Clinical Insights: July/August 2015

Friday, August 28, 2015

STATEMENT OF NEED

The overall goal is to update the healthcare professional’s knowledge of cancer detection and prevention and to understand current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Intended for advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients.

OVERALL EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:

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

ACCREDITATION STATEMENT

Dannemiller is approved by the California Board of Registered Nursing, Provider Number 4229, for 2.0 contact hours. CBRN credit is not accepted by the Michigan and Utah State licensing boards.

DISCLOSURES

The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial companies pertaining to this activity.

METHOD OF PARTICIPATION

  1. Read the articles in this section in its entirety.
  2. Go to http://www.dannemiller.com/onn-jul-aug-2015
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your Certificate of Credit.

This activity is provided free of charge to participants.

Breast Cancer

Exercise Linked to Reduction in Chemotherapy-Induced Cognitive Impairment

Laura Martin

Risk of inflammation and cognitive impairment due to chemotherapy,often called “chemobrain”, may be reduced by maintaining physical activity during treatment, according to a University of Rochester (UR) Medical Center study presented at the 2015 ASCO Annual Meeting. Abstract 9504

The randomized, multicenter, phase III study accrued 619 patients with early-stage cancer who were beginning chemotherapy. Eighty-three percent (n = 514) had breast cancer, while 17% (n = 105) had other typesof cancer. The mean age was 55 years, and 94% (n = 581) were women.

Patients were excluded if they had a diagnosis of leukemia, metastatic disease,or if they were receiving concurrent radiation therapy. Patients had to be sedentary prior to enrollment, which was defined as walking about 4000 steps daily.

Patients were randomized so that half pursued no set exercise regimen during chemotherapy, and the other half were instructed to follow a specific home-based, personalized prescription of aerobic walking and anaerobic resistance band training known as EXCAP (Exercise for Cancer Patients) for 6 weeks. All patients wore a pedometer to track their daily steps.

“Patients were asked to walk on a daily basis and used resistance bands on a daily basis,” said Karen Michelle Mustian, PhD, MPH, lead author on the study and an associate professor in the UR Departments of Surgery and Radiation Oncology, Cancer Control Clinical Research Unit, as well as a Wilmot Cancer Institute researcher. “The regimen is progressively tailored. Based on the individual’s baseline exercise level, they were asked to increase their steps walked 5% to 20% each week and to progressively increase the intensity in the use of resistance bands.”

Thirty-seven percent of study participants received chemotherapy every 2 weeks (n = 229), 62% received chemotherapy every 3 weeks (n = 380), and 1% every 4 weeks (n = 9). Inflammation was assessed at baseline and post intervention using standard serum Luminex assays. Cognitive impairmentwas evaluated using the FACT-Cognitive Function questionnaire, which identified a total cognitive impairment score, cognitive impairment as perceived by the patient, and cognitive impairment as perceived by others.

The results showed that those in the EXCAP group reported less brain fogginess and memory problems overall, and had lower levels of blood inflammation. They also had improved mobility compared with the nonexercise group.

There was a trend for differences in perceived cognitive ability (P <0.10) between groups at post-intervention. Follow-up analyses showed exercise participants receiving 2-week cycles of chemotherapy demonstrated less cognitive impairment overall and across all domains (all P <0.05) except perceived cognitive ability (P <0.10) than controls at post-intervention.T-tests revealed an exercise-induced anti-inflammatory response with down-regulation of pro-inflammatory cytokines (IFNg, IL-8, IL1b) and up-regulation of anti-inflammatory cytokines (IL-6, IL-10, sTNFra) in exercisers (all P <0.05). Conversely, t-tests revealed down-regulation of IL-10 and less up-regulation of sTNFra in the control arm (all P <0.05).

The benefits shown in this study are very promising for early-stage cancer patients undergoing chemotherapy, said Mustian. “To think that a very simple, low-cost, self-directed exercise prescription can create an anti-inflammatory response similar to a drug and protect against cognitive decline in people with cancer is innovative and very exciting,” she said.

Nurse Perspective

 
Marsha Schmit, RN, BSN, CBCN Marsha Schmit, RN, BSN, CBCN
Breast Health Navigator
Hurley Medical Center 
Flint, MI

 

Cognitive impairment is a very real side effect of chemotherapy also known or referred to as chemobrain. For many years, it has been either disregarded or patients have been placated as having to adapt to a new normal. Thanks to a recent study conducted at the University of Rochester (UR) Medical Center, it is believed that exercise may actually reduce cognitive impairment as well as inflammation!

While using a tailored program of walking and use of exercise bands, the patients who were randomized into the exercise program actually reported “less brain fogginess and memory problems overall and even had lower levels of blood inflammation.” They also displayed increased mobility compared to the non-exercise group.

It is exciting to note that exercise does in fact play a very large role in achieving a level of wellness during treatment, but it also plays a significant role in regaining a level of wellness after treatment.

When meeting with breast cancer patients early on, I encourage each one to make this a journey towards wellness and to begin the healing process from the start. It is imperative that they start eating for health and moving their bodies to improve circulation so that they can tolerate treatment well.

Many institutions, including Hurley Medical Center in Flint, Michigan, are establishing programs that allow patients access to a health center at no cost. They are paired with a trainer to identify appropriate exercise and additionally offered meetings with a dietician to determine how to nourish their bodies as they recover from cancer treatment.

These programs are often funded through generous grants. Survivorship programs need to be robust in helping all cancer patients find quality of life! It is my belief and that of current research, that exercise—along with nutrition— play a significant role in accomplishing this. It is my goal to make sure this type of program is available for the patients I serve.

It is not as simple as swallowing a pill, but cancer patients can regain their health and live quality lives if they are provided the resources and are willing to do the hard work to accomplish this.


Study Examines Anastrozole Versus Tamoxifen After DCIS


Lauren M. Green
 
The first study to compare the efficacy and safety of tamoxifen versus anastrozole in women treated for ductal carcinoma in situ (DCIS) suggests that anastrozole may be the better choice for preventing the escalation of DCIS into invasive cancer. Abstract LBA500

Findings from the multicenter, phase III NRG Oncology/NSABP B-35 trial, presented at the 2015 ASCO Annual Meeting, showed that after an average follow-up of 8.6 years, 114 breast cancers were detected in women taking tamoxifen compared with 84 among women who receivedanastrozole. Ten-year breast cancer–free survival was estimated to be 93.5% with anastrozole versus 89.2% with tamoxifen; however, a subgroup analysis showed that anastrozole was not superior to tamoxifen in women >60 years.

