskeletal symptoms with vasomotor andvaginal symptoms being worse in younger women.

In practice, these side effects can often become so intolerable thatpatients stop taking their medications. Before patients are placed on these antihormone drugs, it is important that they are assessed to see if they are currently experiencing these types of symptoms. An assessment of these symptoms, as well as their level of severity, can provide direction for practitioners as they decide on which antihormonedrug to prescribe for the patient.

Patient education about these medications with an emphasis on the expectedside effects is essential. The patient should also be educated about both nonpharmacologic and pharmacologic measures to help minimize the side effects from treatment. A shared decision-making model between practitionersand patients potentially could be used when prescribing patients antihormone medication, taking into account what is best for the patient based on the scientific evidence available as well as their present health symptoms. Incorporating measures such as these hopefully can improve patient outcomes as well as adherence to their medication regimen.


Denosumab Is Not Just for Bone Health—Agent Ups Survival, Too

Lauren M. Green

Denosumab not only promotes bone health, it confers a survival advantage, according to data from a follow-up analysis of the ABCSG-18 trial reported at the 2015 San Antonio Breast Cancer Symposium (SABCS).1

In this phase III trial, adding denosumab to aromatase inhibitor (AI) therapy in postmenopausal women with HR-positive breast cancer yielded a 19% relative survival improvement, reducing the risk of recurrence or death. Thefindings suggest that the agent should be recommended for this population in clinical practice,regardless of the patient’s bone health status.

“We now finally have evidence that bone-targeted treatment is not only successful in treating bony metastases and preventing treatment-induced bone loss. It also reduces recurrence and improves survival, at least in postmenopausal breast cancer patients,” said Michael Gnant, MD, presenting the findings during a press conference at SABCS.

This prospective, double-blind trial enrolled 3425 postmenopausal women at a median age of 64 years, who were receiving adjuvant AI therapy for their early, HR-positive breastcancer at 58 centers in Austria and Sweden between 2006 and 2013. Patients were randomizedevenly to receive 60-mg denosumab subcutaneously every 6 months or placebo.

Gnant, a professor of surgery at the Medical University of Vienna, previously presented data from the ABCSG-18 trial at the 2015 ASCO Annual Meeting showing that twice-yearly,low-dose denosumab reduced the number ofclinical fractures by half, with 176 fractures reported in patients receiving placebo, but only 92 fractures were observed in the denosumabarm.2 “That’s quite a dramatic difference, and there was no measurable difference in toxicity between denosumab and placebo,” noted Gnant.

Because investigators also wanted to see if denosumab would impact survival, they performed a time-driven analysis of disease-free survival (DFS) in September, before the studyis unblinded next year, Gnant explained. For their analysis, the researchers defined a DFS event as “time to any evidence of local or distant metastases, contralateral breast cancer, secondary cancer, or death from any cause.”

More events occurred in the placebo arm than in the denosumab arm, 203 versus 167, respectively, Gnant reported, noting that while this finding was of “borderline statistical significance” due to a low number of events, sensitivity analyses of the data indicate that the DFS difference estimate is a conservative one.

“In absolute figures, the benefit is about 1% after 3 years, 2% after 5 years, and 3% after 7 years of follow up,” Gnant reported.

In an exploratory analysis to uncover any signals of which subgroups might benefit more from adjuvant denosumab, Gnant said there is some indication that the benefits may be greater for those who start their treatment earlier, patients with larger tumors, those with ductal invasive histology, and patients whose tumors are HR-positive.

Specifically, in the group of patients whose tumors were >2 cm (n = 950), Gnant noted, “the absolute difference goes to about 4% after 3 years, 7% at 5 years, and more than 10% at 7 years—that’s quite a relevant difference.”

Gnant reiterated that the agent has a proven track record of safety, with ABCSG-18 showing no difference with denosumab in the occurrence of any-grade adverse events compared with placebo, and no confirmed cases of osteonecrosis of the jaw or atypical fractures.

Although the FDA has approved adjuvant denosumab as a treatment to increase bone massin patients on AI therapy who are at high risk for fracture, it’s typically used only for those with established osteoporosis. With these new data, Gnant said, denosumab should be offered to all postmenopausal women with HR-positive breast cancer on AIs, regardless of their bone health status:

“When I see a new patient next week, I will start her on the two subcutaneous injections every 6 months for 3 years.”

References
1. Gnant M, Pfeiler G, Dubsky PC, et al. The impact of adjuvant denosumab on disease-free survival: results from 3425 postmenopausal patients of the ABCSG-18 trial. Presented at: 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S2-02.
2. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicenter, randomized, double-blind placebo-controlled trial. Lancet. 2015;386(9992):433-443.

Prostate Cancer

Celecoxib and Zoledronic Acid Improve Survival in Metastatic Prostate Cancer

Jason Broderick

Adding celecoxib and zoledronic acid to standard treatment extended survival in men with metastatic prostate cancer commencing first-line hormone therapy, according to updated data from the STAMPEDE trial.

