Clinical Insights: September, 2012

CE lesson worth 1.0 contact hour that is intended for advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients.

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-sept-2012
  • Complete and submit the CE posttest and activity evaluation.
  • Print your Certificate of Credit.

This activity is provided free of charge to participants.

Breast Cancer

Subcutaneous Trastuzumab May Offer

Benefits Over Standard IV Infusion

By Jill Stein

A new formulation of trastuzumab that is administered subcutaneously (SC) over approximately 5 minutes appears to be as effective as the approved bodyweight-based intravenous (IV) regimen given every 3 weeks in women with stage I to III HER2-positive breast cancer, according to results from the phase III HannaH study (Lancet Oncol. 2012;13(9):869-878).

Additionally, the SC formulation, which also has a similar pharmacokinetic profile and safety profile as the IV formulation, may also be a timesaver.

“The shortened duration of administration with SC trastuzumab compared with IV delivery suggests the potential for substantial timesaving for patients, physicians, and nursing staff,” Gustavo Ismael, MD, with the Amaral Carvalho Hospital in São Paulo, Brazil, and his coauthors wrote.

Overall, the new trastuzumab formulation may eventually represent a “valid alternative” to the conventional formulation, the researchers noted.

In the HannaH study, 596 women were randomized 1:1 to either eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either IV (8 mg/kg loading dose, 6 mg/kg maintenance dose) or SC (fixed dose of 600 mg). Chemotherapy consisted of four cycles of docetaxel (75 mg/m2) followed by 4 cycles of fluorouracil (500 mg/m2), epirubicin (75 mg/m2), and cyclophosphamide (500 mg/m2), every 3 weeks. After surgery, patients received IV or SC trastuzumab as assigned to completion of 1 year of treatment.

Study participants had newly diagnosed HER2- positive, operable, locally advanced or inflammatory breast cancer.

The coprimary endpoints were presurgery trastuzumab serum trough concentration (Ctrough) and pathologic complete response (pCR).

The geometric mean presurgery Ctrough was 51.8 μg/mL (coefficient of variation, 52.5%) in the IV group and 69.0 μg/mL (55.8%) in the SC group. The geometric mean ratio of Ctrough SC to Ctrough IV was 1.33 (90% CI, 1.24-1.44). Overall, 118 of 260 patients (45.4%) in the SC group and 107 (40.7%) of 263 patients in the IV group achieved a pCR. The two treatment groups had a similar incidence of grade 3 to 5 adverse events.

The authors said that in addition to improved convenience, SC trastuzumab leads to better compliance, a decrease in pharmacy preparation time, and optimization of medical resources.

They also emphasized that although pCR has been associated with long-term clinical benefit, pCR has not been validated as a surrogate endpoint for predicting clinical benefit. As such, study participants will be followed for at least 2 years, with the possibility of an extended follow-up being considered.

Nurse Perspective on Subcutaneous Trastuzumab

Mari Damhof, RN, BSN, OCN®Willmar Regional Cancer CenterWillmar, MN

This article discusses the promising outlook for subcutaneous (SC) trastuzumab in the HannaH trial. The trial, reported in Lancet Oncology, compared administration of a SC form of trastuzumab with the intravenous (IV) formulation.

The researchers found that both formulations had similar safety and efficacy profiles. The SC injections can be self-administered over 5 minutes by the patients in their own homes after demonstrating safe and correct injection technique. We can view this as positive progress, because it is less invasive for the patients, much more convenient, and certainly more efficient; however, compliance, follow-up care, and proper storage of the medication are always concerns when patients self-administer their medications. Variation in insurance reimbursement for self-administration of SC medications at home versus at a supervised office visit is another important consideration.

These issues need to be addressed with each patient to determine if self-administration will be effective or if more-guided care is needed with medication administration. Even if a patient has to come in every 3 weeks to the clinic for the SC trastuzumab injection, this option offers more convenience than the longer IV infusion

Everolimus Plus Tamoxifen Bests Tamoxifen Alone

in Hormone-Resistant Metastatic Breast Cancer

By Jill Stein

Combining tamoxifen with everolimus (Afinitor) increased the clinical benefit rate (CBR), time to progression (TTP), and overall survival versus tamoxifen alone in postmenopausal women with metastatic breast cancer (mBC) resistant to endocrine therapy, according to data from the phase II TAMRAD study (J Clin Oncol. 2012;30(22):2718-2724). The results also showed that the benefit of the combination treatment was especially pronounced in patients with secondary hormone resistance.

Thomas Bachelot, MD, PhD, director of the Breast Cancer Unit at the Centre Léon Bérard in Lyon, France, and associates randomized 111 postmenopausal women to a daily regimen of tamoxifen (20 mg) plus everolimus (10 mg), or tamoxifen alone (20 mg). Study participants had hormone receptor-positive, HER2-negative mBC that was resistant to aromatase inhibitors (AIs).