“The good news is, tamoxifen and anastrozole are both very effective, but it seems that women have better chances of staying well with anastrozole,” said Richard G. Margolese, MD, lead studyauthor and professor of surgical oncology at the Jewish General Hospital, McGill University, in Montreal, Canada. “Women should also consider differences in side effects when discussing treatment options with their doctors.”

The trial enrolled 3104 postmenopausal women previously treated with lumpectomy and radiation after a diagnosis of hormone receptor–positive DCIS. They were randomly assigned to receive either tamoxifen (20 mg/day) and placebo, or 1 mg of daily anastrozole and placebo. Patients in both arms were eligible to receive the drugs for 5 years.

Margolese noted that the study’s primary objectivewas to reduce the number of breast cancer events, known as a breast cancer–free interval, defined by the researchers as “the time from randomization to any breast cancer event, including local, regional, or distant recurrence or contralateral disease, either invasive or DCIS.”

In women aged <60 years receiving tamoxifen (n = 722), 58 breast cancer events were reported versus 31 among the 725 women assigned to anastrozole. Of 816 women aged ≥60 years in the tamoxifen arm, 56 breast cancer events occurred, versus 53 among the 814 women in that age group who were given anastrozole. Eight deaths were reported due to breast cancer in the tamoxifen group and five in the anastrozole arm.

In women younger than 60 years, anastrozole’s benefit was “conspicuous,” said Margolese, “but in women older than 60, they all do well, and tamoxifen and anastrozole are of equivalent benefit.” “We do not have a goodexplanation for this,” said Margolese, and it willrequire more biologic investigation. Margolese said that anastrozole performed better on all other secondary endpoints, but the differences were relatively small, and the only finding that reached statistical significance was the incidence of contralateral invasive breast cancer, which, he said, “again, was cut by almost half,” in the anastrozole cohort: 36 events in the tamoxifen arm versus 20 with anastrozole.

Investigators also assessed adverse events (AEs). The main side effect of anastrozole is hastening of osteoporosis, and the average annual rate of osteoporotic fractures in the anastrozole arm was 69 per 1000 patients versus 50 with tamoxifen. Tamoxifen is associated with an increased risk of uterine cancer, and the average annual rate per 1000 women for uterine cancer (exclusive of hysterectomies) was 17 with tamoxifen versus 8 with anastrozole.

Neither finding related to these two AEs achieved statistical significance, noted Margolese, adding that severe AEs are “uncommon with both agents—a little bit less common with anastrozole”—suggesting that it may be the preferred option for adjuvant treatment of DCIS, especiallyin women where there is concern about thromboembolism or uterine cancer.


Palbociclib Stalls Progression in HR-Positive Breast Cancer


Jason M. Broderick

Adding palbociclib to standard fulvestrant more than doubled progression-freesurvival (PFS) in pretreated patients with HR-positive, HER2-negative breast cancer, according to study results presented atthe 2015 ASCO Annual Meeting.Abstract LBA502

The results also showed that the CDK 4/6 inhibitor delayed disease progression by over 5 months. These findings come from the double-blind multicenter PALOMA-3 study, which randomized 521 patients with metastaticbreast cancer whose disease progressed on or following endocrine treatment in a 2:1 ratio tofulvestrant plus either palbociclib (n = 347) or placebo (n = 174). Fulvestrant was administered at 500 mg (IM) on days 1 and 15 of cycle 1, and then on day 1 of each cycle thereafter, and patients received oral palbociclib at 125 mg/daycontinuously for the first 3 weeks of each cycle, followed by 1 week off. Treatment cycles were 28 days for both arms. Goserelin was also administeredto pre- and perimenopausal patients. Inboth treatment arms, 79% of patients were sensitive to previous endocrine treatment, 60% had visceral disease, and 79% were postmenopausal. One previous line of chemotherapy for advanced disease was permitted, of which 33% of patients in the overall population had received.

PFS was the primary outcome measure, with secondary objectives focusing on overall survival (OS), response, and safety. Following 195 PFS events, the trial was halted in April 2015 after an independent panel determined the study had met its primary endpoint. Median PFS was 9.2 months with the palbociclib combination versus3.8 months in the placebo arm.

“Palbociclib in combination with fulvestrant is an effective treatment option for women whose cancer progressed on prior endocrine therapy,” said lead study author Nicholas C. Turner, MD, PhD, consultant medical oncologist at The Royal Marsden and Institute of Cancer Research in London, in presenting the findings at ASCO.

“The [PFS] curves separate early and then continue to separate with ongoing follow-up,” he added, and the PFS benefit was observed regardless of menopause status and remained consistent across all prespecified patient subgroups.

Turner said the combination was well tolerated.The most frequently reported toxicities inthe palbociclib arm versus the placebo group were neutropenia (78.8% vs 3.5%), leucopenia (45.5% vs 4.1%), and fatigue (38.0% vs 26.7%).“The incidence of febrile neutropenia…was very rare, and was 0.6% in both arms,” said Turner.

He noted that symptomatic adverse events were “largely similar” in the placebo and palbociclib arms, with a small increase in fatigue, alopecia, and infections for patients receivingthe CDK 4/6 inhibitor.

Hematologic Malignancies

Ibrutinib Regimen Improves PFS by 80% in CLL Study

Jason M. Broderick
 
Adding ibrutinib to standard bendamustine and rituximab (BR) reduced the risk of disease progression by 80% compared with BR plus placebo in patients with pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to results from the phase III HELIOS study. Abstract LBA7005

The significant progression-free survival (PFS) benefit was determined during an interim analysis in March 2015, at which point the study was unblinded and patients receiving placebo were allowed to cross over to the ibrutinib arm.

“This becomes one of the most important changing points in the history of CLL, where the treatment of CLL patients will no longer be BR, but BR with ibrutinib,” lead study author Asher Chanan-Khan, MD, a professor of Medicine at Mayo Clinic, said when presenting the HELIOS data at the 2015 ASCO Annual Meeting.

