Clinical Insights: July/August 2014

Friday, August 22, 2014

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 hour. 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 www.dannemiller.com/onn-jul-aug-2014
  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

Survival and Fertility Benefit When Goserelin Augments Breast Cancer Chemotherapy

Adding goserelin to chemotherapy for women with early-stage hormone receptor (HR)-negative breast cancer helps both to preserve their fertility and to prolong their survival, according to findings of a new study presented at the 2014 ASCO Annual Meeting. Abstract LBA505

The federally funded phase III S0230/POEMS clinical trial demonstrated that women who received the hormone suppressor goserelin along with their chemotherapy were significantly less likely to develop premature ovarian failure and were more likely to have successful pregnancies than women who received chemotherapy alone.

Also in the goserelin arm, women were more likely to be alive 4 years after starting treatment than those in the standard-therapy arm.

“Preserving fertility is a common and important concern among younger women diagnosed with cancer, and these findings offer a simple, new option for women with breast cancer, or possibly other cancers,” said lead study author Halle Moore, MD, a staff physician at the Cleveland Clinic. “Goserelin appears to be not only highly safe but also effective, as it increased the odds of becoming pregnant and delivering a healthy baby following chemotherapy.”

Ovarian failure is a common and potentially devastating side effect of chemotherapy for breast cancer, Moore said. A woman’s risk of ovarian failure depends on the type and dose of her chemotherapy, as well as her age and perhaps ovarian cycling at the time of chemotherapy, she said.

Goserelin and similar luteinizing hormone-releasing hormone (LHRH) analogs temporarily shut down ovarian function, essentially putting the patient into a postmenopausal state, Moore explained; it is speculated that this protects follicles from chemotherapy damage. These medications are widely used to control ovulation timing for infertility procedures, such as in vitro fertilization, and to treat advanced prostate and breast cancer. Prior studies of this approach to preventing ovarian failure have been conducted, Moore said, but with inconclusive results and few data available on pregnancy outcomes.

In this study, 257 premenopausal women aged 18 to 49 years who had stage I-IIIA estrogen- and progesterone-negative breast cancer were randomized to curative- intended treatment with either cyclophosphamide-containing chemotherapy alone (standard arm) or cyclophosphamide-containing chemotherapy plus goserelin. Goserelin was given as a monthly injection starting 1 week before the first dose of chemotherapy. Of the total study population, 218 women were evaluable, and complete primary endpoint data were available for 62% of them, the authors wrote in their abstract.

The study’s primary endpoint was the rate of ovarian failure 2 years after the start of treatment, with ovarian failure defined as no menstrual periods for the prior 6 months and postmenopausal levels of follicle-stimulating hormone (FSH).

Investigators found that 8% of women in the goserelin arm versus 22% of women in the standard arm experienced ovarian failure under those criteria.

“In the stratified analysis, this represented a 70% reduction in ovarian failure with a P value of .04,” Moore said. “Using a less stringent ovarian failure definition of either postmenopausal FHS or absent menstrual periods for the prior 6 months, 45% of patients in the standard arm versus 20% in the goserelin arm experienced ovarian failure.

Similarly, the rate of ovarian dysfunction at 2 years, defined as no menstrual periods for the prior 3 months and either FSH, estradiol, or inhibin B levels in the postmenopausal range, was reduced by close to two-thirds, with 14% of patients in the goserelin arm experiencing ovarian dysfunction compared with 33% in the control arm.”

There was no statistically significant difference in the number of women who reported attempting to conceive in the two arms, the authors wrote. In the control group, Moore said, 11% of patients (12 women) became pregnant; 7% of them (8 women) delivered 12 babies, while another 2 had yet to deliver at the time of data submission. In the goserelin group, 21% of patients (22 individuals) became pregnant, and 15% of them (16 women) delivered 18 babies while 3 remained pregnant at the time of data submission. Some women had more than one pregnancy during the study, and all the pregnancies that were documented occurred after the completion of cancer treatment, Moore said.

The study found that goserelin was not associated with an increased risk of either miscarriage or pregnancy termination, ASCO noted.

Importantly, the researchers also found that goserelin improved disease-free and overall survival. They had considered those endpoints to determine whether goserelin would jeopardize the effectiveness of chemotherapy, and were surprised by the results, Moore said. At 4 years, disease-free survival was 78% in the control group and 89% in the group that took both chemotherapy and goserelin. Fouryear overall survival was 82% in the control group and 92% in the chemotherapy-plus-goserelin group.

“The use of goserelin during curative-intent chemotherapy for early-stage breast cancer led to better preservation of ovarian function than if goserelin had not been given,” Moore said. “This is the first demonstration of improved fertility and more successful pregnancies when goserelin was used. These favorable outcomes are very reassuring regarding the safety of this approach. Premenopausal women beginning therapy for early breast cancer should consider this option for prevention of premature ovarian failure.”

Nurse Perspective

 
Emily Beard, RN, OCN, CBCN Emily Beard, RN, OCN, CBCN
Multidisciplinary Care Coordinator
Oncology Support Services
Northside Hospital Cancer Institute
Atlanta, GA
 

Potential loss of fertility is but one in a cascade of devastating realities facing young breast cancer patients, so this study—even with its limitations and unanswered questions—brings hope and promise to the conversation about fertility preservation options in the face of breast cancer.

I will never forget one such conversation with a young patient, diagnosed with early breast cancer in her mid-30s, who had started a chemotherapy regimen without fully realizing the risks it posed to her ovarian function. “The only thing I have ever wanted is to have children,” she tearfully confided in me after being told the regimen she had been prescribed had rendered her menopausal. She was grateful to be alive, but sad: “I’ve lost my quality of life because now I can’t get pregnant and have a baby.”

Too often the rush to prescribe life-saving treatments overshadows the important discussion about impact of treatment on fertility and options. With young survivor advocacy groups like “Stupid Cancer” and the research-focused Oncofertility Consortium of Northwestern University bringing greater awareness to the issue, and initiatives like the Quality Oncology Practice Initiative (QOPI) cueing oncologists to assess and document a patient’s fertility preferences prior to initiation of treatment, the tide does seem to be turning.

