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Combination treatment with the PI3Kdelta inhibitor idelalisib and rituximab (Rituxan) was associated with a >70% improvement in overall survival (OS) in patients with high-risk relapsed/refractory chronic lymphocytic leukemia (CLL), according to phase III data presented at the 55th annual meeting of the American Society of Hematology. Abstract LBA-6
The idelalisib combination also improved progression- free survival (PFS), the primary endpoint of the trial, by >80% compared with the comparator arm of rituximab plus placebo.
The two regimens had similar adverse-event (AE) profiles, according to lead author Richard Furman, MD, who reported the results at the meeting. The trial was halted and crossover was allowed following a positive risk-benefit review from an independent data monitoring committee at an interim analysis.
“In patients with heavily pretreated, relapsed CLL who are not suitable for cytotoxic chemotherapy and at high risk for poor outcome, idelalisib plus rituximab significantly improved progression-free survival, objective response rate, and overall survival,” said Furman, head of the CLL and Waldenstrom’s Macroglobulinemia Program at Weill Cornell Medical College.
“Idelalisib and rituximab provided effective, durable disease control and improved overall survival for patients with advanced CLL, including high-risk patients,” he continued.
Idelalisib is highly a selective inhibitor of PI3Kdelta, an isoform found primarily in leukocytes. The molecule has a central role in activation, proliferation, migration, and survival of B lymphocytes. The isoform induces hyperactivation in a variety of Bcell malignancies, said Furman.
Favorable results from early clinical trials led to the phase III, multicenter, multinational Study 116. Investigators in North America and Europe randomized 220 patients with relapsed/refractory CLL in a 1:1 ratio to receive rituximab plus either idelalisib (150 mg twice daily) or placebo. Treatment was scheduled to continue for 6 months.
At progression, patients could continue treatment in a single-agent extension study (117). Patients initially randomized to idelalisib received a higher dosage (300 mg twice daily) in the extension study, whereas patients randomized to placebo received the idelalisib dosage from the primary stage.
On average, patients had received three prior regimens and were considered ineligible for additional chemotherapy. Between 80% and 90% of the patients had a Cumulative Illness Rating Score >6; 40% to 45% had a 17p deletion or TP53 mutation; 80% to 85% had unmutated IGHV; and about 40% of the patients had a creatinine clearance of <60 mL/min.
When the trial stopped, the median PFS in the placebo group was 5.5 months, whereas the median had yet to be reached in the idelalisib arm. The difference in PFS translated into an 85% reduction in the hazard for the idelalisib group versus the placebo group (hazard ratio [HR] = 0.15; 95% CI, 0.08-0.28; P <.001).
The 24-week PFS was 93% with idelalisib/rituximab and 46% for placebo/rituximab. The PFS benefit was consistent across all prespecified subgroups, including sex, age, and mutation status.
Analysis of OS yielded a hazard ratio of 0.28, representing a 72% reduction in the hazard for patients treated with idelalisib versus placebo (95% CI, 0.09- 0.86; P = .018).
Objective response rate, a secondary endpoint, was six times higher with idelalisib versus placebo (81% vs 13%; odds ratio = 29.92; P <.0001).
Lymphadenopathy improved in all patients in the idelalisib arm, and 93% of the patients had at least a 50% improvement, the criterion for lymph node response. In contrast, 4% of placebo-treated patients had lymph node responses.
More than 90% of patients in each group had at least one AE. The most common AEs (all grades) in the idelalisib group were pyrexia (29%), fatigue (24%), nausea (24%), chills (22%), and diarrhea (19%). In the placebo arm, the most common AEs (all grades) were infusion-related reaction (28%), fatigue (27%), cough (25%), nausea (22%), and dyspnea (19%).
The incidence of grade ≥3 AEs was 56.4% with idelalisib versus 47.7% with placebo. Serious adverse events occurred in 40% of the idelalisib group and 34.6% of the placebo group.
The discontinuation rate associated with AEs was 8.2% in the idelalisib arm and 10.3% in the placebo group. Additionally, four deaths (3.6%) occurred in the idelalisib group, as did 12 (11.2%) in the placebo group.