The double-blind phase III HELIOS trial randomized 578 previously treated patients with measurable relapsed/refractory CLL/SLL to BR for a maximum of six cycles plus either placebo (n = 289) or 420 mg/day of ibrutinib (n = 289). The median patient age was 64 years, and patients had received an average of two prior therapies. PFS was the primary outcome measure, with secondary endpoints focused on overall survival(OS) and objective response rate (ORR).

The interim analysis was conducted following 50% of events. At the time of the review, 31% (n = 90) of patients had progressed on placebo and crossed over to the ibrutinib arm, as allowed by the study design.

At a median follow-up of 17.2 months, PFS with ibrutinib was not yet reached, as compared with 13.3 months for patients receiving BR alone. The PFS benefit held up across subgroups of high-risk patients.

ORR was 82.7% in the ibrutinib arm versus 67.8% in the control group (P <.0001). Complete response (CR) rates (including CR with incomplete blood count recovery) were 10.4% versus 2.8% with ibrutinib versus placebo, respectively.

The toxicity profile was similar between the two study arms, and the adverse events (AEs) in the triplet arm were consistent with previously reported safety outcomes for ibrutinib and BR.

“The side effect profile was very tolerable and expected for each of the individual drugs that was in this regimen,” said Chanan-Khan.

The most frequently reported all-grade AEs in the ibrutinib versus the placebo arm were neutropenia (58.2% vs 54.7%), nausea (36.9% vs35.2%), diarrhea (35.5% vs 23.7%), thrombocytopenia (30.7% vs. 24.4%), pyrexia (24.7% vs. 22%), anemia (22.6% vs 28.9%), and fatigue (21.6% vs22.6%). Neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% in each arm) were the most commonly reported grade 3/4 AEs.

Rates of grade 1/2 bleeding were higher in the triplet versus the BR-alone arm, including hematoma (8% vs 1%), contusion (7.7% vs 3.1%), epistaxis (5.9% vs 3.1%), ecchymosis (3.1% vs 0.7%), and petechiae (2.8% vs 0.3%). Grade ≥3 hemorrhage occurred in 3.8% of patients receiving the triplet, compared with 1.7%for those receiving BR alone. Grade 3/4 major hemorrhage and atrial fibrillation rates were 2.1% versus 1.7% and 2.8% versus 0.7% in theibrutinib versus placebo arms, respectively. AEsled to treatment discontinuation in 14.2% and 11.8% of patients in the triplet and control arms, respectively.

The FDA initially approved ibrutinib in November 2013 for patients with mantle cell lymphoma following at least one prior therapy. In February 2014, the FDA approved ibrutinib for patients with previously treated CLL, which was then followed by a full FDA approval and a new indication for high-risk patients with 17p deletionsin July 2014. Ibrutinib was also granted an indication for Waldenström’s macroglobulinemia in January 2015.

“We knew ibrutinib was an effective single-agent treatment option with an established safety profile, and we now have additional evidence suggesting that ibrutinib improves outcomes when combined with existing treatment regimens,”noted HELIOS investigator Simon Rule, MD, consultant hematologist, Department of Hematology, and Head of the Lymphoma Service, Derriford Hospital in the United Kingdom. “Theresults from the HELIOS trial are very encouragingfor previously treated patients with CLL or SLL and suggest that the ibrutinib combination may be an option for these patients moving forward." 

Nurse Perspective

 
Phyllis McKiernan, MSN, APN, OCN Phyllis McKiernan, MSN, APN, OCN
Blood and Marrow Transplant Program
John Theurer Cancer Center
Hackensack, NJ
 
Targeted therapies combined with chemotherapy regimens continue to change the paradigm of cancer care by improving outcomes and survival. Ibrutinib targets Bruton tyrosine kinase (BTK) and blocks B-cell signaling that promotes cancer cell growth. Single agent ibrutinib in advanced CLL and mantle cell lymphoma has been an effective treatment option. These latest data from the HELIOS trial show that in CLL, the addition of ibrutinib to bendamustine and rituximab (BR) reduced the risk of progression compared to patients receiving BR with placebo. Overall response rates and complete responses were also increased in the ibrutinib-BR arm. The results were so compelling at the interim analysis that patients were then permitted to cross over to the ibrutinib-BR arm.

Improving therapeutic outcomes without adding toxicity for patients who have progressed or who fail to respond to standard therapy has always been challenging. In this trial, adverse events were similar in both arms, although bleeding events occurred more frequently in the ibrutinib-BR arm. Atrial fibrillation is a known side effect of ibrutinib and therefore was seen more in the triple-drug arm, although it remains an infrequent complication. Both arms had acceptable toxicity profiles, and the majority of patients were able to complete treatment.

Combination chemotherapy regimens are used to increase tumor cell kill, but the limiting factor has always been toxicity. By combining targeted therapies and chemotherapy, we have been able to improve outcomes for patients with advanced disease and keep toxicity manageable. Having options for patients with refractory CLL is important, but targeted therapies may be effective when used up front and may delay progression or mitigate the need for salvage therapy.

Ibrutinib has been shown to be safe and effective used as a single agent or in combination with chemotherapy in advanced CLL, and with further study, may become part of standard treatment. 

Skin Cancer

Vitamin B3 Form Preventive for Those With Prior Skin Cancer

Lauren M. Green

For those with a history of nonmelanoma skin cancer (NMSC), reducing their risk of recurrence can be as simple as taking the vitamin B3 pill nicotinamide, according to findings of a phase III trial reported at the ASCO Annual Meeting. Abstract 9000

The study found that the risk of new NMSC in study participants who took a 500-mg nicotinamide tablet twice daily was reduced by 23% compared with placebo.

“This is an affordable, chemoprevention strategy which can be instantly translated into clinical practice,” said senior study author Diona Damian, MBBS, PhD, and professor of dermatology at the University of Sydney in Australia.

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin cancers among fair-skinned populations. In the United States, an estimated 5 million people are treated for NMSC every year at a cost of $4.8 billion. The incidence is rising worldwide as the population ages, despite intensive campaigns stressing the importance of sun protection.