However, for patients facing fertility loss, there are few interventions, and many that do exist require expensive and time-consuming procedures. To date many women wishing to preserve fertility have had to prioritize and accept that the choice to do so may delay initiation of chemotherapy, and therefore decrease survival. There has long been controversy and concern that drugs aimed at protecting ovarian function might actually interfere with the efficacy of chemotherapy, but this study suggests that goserelin does not reduce the effectiveness of cytotoxic treatment, and it might even improve it!

Although the POEMS study leaves many important questions unanswered and has multiple caveats—the low overall accrual and lack of endpoint data in a large cohort of participants is significant—the results are compelling enough to suggest that goserelin (and perhaps other luteinizing hormone-releasing hormone [LHRH] analogs) does improve fertility outcomes and survival rates in women with hormone receptor-negative breast cancers.

So the time is right for more research, especially related to what role, if any, there is for LHRH analogs in treatment regimens for other types of cancer, including perhaps hormone receptor–positive cancers. As nurses we must be advocates for our patients, encouraging participation in clinical research like this so that important quality of life issues continue to be addressed.

 

Dosing Zoledronic Acid Less Often Doesn’t Reduce Efficacy

Phase III trial results presented at the 2014 ASCO Annual Meeting showed that the dosing frequency of zoledronic acid can be reduced by 67% without compromising effectiveness in women with breast cancer and bone metastases, potentially lowering the risk of serious adverse events. Abstract LBA9500.

“[Less frequent dosing] means [patients] have more time to spend with their family and friends doing things that they care about rather than visiting the doctor’s office; it means less toxicity . . . and less cost. So I think that this is really part of the value equation,” said ASCO panel moderator Patricia Ganz, MD, director of Cancer Prevention and Control Research at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

Zoledronic acid, a third-generation bisphosphonate, is used to reduce complications from bone metastases in women with breast cancer. Standard administration is 4 mg every 3 to 4 weeks for the first year following diagnoses of metastases. However, an optimal treatment regimen following the induction period has yet to be established, and there are safety concerns (eg, osteonecrosis of the jaw [ONJ], chronic kidney function impairment) with long-term bisphosphonate use.

The double-blind, multicenter, phase III OPTIMIZE- 2 trial included 403 women (median age, 59 years) with bone metastases from breast cancer who were previously treated with IV bisphosphonates monthly for 10 to 15 months. Patients had received at least nine doses of either zoledronic acid or pamidronate.

At a 1:1 randomization, patients continued bisphosphonate therapy with 4 mg of IV zoledronic acid either monthly (n = 200) or every 3 months (n = 203) for 1 year. To maintain the blind, patients receiving treatment every 12 weeks were given a placebo between doses. Patient characteristics at baseline were similar between the treatment arms. The study initially included a placebo-only arm that was terminated due to poor accrual.

The results established that after a median follow- up of 11.9 months, administering zoledronic every 12 weeks was noninferior to a monthly regimen. There was a 1.2% difference in skeletalrelated event (SRE) rates between the arms, with SREs occurring in 22% (n = 44) of patients in the monthly arm and in 23.2% (n = 47) in the every 3–month arm (95% CI, 7.5%-9.8%; P = .724).

Secondary endpoints were comparable between the two treatment arms, as well. The mean skeletal morbidity rate was 0.46 and 0.50 (P = .854) in the higher- and lower-frequency arms, respectively. The times to first SRE (HR = 1.06; 95% CI, 0.70-1.60; P = .792) and changes from baseline in bone turnover markers were also similar.

The toxicity profiles were also comparable between the two dosing schedules, with a similar incidence of adverse events (AEs). Grade 3/4 AEs were reported in 47.5% (n = 94) and 42.6% (n = 86) of patients in the monthly and every 3– month arms, respectively. Pain levels and use of pain medications also did not vary between the two arms.

The reduced-frequency arm did have a lower incidence of some of the more serious side effects associated with zoledronic acid. There were two cases (1%) of ONJ in patients receiving monthly treatment, compared with no cases in patients receiving therapy every 3 months. Increased renal toxicities also occurred with the higher-frequency regimen, at 9.6% (n = 19) versus 7.9% (n = 16).

Commenting on the nonsignificance of the efficacy results, lead author Gabriel N. Hortobagyi, MD, professor of Medicine at the MD Anderson Cancer Center, said, “Due to design limitations and statistical concerns, the noninferiority claim should be interpreted with caution.”

 

Colorectal Cancer

Survival Comparable With Bevacizumab, Cetuximab in mCRC

Frontline therapy with bevacizumab or cetuximab combined with either FOLFOX or FOLFIRI yielded a comparable survival benefit of approximately 29 months in patients with KRAS wild-type metastatic colorectal cancer (mCRC), according to results from the phase III CALGB/SWOG 80405 trial. Abstract LBA3

“Either bevacizumab or cetuximab with either FOLFIRI or FOLFOX are perfectly reasonable options for first-line therapy in this population of patients,” lead author Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California in San Francisco, said in announcing the findings at the 2014 ASCO Meeting.

Historically, the combination of bevacizumab and FOLFOX has been widely used in treating patients with mCRC in the United States, whereas European physicians more frequently prescribe cetuximab-based regimens.

At last year’s ASCO annual meeting, results from the phase III FIRE-3 study showed a survival benefit with cetuximab over bevacizumab in KRAS wild-type patients but did not demonstrate an improvement in progression-free survival or overall response. It has been hypothesized that downstream treatments may have impacted the trial outcome.

In the final 80405 trial design, 1137 patients with treatment-naïve KRAS wild-type (codons 12 and 13) mCRC (performance status 0-1) were randomized in a 1:1 ratio to cetuximab (n = 578) or bevacizumab (n = 559) plus physician’s choice of FOLFOX or FOLFIRI. Cetuximab was administered at an induction dose of 400 mg/m2 followed by 250 mg/m2 weekly, and patients received bevacizumab at 5 mg/kg every 2 weeks. Among all patients, 26.6% were treated with FOLFIRI, and 73.4% received FOLFOX. Treatment was continued until curative surgery, disease progression, or unacceptable toxicity.