A higher cumulative dose of the proteasome inhibitor bortezomib, including a longer duration of treatment and/or higher dose intensity, appears to improve overall survival (OS) in patients with previously untreated multiple myeloma (MM), according to a retrospective analysis of the phase III VISTA study. Abstract 1968
Those patients in VISTA who received a cumulative bortezomib dose ≥39 mg/m2 had a median OS that was 20 months longer than those who received a cumulative dose <39 mg/m2, said María- Victoria Mateos, MD, at the 55th annual meeting of the American Society of Hematology.
Continued bortezomib maintenance treatment to increase cumulative dose and drug exposure may, therefore, be important to improving OS in newly treated patients with MM, according to Mateos, from Hospital Universitario Salamanca, Spain.
“Continued bortezomib treatment following attainment of complete response may also be associated with improved OS,” she added.
In VISTA, 682 untreated, newly diagnosed patients with MM, who were not candidates for stem cell transplantation, were randomized to bortezomib in addition to melphalan and prednisone or melphalan plus prednisone alone. Patients randomized to bortezomib had a 35% reduction in risk of death at any time. Overall survival was 68.5% at 3 years in the bortezomib group compared with 54% in the melphalan and prednisone arm. At 5 years, the risk of mortality was reduced by 31% with the addition of bortezomib to the regimen, despite the significant use of subsequent therapy.
The current analysis examined the response in the 340 patients randomly assigned to bortezomib, half of whom received a cumulative dose <39 mg/m2 and half of whom received ≥39 mg/ m2. Median treatment durations were 2.5 months and 12.1 months, respectively. Patient characteristics were balanced between the two groups, except for age (mean age: 74 years vs 71 years, respectively; P <.0001).
Median OS was 66.3 months in patients receiving ≥39 mg/m2 versus 46.2 months in those receiving <39 mg/m2 (hazard ratio [HR] = 0.53; P <.0001). The HR for OS between the two groups when adjusted for age was .56 (P = .0002) in favor of the higher cumulative dose group.
Among the patients who survived past the 180-day threshold, median OS was longer in the higher versus lower cumulative dose group (60.4 vs 50.3 months; HR = .709; P = .04).
An exploratory analysis assessed the impact of continuing treatment following attainment of a complete response (CR) on OS. Among the 102 patients in VISTA who achieved a CR, the median OS was 55.5 months for those who received two or fewer treatment cycles beyond CR compared with 64.6 months for those who received >2 treatment cycles beyond CR (HR = .71). The median duration of CR was 16.9 months and 20.3 months, respectively.
Eighty-six percent of patients in the higher cumulative dose group completed treatment, compared with 31% in the lower cumulative dose group. According to the authors, early discontinuation was primarily associated with toxicity and appeared more common in older patients. Reasons for discontinuation of therapy included adverse events (27% with <39 mg/m2 vs 4% with ≥39 mg/m2), patient choice (17% vs 2%), disease progression (9% vs 5%), and mortality (8% vs 1%).
Maintenance bortezomib can be achieved through several approaches, the authors reported, including switching to the subcutaneous formulation, modifying the dose/schedule, and proactively managing adverse events.
Phyllis McKiernan, MSN, APN, OCN
Blood and Marrow Transplant Program
John Theurer Cancer CenterHackensack, NJ
For older patients with multiple myeloma who are not candidates for stem cell transplantation, melphalan has a proven efficacy and has played a critical role in standard therapeutic regimens. The use of novel agents such as proteasome inhibitors and immunomodulatory agents has showed improved outcomes (SEER data 2003-2009); therefore, adding a novel agent to melphalan-containing regimens has become an effective strategy. At the 2013 annual meeting of the American Society of Hematology, two oral abstracts pertaining to the use of melphalan were presented that could lead to a change in the standard of care for this patient population.
of care for this patient population. The phase III VISTA trial had previously demonstrated improvement in overall survival (OS) in transplant-ineligible patients who were treated with a combination of bortezomib, melphalan, and prednisone versus melphalan and prednisone alone.1 During an oral abstract presentation, Maria-Victoria Mateos, MD, reported a retrospective analysis of the data from the VISTA trial showing a survival benefit in patients who received a higher cumulative dose of bortezomib. Patients who received the lower overall dose were slightly older and discontinued therapy more frequently for adverse effects, choice, disease progression, and mortality; those who received the higher cumulative doses—indicating longer duration of therapy—had improved OS. A strategy to achieve longer duration of therapy could be to modify doses or schedules and to manage toxicities, especially for older patients, thus maximizing cumulative doses of bortezomib.