Building on previous phase II studies demonstrating that nicotinamide reduced precancerous actinic keratoses (AKs) in heavily sun-damaged Australian patients, the research team designed a phase III, double-blind, randomized controlled trial involving 383 patients who had at least two prior skin cancers in the past 5 years (mean = 8; range 2–52); approximately two-thirds of the participants were men, and the median age was 66 (range 30-91 years). Many of the patients had ongoing medical issues, such as heart disease, arthritis, high blood pressure, and chronic lung disease. “This was a ‘warts-and-all’ population, the sort of people that we treat every day in the clinic,” said Damian.

Participants were randomized 1:1 to receive twice-daily nicotinamide or placebo for 12 months; thorough skin checks were performed every 3 months by a dermatologist, and newskin cancers were confirmed on biopsy. The estimated relative rate reduction (RRR) in new NMSC was 0.23 (95% CI, 0.04 to 0.38; P = .02) in patients who received the vitamin; treatment effects were comparable for both BCC (RRR = 0.20; 95% CI, -0.06 to 0.39; P = .01) and SCC (RRR = 0.30; 95% CI, 0 to 0.51; P = .05).

“Interestingly, this reduction in skin cancers seemed to start at the first 3-month visit,” said Damian. “However, when people stopped taking the vitamin after 12 months, the benefit was no longer seen.”

Researchers also looked at the number of AKs, the study’s secondary endpoint, and nicotinamide also reduced these by approximately 15%, said Damian, even in a very sun-damaged group, who had an average 15 keratoses per person at baseline.

Damian stressed that it is only the B3 formulation nicotinamide that can be recommended and not niacin (nicotinic acid) formulations which can be more toxic (eg, headaches, flushing, low blood pressure).

“Nicotinamide was very well tolerated. There was no difference in adverse events or blood parameters in the two arms,” she continued. She said nicotinamide also does not pose problems with drug interactions, which is particularly beneficial for older patients who are often prescribed multiple medications. Damian said that based on these results, nicotinamide, “is ready to move straight into the clinic,” for those “who already have a skin cancer track record,” adding, however, “it is not something that we recommend at this stage for the general population.”

Nurse Perspective

 
Laura Newton, MA, RD Laura Newtonn Rutledge, MA, RD
Assistant Professor
Department of Nutrition Sciences
University of Alabama at Birmingham
Birmingham, AL
 
While we often think of cancer prevention and vitamin prevention in terms of vitamin’s antioxidant ability (specifically vitamins A, C, and E), this study found that high-dose consumption of a particular form of vitamin B3 significantly reduced nonmelanoma skin cancer.

There are a few important factors to point out regarding this study. It should be noted that this study was conducted only in those with a history of skin cancer; therefore the applicability to the general population is not known,but the potential of simply taking a dietary supplement to prevent skin cancer is intriguing. Also, the form of vitamin B3 used in the study was nicotinamide, a form of niacin.

The most commonly available niacin supplements are niacin, nicotinic acid, and inositol nicotinate. Niacin and nicotinic acid in particular may cause some unpleasant side effects, such as flushing, headache, and stomach upset when taken in high doses. Nicotinamide, used in this study, does not produce those effects but is also not as widely available on drugstore shelves.

Historically, large-scale studies utilizing dietary supplements as a means of cancer prevention have not yielded the same promising results as have studies examining dietary patterns of food intake and cancer risk. As dieticians, we always recommend people to obtain nutrients from food as opposed to supplements. However, the dose of nicotinamide used in this study was 500 mg twice daily, which is unrealistic to achieve with dietary sources. The Dietary Reference Intake (DRI) for niacin is 14 mg/day for women and 16 mg/day for men, so even a general multivitamin that meets the DRI would provide less than 20% of the amount used in this study.

Caution should always be encouraged to patients in relation to dietary supplements. While the FDA has established standards for dietary supplements in terms of purity, strength, and composition, they do not review or approve products before they are marketed. This opens the possibility of product contamination with other substances or even a variation in the amount of supplementcontained in the product itself. Some companies choose to have their supplements independently tested and certified by a nonprofit program such as NSF International or USP. These programs test supplements for content, purity, and freedom from contaminants.

Patients should be encouraged to look for these seals on products if they choose to utilize supplements. Another safety concern regarding supplements is the possibility of drug interactions. While some drug interactions have been identified, little research in this area has been conducted. Finally, it is always imperative to ask patients about any dietary or herbal supplement they take and to make sure the entire healthcare team is aware of supplements or other forms of complementary health approaches their patients practice.

Head and Neck Cancer

Pembrolizumab Shows "Remarkable Efficacy" in HNSCC

Lauren M. Green

In a multisite study offering the largest experience to date of how immunotherapy can be deployed in patients with head and neck cancer, the anti-PD-1 antibody pembrolizumab produced broad and durable responses in patients with advanced disease. Abstract LBA6008

Fifty-six percent of patients in the study experienced some tumor shrinkage with pembrolizumab, and 86% of patients continued torespond to treatment at data cutoff March 23, 2015. Overall, pembrolizumab produced an overall response rate (ORR) of 25%, and it proved active in both HPV-positive and HPV-negative patients.

“The efficacy was remarkable—pembrolizumab seems to be roughly twice as effective, whenmeasured by response, as our only targetedtherapy, cetuximab,” said Tanguy Seiwart, MD,an assistant professor of medicine and associate leader of the head and neck cancer program atthe University of Chicago, who presented theresults at the 2015 ASCO Annual Meeting.

Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) has a poorprognosis with a median overall survival of only 13 months in patients treated in thefirst-line setting and 6 months in previously treated patients—the majority of patients in thisstudy, which builds on earlier findings fromKEYNOTE-012 (NCT01848834). In that study,pembrolizumab administered at 10 mg/kg every2 weeks had a 20% response rate in patientswith advanced HNSCC whose tumors were PDL1– positive.

Findings of the study reported at ASCO are from an expansion cohort involving 132advanced HNSCC patients who were recruited regardless of their PD-L1 or HPV status. Importantly, said Seiwert, patients in this cohort received a fixed dose of pembrolizumab (200 mg/every 3 weeks), representing “a very convenient dosing schedule.” Patients were treated as long as they didn’t show progression of disease or as long as they demonstrated clinical improvement, Seiwert explained.