“In the metastatic subset, [the combination] improves failure-free and overall survival,” Nicholas D. James, MD, of the University of Warwick and Queen Elizabeth Hospital Birmingham in the United Kingdom, said when presenting the data at the 2016 Genitourinary (GU) Cancers Symposium. “At the very least, we feel these data merit further evaluation.”

This multi-arm, multistage trial accrued men with high-risk, locally advanced, metastatic or recurrent hormone-naive prostate cancer commencing standard of care (SOC) first-line treatment, defined as long-term androgen deprivation therapy with or without radiotherapy.

The analysis presented at the GU symposium included 1245 patients randomized in a 2:1:1 ratio between October 2005 and April 2011 to SOC (n = 622), SOC plus the COX-2 inhibitor celecoxib (n = 312), or SOC plus celecoxib and zoledronic acid (n = 311).

The median patient age was 65 years, with a median PSA of 66 ng/mL, and 61% of patients had metastatic disease, 14% were N+/X M0, and 25% were N0M0. Patients received celecoxib twice daily for up to 1 year. Zoledronic acid was given at an induction dose of 4 mg every 3 weeks for 6 cycles, and then every 4 weeks for up to 2 years. The primary outcome measure was overall survival (OS), with secondary endpoints including failure-free survival (FFS) and safety.

James noted that accrual to the 2 celecoxib arms from the STAMPEDE trial had previously been halted by an independent committee after a failure to show that the treatment improved FFS when compared with SOC. The analysis presented at the GU Symposium was part of a preplanned analysis included in the trial design for all of the treatment arms.

At the time of the analysis, 459 (36%) men had died of prostate cancer, 113 (9%) had died of other causes, and 668 (55%) were alive. There were 295 control arm deaths, 82% of which were due to prostate cancer.

The addition of celecoxib alone to SOC did not significantly improve FFS or OS. The median OS was 68 months with a 5-year OS of 54% for both SOC alone and with the addition of celecoxib.

In the overall population, adding zoledronic acid to celecoxib and SOC also did not significantly improve FFS or OS versus SOC alone. Median FFS was 24 months in the combination arm versus 19 months in the control arm, and median OS was 74 months with the combination versus 68 months in the control arm. However, in a subgroup of patients with metastases at baseline, there was a significant improvement in both OS and FFS for the celecoxib/zoledronic acid arm compared with the control arm.

Toxicities were similar across the treatment arms. Grade 3-5 adverse events (AEs) were reported in 31% of the lecoxib/zoledronic acid arm, 33% of the celecoxib arm, and 35% of the SOC arm.

The most frequently reported grade 3-5 AEs were endocrine disorder (10%, 11%, 14%, respectively), musculoskeletal (5%, 8%, 7%), renal (5%, 4%, 6%), and gastrointestinal disorder (5%, 4%, 3%). The rate of grade 3-5 cardiac disorder was 3% for each arm.

James compared the impact of the celecoxib/zoledronic acid combination in the metastatic setting to the benefit demonstrated with the addition of docetaxel.

“The magnitude of the [celecoxib/zoledronic] effect is very similar to the effect that we showed with docetaxel last year.”

Reference
James ND, Sydes MR, Clarke NW, et al. Celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: Survival results from STAMPEDE (NCT00268476). J Clin Oncol. 2016;34(suppl 2S; abstr 162).
 
 Nurse Perspective  
 
Frank delaRama Frank delaRama, RN, MSN, AOCNS
Clinical Nurse Specialist Oncology Genomics
Prostate Cancer Nurse Navigator
Palo Alto Medical Foundation
Palo Alto, CA
The STAMPEDE trial is a large study that aimed to evaluate the addition of further treatments to androgen deprivation therapy (ADT), including docetaxel, zoledronic acid, celecoxib, abiraterone, enzalutamide, and (among newly diagnosed M1 patients only) radiotherapy. In the analysis presented here by Nicholas James, MD, combination therapy with celecoxib and zoledronic acid may have a specific beneficial effect to men with metastatic disease starting first-line hormone therapy. This beneficial effect was not seen in men with only advanced disease (N+/X M0 or N0M0) that were given this combination therapy.

Other studies have found that COX-2 inhibitors, such as celecoxib, could slow down the growth and invasiveness of prostate cancer cells. Zoledronic acid is a well-established therapy that works to prevent skeletal complications in those with bony metastases. Men with advancing or newly metastatic prostate cancer are prescribed hormone therapy, knowing that it is not about if the cancer will progress, but when. There are many promising agents, such as celecoxib and zoledronic acid, that are successful in treating a particular aspect of prostate cancer. The question is if a combination of therapies can somehow work better than monotherapy, and the STAMPEDE trial may be vital in our quest to solve this puzzle.

As combination therapies develop, nursing research could concurrently address the potential side effect management issues that may arise. For most of these proposed agents, nurses are already well equipped to help patients with the side effects of each medication on its own. The unknown would be perhaps if the different agents given together may potentiate (or neutralize) any expected side effects.

The findings on combination therapies here are encouraging and may have great impact on our patients with late-stage or metastatic disease who are battling toward days to months of survival, as opposed to the years to decades our patients with early-stage, localized disease often experience.
 
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