While adding novel agents to melphalan-containing regimens can be efficacious and improve survival, the toxicities of melphalan cannot be ignored. Melphalan can cause significant cytopenias and is associated with a risk of secondary malignancies such as myelodysplasia or leukemia,2 an issue for patients who are surviving longer due to improved therapies.
During the plenary session, Thierry Facon, MD, presented the results of the FIRST trial, reporting the combination of continuous lenalidomide and low-dose dexamethasone (continuous Rd) versus melphalan, prednisone, and thalidomide improved progressionfree survival and may improve OS for older, transplant-ineligible patients. Patients who received continuous Rd were more likely to continue therapy, had a decreased incidence of secondary hematologic malignancies, and experienced less cytopenia.
This new data could ultimately lead to a shift in the standard of care away from melphalan and the associated toxicities. Unanswered questions remain as to the definitive impact on OS, although the trend is favorable. Clearly, for now, the use of continuous Rd can be an effective, safe, and tolerable regimen for older patients with myeloma.
1. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31(4):31-45.
2. Dispenzieri A, Lacy MQ, Greipp PR. Multiple Myeloma. In: Greer JP, Foerster J, Rodgers GM, eds. Wintrobe’s Clinical Hematology. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:2417—2418.
The combination of continuous lenalidomide and low-dose dexamethasone (continuous Rd) extends progression-free survival (PFS) and trends toward improving overall survival (OS) compared with the standard combination of melphalan, prednisone, and thalidomide (MPT) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM). Results from an international phase III study comparing the two regimens, known as FIRST (Frontline Investigation of Lenalidomide Plus Dexamethasone Versus Standard Thalidomide), were presented by Thierry Facon, MD, at the 55th annual meeting of the American Society of Hematology. Abstract 2
The favorable effect of continuous Rd on clinical outcomes establishes it as “a new standard of care,” said Facon, professor of Hematology, Service des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille in France. Continuous treatment had typically been reserved for patients who relapsed following 72 weeks of induction therapy, due to toxicities associated with longterm therapy.
Fixed durations of MPT and bortezomibmelphalan- prednisone are preferred regimens for patients with NDMM ineligible for stem cell transplant as recommended by the National Comprehensive Cancer Network, he noted.
In FIRST, 1623 patients who were ≥65 years old or otherwise ineligible for autologous stem cell transplantation were randomized to one of three treatment arms: continuous Rd until disease progression; Rd for 18 28-day cycles (Rd18) for 72 weeks; or MPT for up to 12 42-day cycles for 72 weeks.
The median age of patients enrolled was 73 years; 35% of patients were ≥75 years old, and 41% of patients had International Staging System stage 3 disease.
Intervention in early or “smoldering” myeloma with a three-drug regimen led to complete responses (CRs) in a group of high-risk patients, suggesting a window of opportunity that may delay or prevent progression to a debilitating disease state, according to results of a small pilot study. Abstract 1939.
All 12 patients had attained at least a very good partial response after completing two cycles of carfilzomib, lenalidomide, and dexamethasone (CRd). After four cycles of therapy, 7 of the 12 had CR or stringent CR (sCR). Following completion of the eight planned cycles of therapy, all 12 patients had attained near CR (nCR), CR, or sCR, according to C. Ola Landgren, MD, PhD, senior investigator in the Multiple Myeloma Section of the National Cancer Institute.
Investigators have begun enrolling 16 additional patients in an expansion-cohort evaluation of the CRd followed by lenalidomide extended-dose (CRd-R) regimen.“With follow-up beyond 2 years, investigators can begin to think that the regimen delays progression to multiple myeloma, because untreated high-risk patients progress to multiple myeloma after a median duration of about 2 years. If patients remained in a negative minimum residual disease state for 5 years or beyond, the discussion could turn to the possibility that the regimen actually prevents progression to multiple myeloma,” Landgren said.
