Clinical Insights: March/April, 2013

CE lesson worth 1.0 contact hour that is focused on supportive care and research from the 2013 Genitourinary and Gastrointestinal Cancers Symposia.

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 1.0 contact hours. RNs outside California must verify with their licensing agency for approval of this course.

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

  • Read the articles in this section in its entirety.
  • Go to www.dannemiller.com/onn-mar-apr-2013.
  • Complete and submit the CE posttest and activity evaluation.
  • Print your Certificate of Credit.

This activity is provided free of charge to participants.

2013 Genitourinary Cancers Symposium

Shortened Hormone Therapy Course

Feasible for High-Risk Prostate Cancer

By Alice Goodman

Shortening the course of androgen blockade (AB) therapy from 36 months to 18 months when combined with radiation therapy does not appear to compromise outcomes in patients with high-risk prostate cancer, according to results of a randomized, multicenter, phase III study reported at the 4th Annual Genitourinary Symposium held February 14-16, 2013, in Orlando, Florida (Abstract 3).

The study found that both overall survival (OS) and disease-specific survival (DSS) were similar in patients who received 36 or 18 months of treatment.

Hormone therapy is associated with uncomfortable and disturbing side effects that negatively impact quality of life. These include hot flashes, decreased libido, impotence, and fatigue.

“A long list of side effects makes the lives of most of our patients quite miserable,” commented lead author Abdenour Nabid, MD, associate professor at Centre Hospitalier de Universitaire de Sherbrooke in Sherbrooke, Canada. “A shorter course could reduce the quantity and intensity of its unpleasant side effects as well as treatment costs. We hope these results will convince doctors that they can stop hormone therapy after 1.5 years instead of 2 to 3 years.”

The study enrolled 630 patients with node-negative, high-risk prostate cancer treated with radiotherapy to the pelvic area and prostate bed. They were randomized to either 36 months (n = 310) or 18 months (n = 320) of AB therapy (bicalutamide 50 mg for 1 month plus goserelin 10.8 mg every 3 months) given before, during, and after radiation.

Patient characteristics were well balanced between the two arms, with a median age of 71 years, median PSA of >20 ng/mL, and a median Gleason score of >7. The majority of patients had stage T3-4 disease.

At a median follow-up of 77 months, the two groups had no significant difference in biochemical failure, metastasis, bone-only metastasis, and cause of death. Mortality rates were 22.9% (71 patients) in the longerduration hormone therapy arm versus 23.8% (76 patients) in the shorter-duration arm. Of 147 deaths, 116 were deemed unrelated to prostate cancer.

Five-year OS was 92.1% in the longer-duration arm versus 86.8% in the shorter-duration arm, and 10-year OS was 63.6% versus 63.2%, respectively. Five-year DSS was 97.6% and 96.4%, respectively, and 10-year DSS rates were 87.2% in both arms.

Nurse Perspective on Shortened Hormonal Therapy

David Leos, RN, MBA, OCN®Clinical Trials NurseMD Anderson Cancer CenterHouston, Texas

This study potentially represents a very meaningful advance in the treatment of localized prostate cancer. As pointed out, the symptom burden for patients undergoing the current bimodality standard of care is quite significant.

Improved survival data in most cases can be the motivating factor for patients and their healthcare providers to consider the benefits of longer treatment courses to outweigh the risks. This study’s results, if borne out in the review process, are very compelling in the context of presenting a 50% reduction in treatment duration while still delivering efficacious care.

In this case, “more” appears not to be significantly better than “less.” The fact that this study did not involve the introduction of a new androgen blocker or other type of agent or a new radiation treatment technique could represent other gains.

In the context of affordability of care or quality of life, advantages to such new and/or extended treatment approaches can be somewhat offset by significantly higher costs to the patient and/or the insurer or increased side effects. With respect to the latter concern, it would be interesting to see data on the quality of-life comparison between the two treatment arms. While this study’s results will no doubt be welcome news, one could wonder why this potential treatment “threshold” was not previously revealed in the typical dose-/time-escalating process of determining the length of treatment for the current standard of care.