Median patient age in the study was 59 years and 61% of patients were male. Overall survival (OS) was the primary endpoint.

At a median follow-up of 24 months, OS was 29 months (95% CI, 25.7-31.2) in the bevacizumab arm and 29.9 months (95% CI 27.0-32.9) in the cetuximab arm.

“The overall survival exceeding 29 months in both arms really establishes a new benchmark for the treatment of patients with colorectal cancer,” Venook said.

With the secondary endpoint of progressionfree survival, disease progression was delayed by a median of 10.8 months (95% CI, 9.7-11.4) in patients receiving bevacizumab compared with 10.4 months (95% CI, 9.6-11.3) in the cetuximab group.

The treatment side effects in the trial were comparable to those reported with these agents in previous clinical research. Common toxicities associated with bevacizumab include high blood pressure, headache, mouth sores, nosebleed, diarrhea, bleeding from the rectum, loss of appetite, fatigue, and weakness. With cetuximab therapy, the most frequently reported side effects include acne-like rash, itching, changes in fingernails and toenails, infections, fatigue, and low blood electrolyte levels.

The toxicities associated with FOLFOX and FOLFIRI also vary. FOLFOX can cause neuropathy which results in treatment discontinuation, whereas FOLFIRI is associated with higher rates of alopecia and diarrhea.

With the comparable efficacy established in the 80405 study, and the similar costs of cetuximab and bevacizumab therapy, Venook said, “[The choice of] first-line therapy should reflect the patient’s preference or concern for potential side effects.”

Another targeted therapy, panitumumab, was recently approved in combination with chemotherapy as a frontline treatment for patients with KRAS wild-type mCRC. One of the studies on which the FDA based its approval was the phase III ASPECCT trial, in which single-agent panitumumab was shown to be noninferior to cetuximab in patients with previously treated KRAS wildtype mCRC.

Venook said it is likely that the 80405 results could be extrapolated to panitumumab, and that the three targeted agents are all valid frontline options in treating KRAS wild-type mCRC. “This is an evolving field, but I would assume [these results] apply to panitumumab, as well.”

Nurse Perspective

 
Laura Metcalfe Laura Metcalfe, MSN, RN, APN,C, AOCNS
John Theurer Cancer Center
Hackensack, NJ
 

The results from CALGB/SWOG 80405 served to confirm what oncology clinicians have known for a few years now. I have attended several conferences where it has even been described as “dealer’s choice,” when it comes to deciding on the best sequencing of these regimens. As stated in the article, FOLFOX/bevacizumab is the most common frontline therapy in the United States, while in Europe cetuximab-based regimens are more common.

In our practice, FOLFOX/bevacizumab is our frontline therapy unless there is some contraindication. For example, if a patient already has neuropathy, be it from diabetes or some other cause, we would likely not want to use oxaliplatin. Also, if the patient uses his/her hands in their profession, eg, a surgeon or a musician, we also might choose to avoid oxaliplatin. Coronary artery disease might preclude the use of bevacizumab.

In the absence of any contraindication, FOLFOX and bevacizumab has a much better side effect profile and remains our preferred regimen. No hair loss and no skin rash and minimal nausea and diarrhea make it a very well tolerated regimen. We try to reserve the cetuximab/irinotecan or panitumumab/irinotecan regimens for later progressions. Many of our FOLFOX/bevacizumab patients are working and are able to continue working while receiving treatment. In general, they look and feel well. The hair loss and skin rash associated with cetuximab/ irinotecan or panitumumab/irinotecan regimens leave patients with altered body image and often reluctance to see people who now can see that they are “sick.” Also, the irinotecan-induced diarrhea often makes leaving the house difficult due to concerns of “not making it” to the bathroom on time.

Obviously, when treating mCRC extending the patient’s life while maintaining as much quality of life as possible is our primary endpoint. Given that both of the regimens show comparable survival rates, FOLFOX/bevacizumab remains our first-line regimen of choice assuming no contraindications.

 

Hematologic Malignancies

Novel Rituximab Combinations Highly Effective in CLL

The novel agents idelalisib and ABT-199 in combination with rituximab have demonstrated impressive activity with manageable toxicity for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to two separate studies presented in a poster highlight session at the 2014 ASCO Annual Meeting.

Idelalisib Efficacy Established in Phase III

At the second interim analysis of the phase III Study 116 trial, the combination of the PI3K-delta inhibitor idelalisib and rituximab demonstrated an improvement in progression-free survival (PFS) of 82% and a 72% elevation in overall survival (OS). Abstract 7012

“[Study 116] clearly demonstrates that adding idelalisib to rituximab is superior. Patients have a longer duration of response and they live longer— a dramatic benefit from that standpoint,” said study author Steven E. Coutre, MD, a professor of medicine (hematology) at the Stanford University Medical Center. “If you’re a practicing oncologist and you think about the patients that you’ve treated with rituximab in this setting, then adding idelalisib to that would make sense based on these results.”

In the phase III study, 220 patients with a median age of 71 years were randomized in a 1:1 ratio to receive rituximab plus idelalisib (n = 110) or rituximab and placebo (n = 110).

Patients in the study had received three prior therapies, including prior treatment with rituximab.

Based on findings from the first analysis, the trial was halted and crossover was allowed following a positive risk–benefit review. At the second analysis of the study, the median PFS for idelalisib plus rituximab had not been reached, compared with 5.5 months with placebo plus rituximab. At 24 weeks, 90% of patients treated with idelalisib remained progression-free compared with 50% with placebo.

The ORR with idelalisib was 77% versus 15% with placebo. Of evaluable patients, 92% treated with idelalisib experienced a greater than 50% reduction in lymph node size compared with 6% with placebo.

Adverse events of any grade occurred in 95% of patients in both arms of the trial. The incidence of grade 3/4 adverse events was 64% with idelalisib versus 52% with placebo. The discontinuation rate associated with adverse events was 5% in the idelalisib arm and 6% in the placebo group.