Of the 535 patients enrolled in the continuous Rd arm, 121 (23%) were still on treatment assignment after a median follow-up of 37 months. “More patients allocated to lenalidomide-containing arms completed 72 weeks of treatment compared with patients allocated to MPT,” Facon said. Two hundred eight patients (39%) in the continuous Rd arm were treated for more than 2 years. Eleven percent withdrew from continuous Rd due to adverse events, compared with 13% randomized to Rd18 and 14% randomized to MPT.
The trial met its primary endpoint, demonstrating a 28% improvement in PFS with continuous Rd compared with MPT (HR = 0.72; P = .00006). Three-year PFS was 42% in patients randomized to continuous Rd, 23% in those randomized to Rd18, and 23% in those randomized to MPT. “At this time point [3 years], we had an approximate 1-year difference in the PFS curves,” he said.
Median PFS was 25.5 months in the continuous Rd arm, 20.7 months in the Rd18 arm, and 21.2 months in the MPT arm.
A preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of continuous Rd versus MPT (HR = 0.78; P = .01685), although the prespecified boundary (P <.0096) was not crossed. Four-year OS rates were 59.4% in the continuous Rd arm, 55.7% in the Rd18 arm, and 51.4% in the MPT arm.
Safety profiles were similar between treatment regimens, but patients treated with continuous Rd showed fewer secondary hematologic malignancies than those treated with MPT, Facon said. Hematologic malignancies occurred in 0.4% of patients assigned to continuous Rd compared with 2.2% assigned to MPT; the overall incidence of solid tumors was identical (2.8%).
Relevant grade 3/4 adverse events in the continuous Rd arm versus the MPT arm were as follows: neutropenia (28% vs 45%), thrombocytopenia (8% vs 11%), febrile neutropenia (1% vs 3%), infection (29% vs 17%), neuropathy (5% vs 15%), and deep vein thrombosis (5% vs 3%).
Several trials of ibrutinib, an oral kinase inhibitor, either alone or in combination with currently used therapies for patients with chronic lymphocytic leukemia (CLL) were presented at the 2013 ASH annual meeting.
On February 12, the FDA announced an expansion of its approval of ibrutinib to include the treatment of patients with CLL who have received at least one previous therapy. Ibrutinib was previously approved as a monotherapy for patients with mantle cell lymphoma who have received at least one prior therapy.
Ibrutinib specifically inhibits the Bruton’s tyrosine kinase (BTK), a crucial component of both normal and malignant B-cell receptor signaling that has been shown to modulate the tumor microenvironment and promote survival and growth of CLL. The drug has shown less toxicity for patients compared with standard regimens.
In the phase Ib/II PCYC-1102 monotherapy study in relapsed, refractory CLL (n = 85), patients who received 420 mg of ibrutinib daily had an overall response rate (ORR) of 71% (N Engl J Med. 2013;369:32-42). The estimated progression-free survival (PFS) rate at 26 months was 75%.
“This is one of several compounds that are targeting specific pathways in the CLL cell that will likely lead to long-term control and possibly cure of this disease,” said Philip L. McCarthy, MD, of the Blood and Marrow Transplant Program at the Roswell Park Cancer Institute in Buffalo.
Combining ibrutinib with the chemoimmunotherapy regimen of bendamustine plus rituximab demonstrated a high level of activity and was tolerable for patients with relapsed or refractory CLL. Presenting the final results of the 30-patient study, Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston, said those patients with a molecular marker of highrisk disease and those with bulky disease were as likely to respond as all patients on the trial. Abstract 525
The ORR was 93.4% (28/30) including five complete responses and three nodal partial responses, with no differences in responses based on risk features such as a 17p deletion. An additional patient had a partial response with lymphocytosis (PRL). The estimated PFS at 12 months was 90%, but the median PFS has not yet been reached.
Twenty-one of the patients are continuing on an ibrutinib extension study and 18 are still on treatment about 12 months later with no evidence of progression, Brown said during her presentation. Nine patients have discontinued, with five going on to a stem cell transplant and four with disease progression.
Patients tolerated the three-drug regimen relatively well: the median number of completed cycles was the full six. No patients have discontinued the drug due to adverse events (AEs) and no deaths were reported on the study.
The most frequent treatment-related AEs were diarrhea (70%), nausea (66.7%), fatigue (46.7%), neutropenia (40%), and upper respiratory tract infection (36.7%). Grade ≥3 AEs included neutropenia (40%), maculopapular rash (10%), and fatigue (10%), as well as cellulitis, thrombocytopenia, and febrile neutropenia (6.7% each).