Aggressive Prostate Cancer Risks Higher

in Elderly, African-American Men

By Alice Goodman

A large, retrospective study has found that high-risk prostate cancer that can only be detected through prostatespecific antigen (PSA) testing is more likely to occur among men over the age of 75 and in African Americans, according to research reported at the 2013 Genitourinary (GU) Cancers Symposium (Abstract 50).

The findings come amid a continuing debate over the merits of PSA screening, particularly after the US Preventive Services Task Force (USPSTF) recommended against routine screening for the general male population last May based on the finding that the harms of overdiagnosis outweigh the potential benefits of screening.

The results of this study suggest that PSA testing can be useful in identifying an aggressive form of prostate cancer in asymptomatic men with early disease that is not detectable by physical exam or other tests.

In their population-based study, researchers from the University of Rochester Medical Center in New York determined that elderly men account for approximately 40% of all cases of high-risk, PSA-detected prostate cancer and are 9.4 times more likely than men under the age of 50 to be high risk. African-American men of any age are more likely than white men to have high-risk disease.

In addition, intermediate-risk prostate cancer was more likely to occur among elderly and African- American men, the study found.

“To the best of our knowledge, this is the largest analysis exclusively consisting of PSA-detected prostate cancer (T1cN0M0 disease). We found that men age 75 and older and African Americans are at highest risk of intermediate or high-risk disease,” stated lead author Hong Zhang, MD, PhD, an associate professor of Radiation Oncology at the University of Rochester, during a press conference before the symposium where the results were announced.

“If we stop PSA screening altogether, there is no other method to detect this form of prostate cancer sufficiently early to have the best chance of helping this group of high-risk patients,” Zhang said. “The findings of this study will help physicians and certain patients make more informed decisions on whether or not they want to proceed with PSA testing, although more research (and longer follow-up) is needed to determine the effects of early detection and intervention on outcome in these high-risk patients.”

The study included 70,345 men with early-stage, node-negative prostate cancer diagnosed between 2004-2008 enrolled in the Surveillance, Epidemiology, and End Results (SEER) database.

PSA criteria and Gleason stage were utilized to determine the probability of developing low-, intermediate-, and high-risk prostate cancer. Low risk was defined as PSA <10 ng/mL and Gleason score ≤6; intermediate risk was defined as PSA 10-20 ng/ mL and/or Gleason score 7; and high-risk disease was defined as PSA >20 ng/mL and/or Gleason score ≥8.

Men age 75 or older were 4.47 times more likely to develop intermediate-risk disease and nearly 9.4 times more likely to develop high-risk prostate cancer compared with patients under the age of 50 (P <.01 for both comparisons).

African-American men were also significantly more likely to develop intermediate- and high-risk disease compared with white men; they were 1.5 times more likely to develop intermediate-risk prostate cancer and 1.84 times more likely to develop high-risk prostate cancer (P <.01 for both comparisons).

“Screening recommendations have been all over the map, ranging from ‘everyone should be screened’ above the age of 50 to ‘no one should be screened,’” said Bruce J. Roth, MD, who is a professor of Medicine at Washington University in St. Louis, Missouri. “The answer is somewhere in between, and this study gives us some important information but adds to the complexity of this issue.”

Nurse Perspective on Prostate Cancer Risks

Frank delaRama, RN, MS, AOCNSClinical Nurse Specialist, Oncology/GenomicsProstate Cancer Nurse NavigatorPalo Alto Medical FoundationPalo Alto, CA

Until we have a test for prostate cancer screening that is 100% sensitive and specific for finding localized cancers early, the debate on PSA testing will continue. Without a true consensus, the decision on whether or not to screen for prostate cancer remains ultimately a man’s personal choice.

Guidelines, such as those from the US Preventive Services Task Force and the National Comprehensive Cancer Network, exist in an effort to help men and their healthcare providers plan for cancer screenings, aiming to maximize the benefits and minimize the risks.