Of 117 evaluable patients, 29 patients (24.8%) responded to treatment with pembrolizumab. For patients with HPV-positive HNSCC, the ORR was 20.6%, and in the HPV-negative cohort, the ORR was 27.2%.

“In addition to the 25% response rate,” said Seiwert, “about 25% also had stable disease, so when we take these together, we have a disease control rate of about 50%, which is remarkable in this disease, especially in a heavily pretreated population.” For the 56% of patients whose tumors decreased in size, Seiwert said the responses often occurred early at 8 or 16 weeks, althoughthere were a few outliers with late responses.

“Importantly, those patients that did respond oftentimes continued to have responses—86% of patients had durable responses in this cohort,” he continued, adding that not only are respondersremaining on the therapy, but also many patients who have stable disease, with a total of40 patients staying on the drug.

“Overall, and in keeping with what we already know about pembrolizumab, this was a very well-tolerated agent,” said Seiwert, “certainly better tolerated than what we usually see inhead and neck cancer treated with aggressive chemotherapy and radiotherapy.”

Serious side effects were reported in fewer than 10% of patients. The most common side (9.1%), and decreased appetite and rash, each occurring in 7.6% patients. Four patients discontinued treatment due to immune-relatedAEs: two due to grade 2 interstitial lung diseaseand grade 3 colitis, respectively, and two patients for grade 3 pneumonitis. 

Nurse Perspective 

 
Nicole Spray Colleen M. O’Leary, RN, MSN, AOCNS
Associate Director Nursing Education
James Cancer Hospital and Solve Research Institute
Associate Director  Evidence-Based Practice
Ohio State University Wexner Medical Center
Columbus, OH
 
The findings regarding pembrolizumab and HNSCC certainly are opening up new hopes for patientswho previously had little chance of long-term survival. Understanding themechanism of action of pembrolizumab is the first step for nurses to be able to educate their patients effectively. Too often, nurses simply know that theyare administering anticancer therapies but cannot explain what it is they areadministering.

It is important for nurses to understand the mechanism of this new agent. As stated in the article, pembrolizumab is an anti-PD-1 antibody. What does this mean? T cells in our immune system have receptors to help them recognize certain antigen targets. When the T cell recognizes a tumor antigen on a tumor cell, the T cell becomes activated and eliminates it before it becomes cancer. When T cells become activated, they also need a signal to stop them so that there isn’t over activation. PD-1 is one such inhibitory receptor. Once activated, the T cell increases expression of PD-1 on the cell surface, which allows the T cell to receive a shutdown signal. What certaincancer cells have done are express agents that bind to PD-1 causing inactivation of T cells. Pembroluzimab is able to recognize and bind to PD-1 before the cancer cell agents have a chance to do this. And, this agent can do that without prematurely inactivating T cells.

As always, knowledge of toxicities and toxicity management is imperative for nurses. Not unlike the results in this study, in all clinical trials related to pembrolizumab, common toxicities (reported in ≥20% of patients) included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.1 Additionally, there were no grade 5 adverse reactions reported and of the ≥10% adverse reactions, none were reported as grade 4.1

Until now, there has been little confidence in providing long-term survival for these patients. With the advent of this agent that has shown to be twice as effective as cetuximab (the only other monoclonal antibody being used for HNSCC), greater hope for increased overall response rates is bounding forward. Nurses caring for patients with HNSCC should be alert to the changing treatment landscape for their patients and have confidence in the fact that we are moving ever closer to the goal.
___________________________________________________________________________
Reference
1. Keytruda (pembrlizumab) [package insert]. Whitehouse, NJ: Merck & Company, Inc; 2014.


Relieving Nausea With Olanzapine in Patients Treated for Head and Neck Cancer


Laura Martin

Nausea and vomiting associated with anticancer therapies continue to be among patients’ most troubling symptoms. Findings of a clinical trial reported at the 2015 ASCO Annual Meeting found that the medication olanzapine demonstrated comparative benefits in relieving these symptoms, especially for the relief of nausea overall and during the posttreatment phase 2-5 days after chemotherapy. Abstract 9502

The randomized, double-blind, phase III trial compared olanzapine with fosaprepitant in patients receiving concurrent highly emetogenic cisplatin-based chemotherapy (HEC) and local radiation therapy for advanced-stage head and neck and esophageal cancer.

One group enrolled 50 patients who received 10 mg of olanzapine, along with .025 mg of palonosetron, and 20 mg of dexamethasone on day 1, followed by 10 mg of olanzapine on days 2 to 4. In the second cohort, 49 patients received 150 mg of fosaprepitant plus .025 mg of palonosetron and 12 mg of dexamethasone on day 1 followed by 4 mg of dexamethasone on days 2 to 3.

Patients were evaluated during the acute period (24 hours postchemotherapy), the delayed period (2–5 days ostchemotherapy), and overall (0–120 hours postchemotherapy). The primary endpoint was complete response (CR). The secondary endpoint was a nausea score of zero on a scale of 0 to 10, with 10 equaling a high level of nausea and zero equaling no nausea.

CR was 88% in the olanzapine group and 84% in the fosaprepitant group in the acute timeframe, and 76% in the olanzapine group and 73% in the fosaprepitant group in both the delayed and complete timeframes.

For the secondary endpoint of nausea control, there was no significant difference between the olanzapine group and the fosaprepitant group in the acute phase, with 86% of patients in the olanzapine arm experiencing no nausea compared with 77% in the fosaprepitant arm.

However, there was a significant difference favoring olanzapine in the delayed and overall phases, with 71% of patients in the olanzapine arm experiencing no nausea compared with 41% in the fosaprepitant arm in both phases.This benefit was limited to nausea and did not include vomiting.

“In combination with palonosetron and dexamethasone, olanzapine was comparable to fosaprepitantin the control of emesis in patients receiving concurrent highly emetogenic chemotherapy-radiation treatment,” said lead author on the study, Rudolph M. Navari, MD, PhD, professor of Medicine, associate dean and director, Indiana University School of Medicine.