A 14-month update of a phase II trial of ibrutinib plus rituximab (n = 40) has shown higher response rates for the combination compared with historical response rates with rituximab alone. The combination resulted in a response in 37 of the 39 CLL patients on the trial who could be evaluated. Thirty-four patients achieved a partial remission (87%) and three patients had a complete remission (8%). Abstract 675
The combination resulted in profound activity in high-risk CLL patients and was well tolerated, said Jan Burger, MD, PhD, associate professor of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, who presented the results. “The addition of rituximab clearly accelerates responses in CLL,” said Burger. “But the question is whether this response will translate into substantial benefit for patients in the long run. That is what we are currently testing.”
The combination also improved the quality of life of patients. In self-reported quality-of-life questionnaires, the proportion of patients reporting high quality of life increased from 46% prior to treatment to 89% after 6 months of ibrutinib therapy.
At a median follow-up of 14 months, 31 of the 40 patients are still on treatment (including 16 of 20 patients with a 17p deletion or TP53 mutation) with no disease progression. The estimated overall survival at 18 months is 84%.
Several patients had infection complications including six patients with pneumonia and three upper respiratory infections. Low-grade adverse events included bruising, subdural hematoma, fatigue, bone pain, and arthralgia.
The combination is currently being tested in an ongoing phase III, randomized, 150-patient clinical trial (NCT01973387).
Jayshree Shah, APN-C, MSN, RN
John Theurer Cancer Center
Chronic lymphocytic leukemia (CLL) is the most common type of cancer in older adults. Recently during the Annual Meeting of the American Society of Hematology, it was noted that the oral kinase inhibitor ibrutinib, used either alone or in combination with currently FDA-approved therapies, showed overall response rates better than anticipated while improving quality of life.
Currently, we have chemotherapies that have shown great response rates, yet without a cure for CLL patients. Ibrutinib being utilized in combination modality with bendamustine and rituximab showed an overall response rate of 93.4% which we have not seen in a long time. When reviewing the results, one must be careful in understanding the breakdown of different grades of adverse events that may have occurred when utilizing combination therapy. In this case, precautions to prevent infection, diarrhea, nausea, fatigue, neutropenia, and rash should be taken early or preventive measures should be in place.
It is very exciting to have an oral agent such as ibrutinib used as a mono or combination therapy. As a healthcare professional, I try to make sure a thorough analysis of the patient history is undertaken before prescribing any chemotherapy in order to avoid adverse events.
Findings from the International Breast Cancer Intervention Study II (IBIS II) examining the efficacy of the aromatase inhibitor anastrozole as a breast cancer preventive show that the oral agent provided significant benefit to postmenopausal women deemed at high risk, reducing their risk of getting the disease by more than half with very few side effects.
The results were announced at the 36th annual San Antonio Breast Cancer Symposium (SABCS) and published online ahead of print simultaneously in the Lancet.1 The researchers noted that their findings are similar to results previously reported for exemestane in breast cancer prevention for postmenopausal women in the MAP.3 trial. In that trial, exemestane reduced the incidence of all breast cancer in that population by 53% and invasive breast cancer by 65% after 3 years of follow-up.2
In the IBIS II study, conducted between 2003 and 2012, 3864 postmenopausal women at high risk for breast cancer from 18 countries were randomly assigned to receive 1 mg oral anastrozole daily (n = 1920) or placebo (n = 1944). The median age of the participants was 59.3 years, and 47% of the women had used HR therapy in the past.
Criteria used to determine high breast cancer risk included having ≥2 blood relatives with breast cancer, having a mother or sister who developed breast cancer before age 50, and having a mother or sister with bilateral breast cancer.