The FDA has approved idelalisib in combination with rituximab for patients with high-risk relapsed or refractory CLL and as a single agent for two types of indolent non-Hodgkin lymphoma (iNHL).

ABT-199 Shows Early Promise

ABT-199 demonstrated promising efficacy in patients who received the drug in combination with rituximab in a phase Ib study, demonstrating an overall response rate (ORR) of 84% when it was combined with rituximab. Patients in the study had a median age of 69 years and had received a median of two prior therapies, including rituximab (91%) and fludarabine (47%). Altogether, 24% of patients entering the trial were refractory to rituximab. Abstract 7013

In 25 evaluable patients, the ORR was 84%, with 36% achieving a complete response (CR) and 48% with a partial response. Lymph node size was reduced by 50% in 94% of patients treated with ABT-199, with a median time to reduction of 12 weeks. Seven patients with a CR were analyzed for minimal residual disease (MRD), of which 5 (71%) were deemed MRD negative.

The initial dose of ABT-199 in the trial began at 50 mg but was modified to 20 mg as a result of a fatal episode of tumor lysis syndrome (TLS) that occurred during the lead-in period. Following this modification and increased monitoring, further TLS events did not occur. These events were not considered to be dose limiting. The final dose selected for phase II studies with induction was 400 mg.

In all 45 patients in the study, the most common all-grade adverse events were neutropenia (51%), nausea (38%), and diarrhea (33%). The most common serious adverse events were neutropenia (47%), anemia (16%), and thrombocytopenia (13%). Febrile neutropenia occurred in 7% of patients.

Nurse Perspective

 
Phyllis McKiernan Phyllis McKiernan, MSN, APN, OCN
Blood and Marrow Transplant Program
John Theurer Cancer Center
Hackensack, NJ
 

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world, and anti- CD20 therapy with monoclonal antibodies has been an effective treatment strategy. Rituximab given in conjunction with chemotherapy is standard first-line treatment for CLL, but can have toxic effects. Combining rituximab with novel agents that target other cell pathways now holds promise for CLL treatment. The key is improving response and survival without increasing toxicity.

In the phase III study presented at ASCO, adding idelalisib to rituximab resulted in superior outcomes for patients with CLL. The results were so striking, the randomization was halted and patients were allowed to cross over from the placebo arm to the idelalisib arm. Although the incidence of grade 3/4 adverse events was slightly higher in the idelalisib arm, the discontinuation rate was low and similar in both arms, indicating no increased toxicity. However, since the study was stopped early, late adverse effects such as diarrhea may develop in some patients. Interestingly, there was a decrease in rituximab-related infusion reactions in the idelalisib arm, a benefit to patients and nurses administering therapy (NEJM. 2014;370(11):997-1007).

ABT-199 is an oral Bcl-2 inhibitor presently being studied in CLL and small lymphocytic lymphoma. In the phase I study, the combination of ABT-199 with rituximab showed very good response rates in patients with previously treated CLL. The most common adverse effects were hematologic, and the combination appears to be well tolerated.

Both novel agents administered with rituximab show efficacy in the treatment of heavily pretreated patients with CLL, some of whom were refractory to rituximab. Thus far, there appears to be no added toxicity, but further study and long-term follow up are needed.

These new combinations may become impressive additions to the therapeutic options for patients with CLL.

 

Prostate Cancer

Adding Chemotherapy to ADT Improves Survival

In what was described as “an almost unprecedented improvement in median survival,” the addition of the chemotherapy drug docetaxel to standard hormone therapy prolonged life for men with newly diagnosed metastatic, hormone-sensitive prostate cancer by nearly 14 months. The survival benefit was the greatest for men with extensive disease spread. The findings from this federally funded, randomized phase III study, CHAARTED (E3805), were reported at the 2014 ASCO meeting. Abstract LBA2

“This is the first study to identify a strategy that prolongs survival in newly diagnosed metastatic prostate cancer,” said lead study author Christopher Sweeney, MBBS, medical oncologist at the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute. “The benefit is substantial and warrants this being a new standard treatment for men who have high-extent disease and are fit for chemotherapy.”

Prostate cancer eventually becomes resistant to first-line treatment with androgen deprivation therapy (ADT) in most patients, and chemotherapy is typically initiated only when that occurs. Docetaxel was approved in 2004 as the first agent to improve overall survival (OS) for patients with metastatic, castration-resistant prostate cancer, and investigators embarked on the E3805 study to determine whether the drug would work in earlier-stage disease, Sweeney said.

In the 8-year, National Cancer Institute–led study, 790 men with newly diagnosed metastatic prostate cancer were randomly assigned 1:1 to receive either ADT alone or ADT with docetaxel, which was dosed at 75mg/m2 every 3 weeks for six cycles within 4 months of starting ADT. After the combination cohort completed six courses of docetaxel, all patients continued on ADT alone. Approximately two-thirds of patients had highextent disease.

At a median follow-up of 29 months, median OS was 44 months in the ADT group and 57.6 months in the ADT-plus-docetaxel group or a 39% higher likelihood of survival in the combination arm at any study timepoint. The relative improvement in median OS was largest (32.2 months ADT-only versus 49.2 months combination) among the 520 patients with high-extent disease, who had either four or more bone metastases or liver or lung metastases, Sweeney said.

Docetaxel also delayed disease progression. At 1 year, the proportion of patients with PSA levels less than 0.2 ng/mL (considered a sign of a better remission) was 11.7% in the ADT group versus 22.7% in the ADT-plus-docetaxel group, Sweeney said. The median time to clinical progression (new symptoms or metastases detected on a scan) was 19.8 months in the ADT group versus 32.7 months in the ADT-plus-docetaxel group, he said, and the measuring time to the development of castration-resistant prostate cancer—whether determined due to a rise in PSA, new symptoms, or scan—was 14.7 months in the ADT group and 20.7 months in the ADT-plus-docetaxel group.

While on treatment, the disease worsened in 145 patients in the combination group, 49 of whom received additional docetaxel. In the ADTonly group, 174 patients experienced worsening of disease, and 129 of them received docetaxel at progression, Sweeney said. At the median 29-month follow-up, he said, there had been 136 deaths in the ADT-alone group versus 101 in the ADT-plus-docetaxel group.