The drugs were both well tolerated, and there were no grade 3 or 4 toxicities in either arm. CR and control of nausea in subsequent chemotherapy cycles were equal to or greater than cycle one for both regimens.

Olanzapine is currently approved by the FDA as an antipsychotic and is not approved for the control of nausea.

“Our results are consistent with current NCCN guidelines, recommending olanzapineregimen as an option for chemotherapy-induced nausea vomiting prophylaxis for patients receiving HEC,” Navari said.


Preventive Neck Lymph Node Surgery Beneficial in Early Oral Cancer


Lauren M. Green

Elective neck dissection performed at the same time patients have surgery for early-stage, node-negative, oral squamous cell cancer significantly improved overall survival and reduced the risk of death and recurrence when compared with a watchful waiting approach according to findings of a phase III randomized trial.Abstract LBA3

These findings should be practice changing, said lead study author Anil D’Cruz, MBBS, MS, FRCS, who presented them at the 2015 ASCO Annual Meeting.

“Our study is the first to conclusively prove that more lives can be saved with elective neck dissection,” said Cruz, adding that the results resolve a question doctors have been asking for more than 5 decades.

That debate has centered on whether it is best to remove surrounding lymph nodes when theprimary oral cancer surgery is performed or to wait to perform therapeutic neck dissection when the patient relapses. Clinical practice in this setting varies widely.

D’Cruz is a professor and chief of the Department of Head and Neck Surgery at Tata Memorial Centre in Mumbai where the trial was carried out between 2004 and 2014. The trial recruited 596 patients with stage I/II oral squamous cell carcinoma (SCC) and no lymph node involvement.

The findings reported at ASCO are drawn from an interim analysis involving 500 patients who after excision of their primary tumor were randomly assigned to therapeutic neck dissection (TND; n = 255), also known as “watch and wait,” or elective neck dissection (END; n = 245).

Both trial arms were balanced based on tumor site and stage: 427 of the cases involved the tongue, 68 were buccal mucosa, and 5 were tumors at the floor of the mouth; 221 patients hadstage I tumors, and 279 were stage II. Overall survival (OS) was the study’s primary endpoint.

After a median follow-up of 39 months, 146 recurrences were reported in the TND arm versus 81 in patients who had END. Three-year OS also was significantly better in the END cohort compared with the TND group: 80.0% vs 67.5%, respectively.

The study’s secondary endpoint, disease-free survival (DFS), also favored the END arm of the trial, with the procedure reducing the risk of recurrence by 55%. Three-year DFS was 69.5% in the END cohort versus 45.9% in patients assigned to TND.

Overall, D’Cruz reported that performing ENDin patients with early oral SCC reduced mortality by 36%, preventing 1 death in every 8 patients and 1 recurrence in every 4 patients who undergo the procedure.

Study authors acknowledged in an ASCO statement that the only drawback to neck dissection is that the procedure can be linked to shoulder problems, which affect 5% to 40% of patients because the nerve that supplies the large muscles associated with shoulder movement crosses the surgical dissection field. Future research should focus on techniques that could minimize this complication, they said.

Lung Cancer

Nivolumab Immunotherapy Found Superior to Docetaxel in a Range of Lung Cancers

Jason M. Broderick
 
The immunotherapy nivolumab (Opdivo) improved overall survival and was less toxic than docetaxel in both nonsquamous and squamous non–small cell lung cancer (NSCLC), according to findings from the phase III CheckMate-057 trial reported at at the 2015 ASCO Annual Meeting. Abstract LBA109

“Nivolumab is the first PD-1 inhibitor to significantly improve overall survival as compared to docetaxel in [NSCLC] patients with prior treatment and nonsquamous histology,” said the study’s lead author, Luis Paz-Ares, MD, of the Hospital Universitario Doce de Octubre in Madrid, Spain.

The PD-L1 inhibitor is approved by the FDA for squamous NSCLC, and the results reported here showing nivolumab’s efficacy and safety in nonsquamous NSCLC are notable in part because NSCLC accounts for 85% of all lung cancers, and more than two-thirds of the cases are nonsquamous, ASCO noted in a statement accompanying release of the findings.

“Even five years ago, an effective immunotherapy for lung cancer was largely considered impossible,” noted ASCO expert Gregory A. Masters, MD, FACP, FASCO. “Today, we have such a treatment, and it surpasses the standard treatment in terms of efficacy and patient quality of life.”

The open-label CheckMate-057 trial randomized 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy to nivolumab at 3 mg/kg IV every 2 weeks (n = 292) or docetaxel at 75 mg/m2 intravenously every 3 weeks (n = 290). The treatments were administered until disease progression or unacceptable toxicity. Patients received a median of six and four doses in the nivolumab and docetaxel arms, respectively.

Patients had an ECOG performance status of 0 or 1. The median patient age was 61 years in the nivolumab arm and 64 years in the docetaxel cohort. Prior maintenance with bevacizumab, pemetrexed, or erlotinib was allowed, as was TKI therapy for known EGFR mutations or ALK translocation.

Overall survival (OS) was the primary endpoint, with secondary objectives focused on progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1, efficacy by PD-L1 expression, and safety.

The study was stopped early after an independent monitoring panel determined the primary endpoint of improved OS had been reached. Eligible patients were allowed to continue treatment or cross over to the nivolumab arm in an open-label extension of the study.

The median OS was 12.2 months with nivolumab versus 9.4 months with docetaxel, with a 1-year OS of 50.5% versus 39.0%, respectively.

Agent Well Tolerated Nivolumab was well tolerated and had a better safety profile than docetaxel. Among patients evaluable for safety, all-grade adverse event (AE) rates were 69% versus 88% in the nivolumab and docetaxel arms, respectively. The most common all-grade AEs with nivolumab versus docetaxel were fatigue (16% vs 29%), nausea (12% vs 26%),decreased appetite (11% vs 16%), asthenia (10% vs 18%), and diarrhea (8% vs 23%).

Grade 3–5 adverse events were reported in 10.5% of the nivolumab arm compared with 53.7% of the docetaxel cohort. The most common grade 3/4 AEs with nivolumab were fatigue, nausea, and diarrhea, at 1% each. Twenty-seven percent of patients in the docetaxel arm had grade 3/4 neutropenia versus 0 in the nivolumab arm.