Histologically confirmed breast cancer was the study’s primary endpoint. Forty women in the anastrozole- treated group (2%) and 85 in the placebo group (4%) developed breast cancer after 5 years of follow-up (HR = 0.47; CI, 0.32-0.68; P <.0001)—a finding investigators said would represent a 7-year 5.6% cumulative incidence of breast cancer in the placebo arm versus 2.8% in patients receiving the aromatase inhibitor, a reduction of 53%. Anastrozole also cut the incidence of ER-positive breast cancer by 58%—from 3.3% in placebo-treated patients to 1.4% in those taking anastrozole (P =. 001)—but the agent demonstrated little effect in ER-negative cancers
Adherence to treatment was similar in both arms: 68% in the anastrozole cohort and 72% in the placebo group; the main reason for treatment discontinuation in both groups was adverse events, which occurred in 20% and 15% of each population, respectively.
Overall, the researchers noted, most side effects were not attributable to treatment, and most also increased in the placebo group. Whereas the total number of fractures was similar between the two groups, musculoskeletal adverse events occurred in more women receiving anastrozole versus women receiving placebo (64% and 58%, respectively), a significant difference (P = .0001).
Whereas significant differences were not observed in the incidence of mild or severe arthralgia between the two groups, the researchers reported that the incidence of moderate arthralgia was significantly higher in the treatment arm, as was the incidence of dry eyes among those in the anastrozole group.
Among the unexpected findings reported by investigators was a reduction in other cancers in the treatment group, notably a higher incidence of skin and gastrointestinal (GI) cancers in the placebo arm. Fourteen women in the anastrozole group developed skin cancer versus 27 receiving placebo. For GI cancers, the numbers were 4 and 12, respectively.
The study’s lead author, Jack Cuzick, PhD, head of the Cancer Research UK Centre for Cancer Prevention and director of the Wolfson Institute of Preventive Medicine at Queen Mary University in London, presented the findings at SABCS.
Planned follow-up is at least 10 years and hopefully much longer, he noted.
“We want to determine if anastrozole has a continued impact on cancer incidence even after stopping treatment, if it reduces deaths from breast cancer, and to ensure that there are no long-term adverse side effects.”
1. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomized placebo-controlled trial [published online December 12, 2013]. Lancet. doi:10.1016/S0140-6736(13)62292-62298.
2. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381-2391.
A. Nicole Spray, APRN
Hays Med Breast Center
The results from the International Breast Cancer Intervention Study II that anastrozole can provide benefit in breast cancer reduction in postmenopausal high-risk women are exciting. A 53% reduction in the risk of breast cancer was found by proving that only 2% of the anastrozole-treated group developed breast cancer after 5 years of follow up compared with 4% in the placebo group.
Breast cancer risk assessment is more prevalent now than ever. We now have risk models such as the Tyrer-Cuzick Model, Claus Model, BOADICEA, and BRCAPRO to help calculate a woman’s personal risk of breast cancer. The NCCN has published guidelines for the management of women who are at greater than average risk for breast cancer, usually defined by a score of 20% or more on widely accepted models.
The use of current chemopreventive agents, tamoxifen and raloxifene, are reported to be vastly underutilized. In my clinical opinion, underutilization of these agents is multifactorial. For some women, these drugs are contraindicated due to existing comorbidities. Fear of side effects such as hot flashes, risk of endometrial cancer, venous thromboembolism, and cataracts keep some women from using these agents. Many women have not been educated regarding their personal risk of breast cancer and their options with regard to high-risk management and candidacy for use of a risk-reducing medication.
It is exciting to know that there is another drug to offer women. The potential side effect profile of anastrozole includes musculoskeletal pain and declining bone density. Routine DEXA screening is advised with anastrozole use to detect osteopenia or osteoporosis. As clinicians, we must look at high-risk patients individually and guide them on what risk-reducing medication may be the best option based on their menopausal status and personal and family history.
Interestingly, reduction of skin and gastrointestinal cancers was noted in this study. This is very thought provoking and certainly suggests opportunities for additional research. Furthermore, research could be entertained regarding comparing the available chemopreventive agents head-to-head to determine efficacy. Lastly, it is important as clinicians for us to promote preventive medicine, and we have a unique opportunity to educate highrisk women about their options for breast cancer prevention.