Adverse events in the trial included febrile neutropenia (4% grade 3, 2% grade 4) and grade 3 neuropathy (1% sensory, 1% motor), the authors reported.

This new treatment paradigm will entail earlier, multidisciplinary care involving the collaboration of urologists and oncologists, who both commonly treat men with prostate cancer, Sweeney said. The findings are relevant for men in this patient population who are not too frail for chemotherapy, he added.

 

Exercise Intervention Yields Benefits for Older Patients

A home-based exercise program focused on increased walking and resistance training has been found to significantly reduce overall psychological distress as well as levels of associated proinflammatory cytokines in older patients with prostate cancer. Abstract 9510

“Psychological distress is a common side effect of cancer diagnosis and treatment, and research has shown that such distress is linked with increased systemic inflammation, noted Charles S. Kamen, PhD, a research assistant professor at the University of Rochester Medical Center, in presenting the findings at the 2014 ASCO meeting. The purpose of this study was twofold, he explained: to determine whether an exercise program would reduce both self-reports of psychological distress and associated levels of inflammatory cytokines in a population of older prostate cancer patients.

All patients (n = 58) were undergoing treatment during the intervention (radiation [47%]; ADT [53%]), and were a mean age of 67 years. Thirty-five were randomized to receive the Exercise for Cancer Patients (EXCAP) intervention—a standardized, 6-week, home-based, progressive aerobic and resistance training program—and 23 patients were assigned to the usual care control arm.

Kamen noted that EXCAP was done by patients at home and importantly, was tailored to each patient’s level of fitness which can then be progressively increased, based on how individual patients are performing. Participants were given a pedometer and encouraged to increase the number of steps they walked by between 5% and 20%. For the resistance training component, patients performed a number of upper and lower body exercises using resistance bands.

Adherence to the intervention was excellent, said Kamen, with 97% of patients in the EXCAP arm completing all or some of the exercises that they were prescribed; although there were a number of adverse events, none were deemed related to the study, but due to advancing age, prostate cancer, or other comorbidities.

In addition to reducing overall psychological distress based on total scores on the Profile of Mood States (POMS), EXCAP was found beneficial on POMS subscales, including depression and confusion/bewilderment. Findings related to inflammatory cytokines were also positive, Kamen said, noting that the pattern of results is consistent with a positive effect of EXCAP. Blood tests showed a general decrease in pro-inflammatory cytokines—including significant decreases in IL-6 and IL-8—and an increase in anti-inflammatory cytokines.

“I think the takeaway message from this study is that it is possible to deliver an exercise intervention to older patients,” said Kamen, but tailoring is very important. “Even patients who are older with comorbidities do benefit both physically and psychologically.”

 

Survivorship Care

Trial Suggests Potential Role for DHEA in Relieving Vaginal Symptoms

A randomized multicenter trial examining the efficacy of adding the prohormone dehydroepiandosterone (DHEA) to a vaginal bioadhesive moisturizer in postmenopausal survivors of breast or gynecologic cancer has found that daily rather than as-needed use of such a moisturizer significantly relieves symptoms of vaginal atrophy in these women, and that when DHEA is added, survivors report significant improvements in sexual desire, arousal, pain, and overall sexual function. Abstract 9507

Debra L. Barton, RN, PhD, AOCN, FAAN, a professor at the University of Michigan School of Nursing, presented the findings at the 2014 ASCO meeting. She noted that very few longitudinal studies have examined predictors of sexual health in cancer survivors, despite the distress this symptom is known to cause them.

Current treatment for vaginal dryness due to estrogen depletion has focused on local approaches, such as water-soluble or silicone-based lubricants for use during intercourse, moisturizers to hydrate the vaginal tissues— which many patients find ineffective, noted Barton— and topical estrogen. Barton said the latter represents the “gold standard” for treatment, but it is likely a last resort, particularly in breast cancer survivors due to safety concerns. “There is still a need to find effective treatments that don’t have estrogenic effects outside the vagina,” said Barton

Investigators sought to find out whether a possible solution to these treatment challenges might be found in DHEA. Previous research on the compound has supported the hypothesis that when used vaginally, DHEA is turned into active forms of estrogen or androgen in the target tissue but is not systemically active.

The study, under the auspices of the Alliance for Clinical Trials in Oncology, enrolled 411 postmenopausal women from 82 institutions across the United States and Canada. Eligible women had finished treatment for breast or gynecologic cancer with no evidence of disease and reported having at least moderate vaginal dryness or dyspareunia over the previous 2 months. Women receiving adjuvant endocrine therapy were eligible to participate if the therapy had been initiated at least 8 weeks prior, and no changes in the treatment regimen were expected during the 12 weeks of the study.

Patients were randomized equally (n = 147) to one of three arms: 3.25 mg or 6.5 mg of DHEA (both provided in a bioadhesive moisturizer base) or the base alone. Each treatment was applied daily via a small, prefilled syringe which participants were directed to administer at bedtime, after any sexual activity. Importantly, Barton noted, the bioadhesive moisturizer used in each of the cohorts is not inactive but rather, represents a current standard of care.

Patient characteristics were similar across all three arms. The majority of participants had been treated for breast cancer (97% in each arm), very few (15%-16%) were on tamoxifen therapy, and more than half (55%-56%) were taking aromatase inhibitors (AIs). The most bothersome symptom across all three groups was dyspareunia, experienced by 60%, 59%, and 51% of patients receiving 3.25 mg of DHEA, 6.25 mg, or none, respectively. Dryness was experienced by 40%, 41%, and 49% of patients in each respective arm.

As the study’s primary endpoint, researchers looked to see what effect the intervention had on change from baseline in dryness or dyspareunia. As secondary outcomes, the study elicited side effect reports and survivor assessments of sexual function and quality of life.

At 12 weeks, there was not a statistically significant difference in the two symptoms between the control and the two DHEA arms, said Barton, but there was a trend that DHEA was decreasing symptoms, with the 6.5 mg dose significant at 8 weeks.