This study provides some data that would support prostate cancer screening for men that may fall outside of some guidelines, particularly men >75 years old. With advanced treatment modalities that include radiation and hormones, men well over the age of 75 are able to undergo treatments that have minimal impact on quality of life. When our patients are considering screening (for any cancer), we can pose the question, “If a cancer is found by screening, would you do anything differently?” and, even for our elderly patients, the answer is still often “yes.”

Although flawed, the PSA test is one of very few tools we have in prostate cancer screening. We still need better tools to help characterize prostate cancer findings. Hopefully, emerging technologies in diagnostics, as well as promising work in genomics, will result in better information to offer to our patients in the near future.

Prostate cancer screening, including the PSA test, still demands that men have a thorough discussion with their healthcare providers to decide whether or not to screen. This study adds more data in support of screening in African-American men, as a high-risk population, independent of age. With the study’s findings in men >75, the perceived ceiling for prostate cancer screening by age is less clear.

As healthcare providers, it is our responsibility to help patients identify all their options in cancer screening and potential treatment. The study presents some key discussion points to guide patients through issues in cancer screening and prevention, assisting them with due diligence in their healthcare decisions.

2013 Gastrointestinal Cancers Symposium

Second-Line Docetaxel Improves Survival and Quality of Life in Advanced Esophageal and Stomach Cancers

By Ben Leach

Patients with advanced esophagogastric adenocarcinoma who received the chemotherapy drug docetaxel as a secondline therapy after progressing after their first line of treatment experienced a longer period of overall survival as well as a better quality of life, compared with patients who received active symptom control.

The results of the phase III study (Abstract LBA4), presented at the 2013 Gastrointestinal Cancers Symposium, held January 24-26 in San Francisco, California, represent some of the first definitive evidence that this widely used method of second-line therapy for esophagogastric cancer does have measurable benefits in a disease characterized by poor prognoses and a low median survival.

“Because of the aggressive nature of the disease, all patients who present with advanced disease and up to 70% of patients who present with earlystage disease will ultimately progress after their chemotherapy,” said Hugo Ford, MD, director of cancer services at Addenbrooke’s Hospital in Cambridge, UK, and lead author of the study. “For these patients, we know that the average survival time is only 3 or 4 months.” He added that although second-line chemotherapy is commonly prescribed, “there’s very little good evidence to show that treatment improves quality of life.”

In this trial, 168 patients with locally advanced or metastatic esophagogastric adenocarcinoma whose disease progressed within 6 months of initial chemotherapy were randomized to receive either docetaxel 75 mg/m2 every 3 weeks for up to 6 cycles (n = 84) or active symptom control, which could include any treatment that the physician deemed an appropriate choice to manage the disease (n = 84). The primary endpoint of the study was overall survival (OS), with secondary endpoints including response rate, toxicity, healthrelated quality of life (HRQoL) and healthcare resource use.

The study found that patients who received docetaxel as second-line treatment experienced a median OS of 5.2 months (95% CI, 4.1-5.9), a significant improvement over the median OS of 3.6 months (95% CI, 3.3-4.4) in the active symptom control arm (HR = 0.67; 95% CI, 0.49-0.92; P = .01).

Additionally, Ford reported that there were no significant differences observed in global quality of life or function between the two groups, and those who received docetaxel had a significantly better symptom score for pain than those who received active symptom control. Ford also said that very fit patients with the longest interval between previous chemotherapy and relapse or progression fared better, as was expected. Benefits were observed across all patient groups, and no cohort appeared to do worse if they received chemotherapy, Ford said.

“We conclude as a result of this trial that docetaxel should be the standard second-line treatment for esophagogastric cancer, and we think it’s likely to be the standard arm against which future treatments should be compared,” Ford said.