A new study reported at the 2013 San Antonio Breast Cancer Symposium shows that a prescribed exercise program reduces joint pain in breast cancer survivors taking aromatase inhibitors (AIs), with pain reductions observed at all levels of exercise. These findings have the potential to improve adherence to AIs, which would in turn reduce the number of breast cancer recurrences. Abstract S3-03
“AIs play an important role in the effective treatment of HR-postive breast cancer. Unfortunately, many women discontinue the drug because of unpleasant side effects. In this study, we discover that exercise improves joint pain, the most common side effect of AI use. These results are a promising first step in developing clinical interventions that can improve AI-associated joint pain, and in turn, improve AI adherence, breast cancer survival, and quality of life,” stated lead author Melinda L. Irwin, PhD, MPH, associate professor of chronic disease epidemiology at the Yale School of Public Health and co-leader of the Cancer Prevention and Control Research Program at the Yale Cancer Center in New Haven, Connecticut.
Current NCCN recommendations call for 5 years of treatment with an AI after surgery or other primary treatment for postmenopausal women with stage I—III HR-positive breast cancer, accounting for nearly 70% of all newly diagnosed cases of breast cancer. Up to 50% of patients who take AIs, however, report arthralgias or joint pain and stiffness.
Irwin and colleagues conducted the 12-month Hormones and Physical Exercise (HOPE) study to compare the impact of an exercise program versus usual care on 121 breast cancer survivors who were taking AIs for at least 1.5 years and reported at least moderate joint pain. The women had stage I and II breast cancer and were sedentary but able to exercise, she said.
Study participants were randomized in a 1:1 ratio to a yearlong exercise program (twice-weekly supervised resistance and strength training sessions plus 150 minutes per week of at least moderate-intensity aerobic exercise such as brisk walking) or usual care (including education about the benefits of exercise).
This exercise program is recommended for healthy adults as well as cancer survivors by the American Cancer Society and other organizations. Participants in the experimental arm were provided free gym memberships.
At the end of 1 year, arthralgias (worst pain, pain severity, and pain interference) were reduced down to mild pain levels by 30% as a result of participation in the yearlong exercise program, compared with modest increases or no change in joint pain among participants assigned to usual care.
Improvements with exercise were seen across the board regardless of age, disease stage, cancer treatment (chemotherapy, radiation, or both), and duration of AI treatment.
A dose-response effect was also seen, with participants who attended at least 80% of the supervised exercise sessions having a 25% decrease in worst pain scores, whereas women who attended fewer than 80% of the supervised sessions having a 14% decrease.
Cardiorespiratory fitness also correlated with pain reduction, Irwin noted. Women who experienced a 5% increase in cardiorespiratory fitness had a 29% decrease in worst pain scores compared with a 7% decrease in worst pain scores among women who did not reach that benchmark.
The next group of studies will assess mechanisms that may be influencing the effect of exercise on AI-associated joint pain, such as body weight, inflammation, and muscular strength, as well as the time of onset of pain improvement with exercise.
Mari Damhof RN, BSN, OCN, ONN
Willmar Regional Cancer Center
It is not surprising that once again we find evidence of the benefits and importance of regular exercise. The HOPE study, which evaluated 121 women with hormone-receptor positive breast cancer who were taking aromatase inhibitors, found that exercise can help reduce and relieve up to 50% of joint pain among women who take the medically recommended medication.
The primary reason that women stop taking the treatment is due to the joint stiffness and pain. I have had many women over the past years tell me that they felt their quality of life was reduced due to the joint pain they suffered while taking the aromatase inhibitors. For women who already had a diagnosis of arthritis or joint issues prior to the use of an AI, the pain would often be debilitating.
One patient I worked with who already had arthritis issues and had tried aromatase inhibitor medication changes, ended up stopping the treatment due to the increased pain, which also led to a decrease in her activity level. Then she became depressed because of guilt. Her family told her that she should have continued taking this medication, despite her discomfort, because if her cancer returned it would be her fault for not taking the medication.
Being able to identify women who may have trouble tolerating these medications and providing additional information on side effect treatment will help decrease some of the nonadherence issues. Although the prior attempts of relieving or reducing joint pain with acupuncture, glucosamine, and vitamin D have been somewhat helpful, they obviously have not been effective enough if we still have as many as 20% of patients stopping treatment after the first year. This study provided helpful information, but we need to continue research into promoting adherence among women who need to take this treatment for the best outcome.