Toxicity-related discontinuations occurred in 4.9% of patients receiving nivolumab comparedwith 14.9% of those treated with chemotherapy.

Positive Results on Secondary Endpoints ORR was 19% with the PD-1 inhibitor compared with 12% with chemotherapy. Complete and partial response rates were 1% and 18% in the nivolumab arm and <1% and 12% in thedocetaxel group, respectively. The stable disease rate was 25% and 42% with PD-1 inhibition and chemotherapy, respectively.

Median time to response was 2.1 months with nivolumab versus 2.6 months with docetaxel. Median duration of response was 17.2 months versus 5.6 months in the nivolumab and control arms, respectively. Fifty-two percent of the nivolumab responses are still ongoing compared with 14% of the docetaxel responses. Median PFS was comparable between the cohorts at 2.3 months in the nivolumab arm compared with 4.2 months in the docetaxel group. One-year PFS favored nivolumab at 18.5% versus 8.1% for the control arm.

Higher PD-L1 expression was associated with improved survival outcomes among the 78% of patients for whom PD-L1 status was detectable. “PD-L1 emerged as a clear predictive factor for the benefit from nivolumab treatment,” said Paz-Ares.
 

Nurse Perspective

Betsy Hullender Quinn, MSN, MA, RN, OCN Betsy Hullender Quinn, MSN, MA, RN, OCN
Thoracic Oncology Program Coordinator
Thoracic Oncology Nurse Navigator
Memorial Health Care System
Chattanooga, TN

 

What once seemed unachievable for lung cancer is being achieved. For those patients who are appropriate for nivolumab (previously treated squamous non–small cell lung cancer who have progressive disease on platinum-based doublet chemotherapy), a greater quantity and quality of life is possible.

In my practice as a thoracic oncology nurse navigator, several patients have survived considerably longer than expected with fewer side effects experienced from treatment. Quite a feat considering previous life expectancy is abysmal for those patients with advanced or metastatic disease.

Focusing cancer treatment using the body’s own immune system to combat cancer is only getting started. Multiple studies are in progress using immunotherapy to treat other forms of lung cancer. Statistically, lung cancer has some of the worse survival rates. Are we on the cusp of treatment that
extends life without the burdensome side effects of traditional treatment? I very much hope so!


Prostate Cancer

First Effective Adjuvant Treatment Identified in High-Risk Prostate Cancer

Tony Berberabe, MPH
 
Treatment with an adjuvant combination of docetaxel, androgen deprivation therapy (ADT), and radiation therapy (RT) improved 4-year overall survival (OS) rates in patients with high-risk localized prostate cancer when compared with ADT plus RT alone. Results from the phase IIItrial represent the first to show a benefit for adjuvant therapy in prostate cancer. Abstract LBA5002

The study found that 4-year OS rates were 89% for men who received ADT and RT versus 93% for men treated with ADT, RT, and docetaxel.

“For the first time, improvement in overall survival was observed in men with localized, high-risk, hormone-sensitive prostate cancer who received tolerable adjuvant chemotherapy,” said Howard M. Sandler, MD, MS, chair of radiation oncology at Cedars-Sinai Medical Center, who presented the results at the 2015 ASCO Annual Meeting. “The potential role [of this regimen] is consistent with and supported by our data and other studies such as STAMPEDE and CHAARTED.”

STAMPEDE, which is the largest randomized prostate cancer trial ever conducted, was also presented at the 2015 ASCO meeting. In this study, researchers reported that adding docetaxel to standard hormonal therapy significantly improved survival among men with newly diagnosed hormone-naïve advanced prostate cancer. In the phase III CHAARTED trial, which was presented at the 2014 ASCO Meeting, it was shown that docetaxel in combination with standard hormone therapy extended OS by nearly 14 months.

In the adjuvant study reported at ASCO 2015, 612 men were enrolled in Radiation Therapy Oncology Group (RTOG) 0521 from December 2005 through August 2009. The trial was designed to detect improvement in 4-year OS rates from 86% to 93% with a 51% hazard reduction (HR = 0.49). The primary endpoint was OS.

Patients were eligible for the trial if they had a Gleason score 7-8, any T-stage, and prostate-specific antigen (PSA) >20; Gleason score 8, T2, and any PSA, or Gleason score 9-10, any T-stage, any PSA.

“These patients were the highest of the high risk,” explained Sandler. Locally advanced or high-risk localized prostate cancer has a relatively poor prognosis. Standard treatment involves radiotherapy and long-term hormonal treatment, he added.

All patients received ADT for 24 months and RT for 8 weeks at 75.6 Gy. Patients in the chemotherapy arm received six cycles of docetaxel plus prednisone in 21-day increments, starting 28 days after receiving RT.

After undergoing eligibility review and exclusion, 562 men were determined to be evaluable. The men had a median age of 66 years, median PSA of 15.1; 53% had Gleason score 9–10, and 27% had prostate cancer staged at cT3–4. All patients had PSA levels ≤150, and average follow-up was 5.5 years.

At a median 5.5-year follow-up, 5-year disease-free survival rates were 66% in the standard therapy group versus 73% in the docetaxel group. There was also a reduction in the incidence of distant metastasis and other secondary endpoints with the addition of docetaxel, a significant clinical finding, Sandler noted.

There were 52 centrally reviewed deaths in the ADT/RT arm versus 36 in the chemotherapy group. There were fewer deaths due to prostate cancer or treatment (16 vs 20) or due to other causes or unknown (20 vs 32) with chemotherapy versus without, respectively.

“Whether or not adding chemotherapy becomes a standard of care for this population remains to be seen,” said Sandler. “For the right patient and for the right physician, there might be justification for considering it. This analysis that looked at a 4-year endpoint is relatively early, and additional follow-up will likely be further enlightening.”

The toxicity with the addition of docetaxel was labeled “acceptable” by the study authors. There was one death that was unlikely related to treatment in the ADT plus RT arm and two deaths that were possibly related to treatment in the chemotherapy arm.
 

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
 
Facing high-risk localized prostate cancer often poses a difficult situation where patients, families, and providers feel like they are stuck in a sort of middle ground.