Sexual function, as measured by change from baseline on the Female Sexual Function Index (FSFI), was improved in both DHEA cohorts. The higher dose yielded statistically significant improvements on the full FSFI scale, as well as on most domain subscales (desire, arousal, lubrication, satisfaction, and pain), with the exception of orgasm. Barton added that overall quality of life decreased slightly in the control arm and improved in both DHEA arms, a statistically significant finding.

When women were asked how much their symptoms had changed as a result of this treatment, “more women in the DHEA arms perceived a ‘moderate to very much better’ change than did controls,” Barton said—with 55% of patients in the 3.25-mg arm, 58% in the 6.25 mg group, and 40% in the control arm indicating such improvement.

The grade and frequency of adverse events did not differ significantly between the experimental and control arms; however, hirsutism was reported only in the 6.5-mg arm. Two self-reported side effects of headache (in the 3.2-mg arm) and slight voice change (in both DHEA arms), were worse compared with controls.

Laboratory analysis did not detect evidence of clinically important systemic estrogenic activity, and no changes in estradiol occurred in women receiving AI therapy; both AI- and non-AI–users benefited from the treatment.

“Daily bioadhesive moisturizers used as we prescribed in this study did improve symptoms of vaginal pain and dryness over 12 weeks,” concluded Barton, adding that “DHEA improved symptoms perhaps a bit quicker with the 6.5 mg dose, significantly improving several aspects of sexual function.”

Nurse Perspective

 
A. Nicole Spray, APRN A. Nicole Spray, APRN
Hays Med Breast Center
Hays, KS
 

The magnitude of sexual dysfunction among postmenopausal women and cancer survivors is underestimated. Healthcare providers may not include questions in a review of systems to address sexual dysfunction. Additionally, many patients feel embarrassed to bring this issue to the attention of their primary care provider or treating oncologist. Sexual dysfunction in this population may encompass many different symptoms, including painful intercourse (dyspareunia), vaginal dryness or decrease in lubrication, and decreased arousal, desire, or satisfaction, all of which can lead to a reduction in quality of life.

These results of a randomized trial using a vaginal bioadhesive moisturizer with DHEA in postmenopausal, cancer-surviving women are encouraging. Women used bioadhesive moisturizer with DHEA daily for 12 weeks. Although there was not a statistically significant difference between the control group and the two DHEA arms of the study that varied by dose, women treated with the DHEA were noted to have decreasing sexual dysfunction symptoms.

Moreover, the higher dose of DHEA showed statistically significant improvements in the Female Sexual Function Index and domain subscales including desire, arousal, lubrication, satisfaction, and pain. Of concern to breast cancer survivors, is the risk of using a vaginal cream that may contain unwanted estrogen exposure. The use of DHEA in a bioadhesive moisturizer, in this trial, did not show any evidence of systemic estrogenic activity.

Perhaps some of the benefit of this treatment was due to daily use. I find in clinical practice that the compliance rate with over-the-counter (OTC) vaginal moisturizer is very low. Patient feedback with use of OTC vaginal moisturizers is that they don’t work very well and the intravaginal administration is unpleasant. Perhaps compliance with prescription bioadhesive moisturizer with DHEA would be perceived as a “prescription,” and women would be more likely to be compliant with instructed use as prescribed.

Additionally, in clinical practice, I find many women get discouraged with the lack of immediate results and they give up treatment with vaginal moisturizers. This trial had women use the intravaginal preparation daily for 12 weeks which supports the idea that postmenopausal vaginal changes, with any treatment, take time to improve

As providers and nurses, we should find a way to assess for sexual dysfunction among cancer survivors consistently and offer viable solutions to help with this problem. Incorporating this treatment may help to address sexual dysfunction in postmenopausal, cancer-surviving women.

 

Head and Neck Cancer

Study Supports Dialing Back Radiation in Some HPV-Positive Oropharyngeal Cancers

Patients with less aggressive, human papillomavirus (HPV)-positive oropharyngeal cancer can be effectively treated with a lower-dose radiation regimen depending upon their response to combination induction therapy, according to study results presented at the 2014 ASCO Annual Meeting. Abstract LBA6006

This strategy has the potential to significantly reduce debilitating toxicities typically associated with radiation therapy for patients with this tumor type while maintaining high rates of progression- free survival (PFS) and overall survival (OS), according to lead author Anthony J. Cmelak, MD, who is a professor of Radiation Oncology at the Vanderbilt-Ingram Cancer Center. If validated through further study, he said, the approach could represent a new paradigm for treating patients with non-bulky, HPV-associated disease.

The findings come at a time when the incidence of HPV-associated disease—which typically has a better prognosis than HPV-negative disease—appears to be rising, with approximately 70% of newly diagnosed oropharyngeal cancers related to the virus. In prior studies, patients who were HPV-positive tended to be younger and thus likely to live for 30 or 40 years with adverse events stemming from their cancer treatment, Cmelak said.

This Eastern Cooperative Oncology Group E1308 trial enrolled 90 patients with resectable, stage III or IVA/B oropharyngeal squamous carcinomas. The median age of the participants was 57 years; 46% of the group had never smoked while 84% were not currently smoking.

The phase II trial employed a two-step designin which patients first received an induction regimen consisting of cisplatin (75 mg/m2) on day 1, along with paclitaxel (90 mg/m2) and cetuximab (250 mg/m2) on days 1, 8, and 15, every 21 days for 3 cycles.

After the induction regimen, 62 participants (among 80 evaluable patients) exhibited a complete clinical response, defined as no sign of disease on endoscopic exams. These patients then went on to receive a reduced dose of intensitymodulated radiation therapy (IMRT) of 54 Gy, whereas those who did not respond were treated with the standard 70 Gy IMRT dose. All patients received cetuximab along with radiation.

Among the patients who received the lowerdose IMRT, the 2-year PFS and OS rates were 80% (90% CI, 0.70-0.88) and 93% (90% CI, 0.85-0.97), respectively. Participants who were nonsmokers had the best outcomes; notably, patients with a smoking history of ≤10 pack-years, non-bulky tumors of

By contrast, the 2-year rates for all patients who received high-dose IMRT, which turned out to be 15 participants (3 patients did not receive radiation), were 65% (PFS) and 87% (OS).