Nurse Perspective on Second-Line Docetaxel

Laura Metcalfe, MSN, RN, APN, C, AOCNSJohn Theurer Cancer CenterHackensack, NJ

I cannot say I was surprised when I read the results of this study, as I have seen similar results when we have used docetaxel second-line in many patients in our practice. However, it is always nice to have definitive data to lend support to what we see anecdotally in our patient population. Also, patients are always relieved to know there is a “plan B,” when “plan A” doesn’t work out as they had hoped. In addition to a significant improvement in median overall survival in the treatment arm, there were also significantly better symptom scores for pain. Better symptom management, especially pain management, often translates into better quality of life for many patients, as evidenced by this study.

As oncology nurses, we are very cognizant of the importance of assessing and managing our patients’ pain. I have found that successfully treating a patient’s pain (whether through pharmaceutical or nonpharmaceutical methods), has a huge impact on a patient’s quality of life. Patients in pain often lose their appetite, and therefore lose weight. They also have trouble sleeping, which only compounds how poor they feel. I have often seen this translate into feelings of despair and depression as well. Conversely, when we have successfully treated their pain, we have seen many patients eat better, sleep better, and just feel better overall. I think this is at least as—if not more—important as improvement in overall survival.

Of course, each patient must define quality of life for him or herself. I have learned that some patients will accept some pain to avoid being over-sedated so that they can interact with their loved ones. However, if we can improve quality of life for patients, however they define it, that may be the best thing we can do for them. I will always remember what one patient told me when she decided against second-line chemotherapy. She had not tolerated her prior chemotherapy well and did not want to feel that way again. She said, “I would rather live for a shorter time and still be “grandma.” The side effects of therapy had made her too ill to interact with her grandchildren, and this was not acceptable to her. She chose quality of life over quantity of life. This study has demonstrated, however, that these two concepts do not need to be mutually exclusive.

Extended Survival Benefit with Zaltrap

Seen in Metastatic Colorectal Cancer

By Wayne Kuznar

Patients with metastatic colorectal cancer (mCRC) whose disease had progressed despite treatment with oxaliplatin experienced an improvement in survival by switching to a regimen of ziv-aflibercept (Zaltrap) plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) compared with FOLFIRI alone, according to the results of a large randomized international trial. (J Clin Oncol. 2012:30(suppl 34):abstr 451).

Median overall survival (OS), the primary endpoint of the study, was extended by 1.4 months with the addition of ziv-aflibercept to FOLFIRI, said Paul Ruff, MD, director of Medical Oncology at the University of Witwatersrand, Johannesburg, South Africa, who presented data from the phase III VELOUR study at the 2013 Gastrointestinal Cancers Symposium.

Ziv-aflibercept is a fusion protein that consists of the key domains of the vascular endothelial growth factor (VEGF) receptor-1 and VEGF receptor-2, joined at the Fc portion of human IgG, “to make a very potent agent for binding to VEGF, making it a very potent antiangiogenic agent,” said Ruff.

The FDA approved the drug in August for use in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen.

The VELOUR trial included 1226 patients with mCRC who received prior oxaliplatin-based treatment and whose disease had progressed during or following their last oxaliplatin regimen. Patients who relapsed within 6 months of completing oxaliplatin-based chemotherapy were also eligible. About 30% of patients had prior bevacizumab treatment. They were randomized to receive ziv-aflibercept, 4 mg/kg intravenously or placebo every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary endpoint was OS.

The intent-to-treat analysis showed an OS advantage with ziv-aflibercept. Median OS was 13.5 months in the ziv-aflibercept/FOLFIRI group compared with 12.06 months in the placebo/FOLFIRI group (HR=0.817, P =.032).

A time-course analysis showed that “the [survival] curves continue to separate as time goes on. At 18 months, the benefit of ziv-aflibercept was increased to 2.6 months, and by 24 months, it was 4.4 months, so the benefit seems to continue with time,” Ruff said. The improvement in survival was almost double for ziv-aflibercept at 30 months versus placebo (22.3% vs 12.0%, respectively).