“Curative” therapies such as surgery and radiation are options given to those dealing with low- to intermediate-risk prostate cancer, and the prognosis is favorable for most at this lower level. Active surveillance is on the table for men with very low to low risk as well.

On the other hand, for high-risk prostate cancers that are not localized, or advanced prostate cancers, the focus turns to control versus cure. The goal at this upper level is avoidance of undue symptoms, then palliation as needed.

The frustration of high-risk localized prostate cancers lies within the variety of relatively aggressive treatments with known poor prognosis and marginal outcomes. Most men met with a new diagnosis at this middle level quickly learn about the pros and cons of surgery and various combinations of radiation and hormone therapy. Discussions with physicians and nurses here focus less upon cure, and not yet quite addressing palliation, with the main objective of delaying the need for the next salvage treatment option

. Sandler’s study gives us some encouraging, but early, data that may help men with another adjuvant treatment that can help them deal better with thismiddle ground. In contrast to salvage treatments, adjuvant therapy aims tooptimize the treatment at hand. Docetaxel is already a well-proven chemotherapeutic agent with a manageable side effect profile. The performance status of most men with high-risk localized prostate cancer is usually wellwithin parameters so that they could tolerate the addition of docetaxel to their treatment plan.

As nurses, our knowledge and counseling database of information on docetaxel (and other agents with proposed novel uses) administered with other disease types, can best prepare us to be advocates for patients deciding to undergo new, emerging therapies as clinical trials like this one continue in prostate cancer care.

Survivorship Care

Survivors of Childhood Cancers Living Longer Due to Improvements in Care and Follow-Up

Beth Fand Incollingo

Over the past 30 years, survivors of childhoodcancers have become less likely todie of illnesses caused by their treatment, such as new malignancies or cardiac orlung disease. The improvement is credited, in part, to better cancer treatment and follow-up, including the reduced use of radiotherapy and anthracyclines. Abstract LBA2

These findings come from an analysis of more than 34,000 participants in the federally funded Childhood Cancer Survivor Study (CCSS), which found that among those who have survived at least 5 years, all-cause mortality at 15 years after diagnosis dropped from 12.4% to 6%. The results were reported during the ASCO 2015 Annual Meeting.

“To go back to the 1960s, less than 30% to 40% of children would survive cancer; currently over 83% of children (with the disease) will become 5-year survivors. It’s estimated that, at 2013, there were over 400,000 survivors in the population, and that by 2020 there will be over half a million,” said lead study author Gregory T.Armstrong, MD, MSCE, a pediatric oncologist at St. Jude Children’s Research Hospital.

“However, these 5-year survivors are still at risk for late effects and late mortality. Thus, strategies to reduce late effects by reducing treatment intensity have been used for severaldecades in an attempt to lower mortality rates and improve quality of life."

According to previous research, up to 18% of 5-year survivors of childhood cancer died within 30 years of diagnosis, Armstrong noted during his presentation. Such deaths are attributable to progression or recurrence of the primary cancer, external causes such as accidents or suicide, or other health-related causes—primarily, the late effects of cancer therapy, ASCO explained in a statement.

Investigators used the National Death Index, a record of death information kept by state vital statistics offices, to determine which patients in the cohort had died and when. All participating patients were diagnosed between 1970 and 1999, were younger than 21 years of age at diagnosis, and were followed for a median 21 years. Their cancers included leukemia, lymphoma, malignancies of the central nervous system, Wilms tumor, neuroblastoma, and soft-tissue or bone sarcoma, Armstrong said.

The study found that 3958 patients (12%) died during their follow-up period, with 1618 (41%) of those deaths due to other health-related causes, including the late effects of cancer therapy—in particular, secondary or recurrent cancers.

All-cause mortality dropped by half over the study period—12.4% of patients diagnosed in the early 1970s died within 15 years of diagnosis, compared with only 6% of those diagnosed in the early 1990s. In those who survived at least 5 years, the cumulative incidence of deaths due to other health-related causes—including late effects such as second cancers or heart or lung disease—dropped with each decade. For those diagnosed in the 1970s, the cumulative incidence of deaths from other health-related causes was 3.1%; for those diagnosed in the 1980s, it was 2.4%, and for those diagnosed in the 1990s, it was 1.9%, Armstrong said.

Deaths from subsequent neoplasms in 5-year survivors of childhood cancers dropped in frequency from 1.8% in the early 1970s to 1% in the early 1990s; deaths from cardiac late effects fell from 0.5% to 0.1% in those same time periods, respectively, and deaths from pulmonary late effects from 0.4% to 0.1%, he pointed out.

The improvement was most prevalent among survivors of Wilms tumor, Hodgkin lymphoma, and acute lymphoblastic leukemia (ALL). Cardiac deaths significantly decreased among survivors of all three cancers, although deaths due to secondary cancer decreased among Wilms tumor survivors only. In ALL, deaths at 15 years after diagnosis due to late effects were reduced from 2.8% in the 1970s to 1.9% in the 1990s; in Hodgkin lymphoma, they dropped from 4.2% to 2.1% in those time periods, respectively, and in Wilms tumor, they dropped from 2.2% to 0.4% in those periods, Armstrong said.

Doctors have helped to drive these results by gradually refining treatment through reductions in the intensity of therapy for many pediatric cancers, even as the effectiveness of treatment has risen, Armstrong said. For example, in the 1970s, 86% of patients with ALL received cranial radiotherapy, compared with only 22% in the 1990s. Radiotherapy rates have also been reduced among patients with Hodgkin lymphoma(from 96% to 77%) and Wilms tumor (from 77% to 49%). Furthermore, Armstrong said, patients who develop these three diseases in childhood are now being exposed to less anthracycline.

“The CCSS cohort provides evidence that survivors in more recent eras have a significant reduction in late mortality. For the first time,we’ve been able to attribute that to fewer deathsfrom treatment-related causes or from late effects of the primary therapy, and this includes lower death rates due to subsequent malignantneoplasms and cardiac mortality,” he continued.

“Thus, the strategy of reducing the intensityof therapy to lower the occurrence of late effects, along with promotion of early detection and improved treatment of late effects, is now translatedto extend the lifespan of our survivors.”

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