Although lower-dose IMRT proved beneficial, the strategy would not be appropriate for patients with HPV-negative or larger tumors, Cmelak noted.

Cmelak said the lower-dose IMRT regimen amounted to a 23% reduction in the overall radiation dose compared with the standard. As a result, he said, toxicities experienced by patients in the lower-dose IMRT group were “very mild.”

Only one patient experienced a long-term toxicity of grade 3 severity, and that was an instance of low magnesium at 30 months, Cmelak explained. Other grade 3 toxicities associated with the induction regimen included rash acneiform (21%), neutropenia (9%), and thromboembolism (3%). For concurrent chemoradiotherapy, grade 3 toxicities included mucositis (31%), dysphagia (17%), rash (13%), and lymphopenia (13%).

In general, adverse events associated with high-dose radiation include: hypothyroidism, swallowing dysfunction, dental problems, and an increased risk of stroke, said Cmelak.

Patricia A. Ganz, MD, who served as moderator for the press briefing where the study results was announced, said the epidemiology of oropharyngeal cancer is changing to include higher rates of HPV-associated disease as opposed to risk factors linked to tobacco or alcohol, presenting an opportunity to reduce standard therapies and tailor therapy for these patients.

“This is another way of tailoring and targeting therapy and reducing the long-term toxicities in a group of individual patients who are likely to fare very well with this therapy,” said Ganz, director of the Division of Cancer Prevention and Control Research at UCLA’s Jonsson Comprehensive Cancer Center in Los Angeles.

She said that if patients are “going to survive a long time, we want to modify our upfront therapy” so that they will not experience draining symptoms. “Because late effects can be very substantial in this population . . . we want to modify our upfront therapy so that they will not have these long-term sequelae,” said Ganz. ‘This is really an important survivorship question.”

 

Palliative Care

Discontinuing Statins in Late-Stage Cancer Patients

Patients starting palliative care for advanced cancer are often already on repeat prescriptions of statins to lower cholesterol and reduce risk of a heart attack or stroke, and many of these patients continue on statin therapy until death. This may contribute additional burden to these patients, because side effects from statin use include muscle pain, liver damage, digestive problems, rash/flushing, increased blood sugar levels, and memory loss/confusion, and patients with late-stage cancer are at a greater risk for adverse reactions from statins.

Amy P. Abernethy, MD, PhD, medical oncologist and palliative medicine specialist at the Duke Clinical Research Institute, thinks it is important to carefully consider whether or not a patient, who may be in the final stages of his or her life, should be continued on statins.

“The number of pills in our pill cup doubles at the end of life,” said Abernethy during a briefing on palliative care at the 2014 ASCO Annual Meeting. “For people with life-threatening illness, optimal management of those medications, including which ones we can discontinue, is a critical question about which we are uncertain.”

On behalf of the Palliative Care Cooperative Group, Abernethy presented results from a multisite randomized controlled trial that studied the effects of continuing versus discontinuing statins in the setting of life-limiting illness. The trial was funded by the National Institute for Nursing Research. Abstract LBA9514

“The question at hand is,” said Abernethy “Is it safe to discontinue statins for the patient with less than a year to live?”

Participants in the study (n = 381) were randomized (1:1) to discontinue or continue their statin medication. Adult patients, with a mean age of 74 years and a life expectancy greater than 1 month, with decreased performance status, were included in the study. Patients needed to be on a statin for ≥3 months for the purposes of primary or secondary prevention to qualify for the study.

Outcomes, which were measured at baseline and at least monthly, included survival, cardiovascularrelated events, quality of life (QOL), symptoms, and number of medications. The primary outcome of the study was rate of death within 60 days of randomization. Cost was also a consideration in the study, according to Abernethy.

Almost half of the patients in the study had cancer as their primary diagnosis. Sixty-nine percent of them had used statins for more than 5 years.

Upon analysis, the rate of death within 60 days was similar between the group that continued on statins compared with the group that discontinued statin therapy.

The group discontinuing statins had longer median time-to-death (229 days [90% CI, 186-332] vs 190 days [90% CI, 170-257]; P = .60). The total QOL was significantly better among the group discontinuing statins, and patients in this group experienced fewer symptoms.

Patients who discontinued statins took significantly fewer medications (10.1 vs 10.8; P = .034) and experienced decreased symptoms. Interestingly, few participants in either group experienced cardiovascular events (13 vs 11).

The study authors concluded that in the setting of life-limiting illness such as advanced cancer, it is unlikely that harm will accrue when statins being used for primary or secondary prevention are discontinued. In fact, the authors continued, these patients may even benefit.

According to Abernethy, savings on average equaled $3.37 per patient/per day, which came to an average of $716 per patient. Using a 2014 population estimate, she equated this to about $630 million saved if the discontinuation of statins occurred during the last year of life for these patients, and by 2040, the savings would equate to approximately $1 billion.

Despite the overall benefits, Abernethy feels that the decision remains a personal one.

“We still think that this is a patient-centered decision where clinicians and patients together talk about what to do. However, as clinicians, we can now feel confident that we are not harming our patients by making this decision.”

Nurse Perspective

 
Kristin Barber Kristin Barber, RN, MSN, APRN
Utah Cancer Specialists
Salt Lake City, UT
 

Although statins are a staple of modern-day medicine and have significantly reduced cardiovascular disease in the primary care setting, when we have an incurable oncology patient who has exhausted his or her therapies, there may be multiple medications that are no longer helping and may even be harming patients.

I completely agree that when initiating palliative care, it is important to take a look at the patient’s medications. Unfortunately, when you tell a patient they can stop their cholesterol medication, they think you are killing them. The study done by the National Institute for Nursing Research gives us the evidence to tell patients that not only are we not hastening their death, we may be improving quality of life, side effects, and out-of-pocket costs. All of this can be done while safely discontinuing the drug. The fact that the patient is also able to save approximately $716 offers another incentive.