“The adverse events were those generally expected from antiangiogenic agents, such as hypertension and proteinuria, but that tended to be early and usually fairly manageable,” Ruff said. There were more grade 3/4 adverse events with ziv-aflibercept compared with placebo. Most occurred during the first four cycles of treatment, and the vast majority (76.3%) were single episodes in nature.

Adverse events with ziv-aflibercept did not influence the ability of the patients to receive chemotherapy.

Side Effects With Regorafenib

Occur Early and Tend to Taper

By Wayne Kuznar

The incidence of adverse effects with regorafenib is highest during the first treatment cycle, and then diminishes over time. This time course of regorafenib-associated adverse events was evident in a subanalysis of the phase III CORRECT study conducted in patients with metastatic colorectal cancer (mCRC). In the trial, drug-related side effects tapered off starting with cycle 2, said Axel Grothey, MD, during a poster presentation at the 2013 Gastrointestinal Cancers Symposium. (J Clin Oncol. 2012;30(suppl 34):abstr 467).

“The side effects, if at all, came early, and then got better even if you kept the dose constant,” said Grothey, professor of Oncology and consultant in the Division of Medical Oncology in the Department of Oncology, Mayo Clinic, Rochester, Minnesota. “This is not necessarily a given. When you look at some chemotherapy drugs—for instance, neuropathy or neurotoxicity on oxaliplatin gets worse over time. Often, the impact on neutrophils accumulates over time, so it is not a given that side effects are strongest in the first cycle and then abate over time, but, this is exactly what we saw in the study.”

Regorafenib is an oral multikinase inhibitor that blocks the activity of several protein kinases. On the basis of the CORRECT study, it was approved by the FDA in September 2012 for the treatment of patients with mCRC whose disease has progressed after prior treatment with chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if KRAS wild type.

Patients (n = 505) were randomized to regorafenib in CORRECT, at a dosage of 160 mg for the first 3 weeks of each 4-week cycle. Two hundred fifty-five patients were assigned to placebo. Adverse events led to dose modification in 66.6% of the regorafenib recipients and 22.5% of the placebo recipients. Treatment was discontinued permanently in 17.6% of the regorafenib group and 12.6% of the placebo group because of adverse events.

During cycle 1 of regorafenib, the incidence of fatigue was about 45% and the incidence of hand-foot skin reaction (HFSR) exceeded 30%. These incidence rates dropped to 23% and 26%, respectively, during cycle 2 and remained relatively stable until cycle 6. The rates of fatigue and HFSR decreased further in cycles 7 and 8.

The incidences of hypertension and rash/desquamation were highest in cycle 1, at 20% to 25%, “and tapered to low or no incidence over cycles 2 to 8,” said Grothey.

“The time course suggested an initial flare-up of key side effects, in particular fatigue and HFSR, and then over time these side effects decreased in incidence but also in severity,” he said. “There were a higher number of early grade 3 adverse events, but over time, even if you keep the same dose, these side effects fade away a little bit.”

As a result, the proportion of regorafenib received was highest in cycle 1 and decreased over cycles 2 and 3 as the dosage was adjusted to manage adverse events. The dose density remained relatively stable over cycles 3 through 8. “The dose that people could be maintained on over a longer term was about three-quarters of the dose—instead of 160 mg, it was 120 mg,” he said. “The way adverse events were handled with dose modification was the basis for the positive survival results observed in this study.”

Supportive Care

Nurse-Guided Symptom Management Protocol Improves Fatigue in Patients With Advanced Cancers

By Lauren M. Green

Fatigue in patients with advanced cancer may be alleviated through systematic interventions aimed at managing other physical symptoms, such as pain, nausea, and lack of appetite, according to findings of a new study that examined the impact on fatigue of a nurse-coordinated, patient-tailored treatment (PTT) protocol (J Clin Oncol. 2013;31(6):716-722).

Cancer-related fatigue is especially prevalent in the palliative care setting. Whereas guidelines recommend that clinicians treat the symptoms accompanying fatigue, evidence from randomized clinical trials to support this recommendation is lacking, study authors noted.