A subgroup of older breast cancer patients may be able to forgo radiation therapy (RT) after breast-conserving surgery if they are treated with hormonal therapy and considered to be at low risk for breast cancer recurrence, according to results from the international phase III PRIME 2 trial presented at SABCS 2013. Abstract S2-01
The findings apply to women aged ≥65 years with hormone receptor-positive, axillary node-negative breast cancer. The PRIME 2 trial results were even more compelling in women with high estrogen receptor (ER) expression versus low ER expression.
“Radiotherapy has been known to reduce the risk of breast cancer recurrence three- to fourfold. However, our trial has shown that although this is the case, the proportion of women who actually will have a recurrence without radiotherapy is very small (<5%) 5 years after treatment,” said Ian Kunkler, FRCR, professor of clinical oncology, Edinburgh Cancer Research Center, University of Edinburgh, Scotland. “We have identified a subgroup of older patients at sufficiently low risk of recurrence for whom omission of postoperative radiotherapy after breast-conserving surgery and adjuvant endocrine therapy is a reasonable option.”
PRIME 2 randomized 1326 patients aged 65 or older with hormone receptor-positive, node-negative, T1-2 breast cancer (up to 3 cm) to receive adjuvant RT or none. All patients had clear surgical margins of at least 1 mm, and were receiving adjuvant endocrine therapy. Either grade 3 tumors or lymphovascular invasion was allowed, but not both.
Although the difference in 5-year ipsilateral breast tumor recurrence favored RT (26 patients [4.1%] had recurrence with no RT versus 6 [1.3%] who received RT, the absolute difference was very small. Five-year overall survival was 93.8% with no RT versus 94.2% in patients who received RT.
Investigators also examined the effect of ER-status on local recurrence. The local recurrence rate in patients whose tumors had high ER expression was 3.2% with no RT versus 0.8% with it; low ER expression was associated with an 11.1% recurrence rate without RT and 0% with RT.
Of 89 deaths across both groups, the majority (73%) were not linked to breast cancer. Of the 12 deaths attributed to breast cancer, four patients received postoperative RT and eight did not.
These results suggest that postoperative wholebreast radiation can be safely omitted in women aged 65 years or older with node-negative breast cancer and tumors up to 3 cm, Kunkler said. He added that forgoing radiation is especially reasonable in women whose tumors have high ER expression.
“For every 100 women [from our selected population] treated with radiotherapy, one will have a recurrence anyway, four will have a recurrence prevented, but 95 will have had unnecessary radiotherapy,” Kunkler explained. “Once a patient has radiotherapy, she is unable to have it again on the same breast. If these women had not had radiotherapy, they would have been able to have minor surgery and radiotherapy at recurrence. Besides, radiotherapy has its own health risks, particularly in the elderly, as well as the inconvenience of travel for daily treatment over 3 or 4 weeks.”
David Leos, RN, MBA, OCN
Clinical Research Nurse Supervisor
Department of Radiation Oncology
UT MD Anderson Cancer Center
This article provides evidence to further the concept that in terms of treatment options, less can be more. For this disease population, the study is reminiscent of the seminal National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that proved lumpectomy plus radiation a viable treatment option over radical mastectomy. It also brings to mind an earlier review I did regarding the results of a study showing that shortening androgen blockade did not adversely affect certain prostate cancer outcomes.
As the literature presents additional such findings, media coverage counters with the double-whammy of limitations in access to healthcare coupled with spiraling costs. These results provide some solace that at least in some realms of oncology care, treatment needs could be shrinking.
For this subset of patients and for their care providers, this should be welcome news as it would add some flexibility and mitigation of potential risks in their long-term treatment approach by virtue of being able to hold in reserve the radiation treatment card.
When coupled with recent literature pointing out the association of comorbidities with poorer outcomes in cancer patient populations, these findings gain more merit (Clin Epidemiol. 2013;5[suppl 1]:3-29). Comorbidities are frequently associated with an advanced-age population like the patients enrolled in this study. Therefore, having the option to hold off on additional treatment, shown in this study not to adversely affect overall survival and recurrence rates, would seem prudent and in service of the patient’s interests.
From an economic perspective, instances when insurance approval allows for greater treatment utilization could potentially lead to moral hazard. This is the disassociation of personal harm from risks taken when all or some of the cost is carried elsewhere. Therefore, not needing to automatically undergo radiation treatment could limit personal risk while also serving as a judicious step in overall healthcare resource allocations.