Cancer is quite expensive for all patients, and to be able to confidently tell them there was no increased risk of death in the group that stopped their cholesterol medication is imperative. The article does conclude by stating that ultimately even with the new findings, that it is still the patients’ decision whether or not to take the medication. I think this is a fundamental principle in palliative care.

 

Lung Cancer

Pembrolizumab Induces Robust Responses in PD-L1–Positive NSCLC

The anti-PD-1 humanized antibody pembrolizumab (formerly MK-3475) has robust antitumor activity as a first-line treatment for patients with advanced PD-L1–positive non–small cell lung cancer (NSCLC), according to results from the KEYNOTE-001 phase Ib study reported by Naiyer A. Rizvi, MD, at the 2014 ASCO Annual Meeting. Abstract 8007

The study screened 84 patients for PD-L1, with 73 meeting the criteria for evaluable biopsy samples. Out of these patients, 57 (78%) were deemed PD-L1–positive. Forty-five patients met eligibility criteria for treatment with pembrolizumab, of whom 42 were evaluable by RECIST v1.1 criteria.

Patients having received no prior systemic therapy for metastatic NSCLC and whose tumors expressed PD-L1 were randomized to pembrolizumab at 10 mg/kg every 2 or 3 weeks until disease progression. The first 11 patients were randomized to 2 mg/kg and 10 mg/kg every 3 weeks.

“Eighty percent of these patients experienced some degree of reduction of tumor burden,” said Rizvi, medical oncologist, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center. “Activity was observed across the 2 and 10 mg/kg dose levels, and between 2- and 3-week schedules.”

At the time of the March 3, 2014, data cutoff, the overall response rate by RECIST was 26% and was 47% by investigator-assessed immune-related response criteria (irRC). The disease control rates, defined as complete response, partial response, and stable disease, were 64% and 78% by RECIST and Immune-Related Response Criteria (irRC), respectively. The interim median progression- free survival was 27 weeks by RECIST and 37 weeks by irRC. “These are early data, with 56% of patients still on treatment at the time of data cutoff,” Rizvi said.

At the interim analysis, the median duration of response by either RECIST or irRC had not yet been reached with a median duration of followup of 36 weeks. Altogether, 100% of patients responding by RECIST and 90% by irRC continue to respond to treatment, with 64% and 86%, respectively, remaining on treatment.

Of the 45 patients treated, time on therapy was a mean of 154 days (median number of cycles = 9). With a minimum of 18 weeks of follow-up, 18% discontinued because of adverse events, only two of which were considered treatment-related (one patient with grade 3 pneumonitis and one with grade 2 acute kidney injury), 16% discontinued because of radiographic disease progression, and 11% because of investigator or patient choice, leaving 25 patients (56%) remaining on treatment at the time of data cutoff.

Treatment-related adverse events (TRAEs) that occurred with >5% frequency were all grade 1/2. The most common TRAEs were fatigue (22%), pruritus (13%), hypothyroidism (9%), dermatitis acneiform (7%), diarrhea (7%), dyspnea (7%), and rash (7%). There were three episodes of grade 3/4 TRAEs: one case each of grade 4 blood creatine phosphokinase elevation, grade 3 pericardial effusion, and grade 3 pneumonitis.

 

Ceritinib Demonstrates Durable Response in ALK-Positive Lung Cancer

The second-generation oral ALK inhibitor ceritinib (Zykadia; LDK378) demonstrated rapid and durable responses in patients with ALK-positive, metastatic, non–small cell lung cancer (NSCLC)—regardless of whether they had been previously treated with crizotinib—achieving overall response rates of 60% or more in each subgroup of patients who had received 0-3 prior therapies for their advanced lung cancer. Abstract 8003

These longer term results from the international phase I ASCEND-1 clinical trial were presented at the 2014 ASCO meeting by Dong-Wan Kim, MD, PhD, of the Seoul National University Hospital in South Korea. Initial results from this trial had established a recommended 750 mg daily dose of ceritinib for use in the expansion cohorts.

The international, multicenter study reported here involved 246 patients with ALK-positive NSCLC: 163 patients were previously treated with crizotinib, and 83 patients were ALK inhibitor naïve. The median age was 53 years (range: 22-80), and 62% were never-smokers. Kim noted that overall, 42.7% of patients in the study (n = 105) were heavily treated (≥3 prior therapies).

Of the 144 evaluable patients, the median duration of response was 9.69 and 7.39 months for all patients and ALK inhibitor–treated patients, respectively, and the progression free survival (PFS) was 8.21 and 6.9 months for each respective group. Analysis of ALK inhibitor–naïve patients is ongoing.

Ceritinib also was found to be active in patients with brain metastases. The overall response rate was 54% (67 of 124 patients), and the median PFS was 6.9 months.

As of the October 31, 2013 data cutoff, 52% (128 patients) were still on treatment. Of the patients who discontinued the trial, 9.4% did so due to adverse events (AEs). Dose reductions occurred in 52.2% of patients (n = 133), and all were due to an AE, the researchers noted.

The most common all-grade AEs across all patients were gastrointestinal: diarrhea (86%), nausea (80%), vomiting (60%), and abdominal pain (54%), though only a small percentage of each were grade 3 or 4: 6%, 4%, 4%, and 2%, respectively. High-grade laboratory abnormalities (grade 3/4) were elevated ALT, AST, and glucose, 27%, 13%, and 13%, respectively. Ten patients developed pneumonitis. Two patients discontinued treatment, and there was one patient death, attributed to pneumonitis.

The 50% dose reduction rate indicates that although the adverse events are manageable by supportive measures or dose reductions, ceritinib is a more difficult drug to administer compared with crizotinib in many patients, noted D. Ross Camidge, MD, PhD, associate professor of medical oncology at the University of Colorado in Denver, who was not part of the study. “Developing a standardized algorithm based on good data to manage the side effects will be key.”

Phase III trials of ceritinib that are currently recruiting patients include NCT01828112, comparing the drug to chemotherapy in ALK-positive NSCLC patients who have received prior chemotherapy and crizotinib, and NCT01828099, evaluating ceritinib in those who are both chemotherapy- and crizotinib-naïve.

 


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