For this trial, 152 patients with a solid malignancy receiving palliative treatment at the outpatient clinic of the Erasmus Medical Center (MC)-Daniel den Hoed Cancer Center in Rotterdam, the Netherlands, were randomized evenly to receive either PTT or care as usual (CAU). Eligible patients had a fatigue score of ≥4, Eastern Cooperative Oncology Group performance status of ≤2, and a life expectancy of ≥4 months. Baseline patient characteristics did not differ significantly between the two arms.

Patients in the PTT group were monitored by a nurse specialist four times over 10 weeks: within 1 week of assignment, and then on three more occasions. During the sessions with the nurse, patients were asked to rate the intensity of nine physical symptoms (Box), but not their fatigue itself. Nurse-coordinated interventions were then devised based on patient-reported symptom severity. The interventions included patient education, starting or adjusting symptom-control medications, referral to other specialists, and additional diagnostic assessments. For patients reporting multiple symptoms, nurses would manage as many symptoms as possible, focusing on the ones patients reported as being the most difficult for them.

Physical Symptoms

Pain

Nausea

Vomiting

Constipation

Diarrhea

Lack of Appetite

Shortness of Breath

Cough

Dry Mouth

Treatment decisions for patients in the CAU group were not guided by a specific protocol, nor were these patients systematically monitored through planned visits with a nurse specialist.

Investigators used the Multidimensional Fatigue Inventory (MFI) to measure the study’s primary outcome, MFI-General Fatigue. That measurement is one of the instrument’s five dimensions of fatigue, in addition to physical fatigue, reduced activity, reduced motivation, and mental fatigue. Researchers reported a significant difference in MFI-General Fatigue in favor of the PTT group at their second assessment (effect size, 0.26; P = .007) and third (effect size, 0.35; P = .005), though no significant difference in their fatigue scores was found at their last assessment.

Significant differences favoring the PTT group were also reported for two other MFI dimensions (reduced anxiety and motivation), though no significant differences were found in MFI-physical and mental fatigue. Patients receiving the interventions also reported that fatigue interfered less with daily life, while patients in the CAU group said it interfered more.

The most bothersome symptoms reported by patients during all of the intervention sessions were pain, shortness of breath, and lack of appetite.

Researchers, led by Pleun J. de Raaf, MD, of the Department of Medical Oncology at the Erasmus MC, noted that to their knowledge, this study marks the first randomized, controlled trial to present evidence for the role of optimizing treatment of other symptoms in helping to address cancer fatigue.

Although the study did not reach its aim for a 0.5 medium effect, the researchers noted that, “because treatment options for fatigue in patients with advanced cancer are scarce, we would argue that even small improvements in fatigue should be considered clinically relevant.” They recommended that a protocol for monitoring and treating other physical symptoms be routinely included in fatigue management treatment plans for this population and that such patients be referred to nurses trained in palliative care for symptom monitoring, patient education, and referral to other providers when needed.

Nurse Perspective on Nurse-Guided Symptom Management

Kristin Barber, RN, MSN, APRNUtah Cancer SpecialistsSalt Lake City, UT

This study concept was a very good idea. Although the study did not achieve its medium effect goal of 0.5, I do believe there is evidence here for adoption in practice.

There is no doubt in my mind that fatigue can be intensified and is complicated by other symptoms such as pain, nausea, lack of appetite, and diarrhea, all of which were addressed in this study. We also know that fatigue can be worsened by depression, anxiety, sleep disturbances, and deconditioning or muscle weakness.

Some possible problems with the study were the failure to include additional factors; maybe this specific intervention of four nurse specialist visits is not the ideal intervention, or possibly this patient population had sicker patients who were not expected to improve and were near end of life or hospice.

In any case, the information reminds us as practitioners to constantly assess fatigue. The research did show improvement for patients in visits one and two, meaning that it is a valuable intervention that may be incorporated in practice. It also identified the three most bothersome symptoms to be pain, shortness of breath and lack of appetite, therefore, identifying these as needs for further clinical trials.

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