Because the biologic mechanisms that underlie primary and secondary hormone resistance may not be the same, subjects were stratified by primary and secondary resistance. Primary resistance was defined as relapse during or ≤6 months after completion of adjuvant AI treatment or progression in the metastatic setting ≤6 months following the start of AI treatment. Patients with secondary resistance had relapsed either >6 months after adjuvant AI therapy or after they had been responding to AI therapy in the metastatic setting for ≥6 months.

Hormone resistance in mBC is probably partially explained by “cross-talk” between signal transduction pathways, the researchers explained. The potent oral mTOR inhibitor everolimus has been shown to restore the sensitivity of endocrineresistant breast cancer cells to endocrine therapy, and has also shown anticancer activity in earlyphase mBC clinical studies.

The primary efficacy endpoint of the TAMRAD study was the 6-month CBR, defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. The 6-month CBR rates were 61% (95% CI, 47%-74%) in the tamoxifen-plus-everolimus group versus 42% (95% CI, 29%-56%) in patients receiving tamoxifen alone.

The median TTP was 8.6 months (95% CI, 5.9-13.9) and 4.5 months (95% CI, 3.6-8.7) in the combination arm and tamoxifen-alone group, respectively (exploratory P = .002), which corresponded to a 46% reduction in the risk of progression (hazard ratio [HR] = 0.54; 95% CI, 0.36-0.81).

The potent oral mTOR inhibitor everolimus has been shown to restore the sensitivity of endocrine-resistant breast cancer cells to endocrine therapy, and has also shown anticancer activity in earlyphase mBC clinical studies.

The analysis also revealed a 55% reduction in the risk of death associated with combination therapy (HR = 0.45; 95% CI, 0.24-0.81; exploratory P = .007).

Patients with secondary hormone resistance benefited more from combination therapy than patients with primary hormone resistance. In patients with secondary resistance, the CBR was 74% with tamoxifen plus everolimus and 48% with tamoxifen alone. The corresponding percentages were 46% and 36% in patients with primary resistance.

The toxicities associated with combination therapy were consistent with those previously reported for tamoxifen and everolimus and included primarily fatigue, stomatitis, rash, anorexia, and diarrhea. Most were of grade 1 or 2 severity and could be managed without the need to stop everolimus treatment.

Bachelot et al said their results suggest that the combination of tamoxifen and everolimus may reverse hormone resistance in postmenopausal women with mBC resistant to AIs. Many earlier studies targeting pathways that are believed to help promote AI resistance have been unable to show consistent efficacy in estrogen receptor-positive, HER-2 negative mBC.

Nurse Perspective on Everolimus Plus Tamoxifen

Janice Famorca Tran, RN, MS, AOCNP®, CBCN®, ANP-CTexas OncologyHouston, TX

Breast cancer is the most common cancer among American women and the second leading cause of cancer death, according to the American Cancer Society, which estimates that approximately 39,510 women will die from the disease this year.

The natural biology of hormone receptor-positive breast cancer is associated with late recurrences, with an annual rate of distant recurrence following adjuvant therapy of 1%-4% (J Clin Oncol. 2008;26(12):1948-1955). Most patients with metastatic disease ultimately develop resistance to anti-estrogen therapies. In anti-estrogen—esistant breast cancer, there is reciprocal cross-talk between estrogen receptor and other signal transduction pathways, including the P13K/mTOR pathway.

The results of the TAMRAD study provide promising results for the hormone-positive metastatic breast cancer population. This trial explored the use of everolimus in combination with tamoxifen, versus tamoxifen alone in patients with metastatic breast cancer previously treated with an aromatase inhibitor. The combination arm of everolimus and tamoxifen demonstrated a significantly prolonged median time to progression, 8.6 months versus 4.5 months with tamoxifen only. The addition of the mTOR inhibitor everolimus, however, is not without increased toxicity. Clinicians should have an understanding of toxicity management, including appropriate delays and dose reductions.

The data from the TAMRAD study support the evolving role of targeted therapies in the treatment of metastatic breast cancer. The addition of targeted agents such as everolimus has proven to be useful in overcoming resistance to antihormonal therapy. The positive results seen in BOLERO-2 and now TAMRAD provide new hope and promise for our breast cancer patients.

Supportive Care

Aprepitant Helps Prevent CINV

in Men With Germ Cell Tumors

By Jill Stein

The addition of aprepitant to standard antiemetic prophylaxis significantly improved the complete response (CR) rate in patients with germ cell tumors undergoing 5-day cisplatin combination chemotherapy regimens, according to the results of a phase III study (J Clin Oncol. doi:10.1200/JCO.2011.39.5558).

The data also showed that aprepitant, a potent and selective oral nonpeptide neurokinin-1 receptor antagonist (NK1-RA), is well tolerated and does not increase the frequency of adverse events.

Aprepitant and the corticosteroid dexamethasone are routinely given for the prevention of chemotherapy- induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy with single-day, cisplatin combination chemotherapy, Lawrence H. Einhorn, MD, Distinguished Professor of Medicine at Indiana University School of Medicine in Indianapolis, and colleagues observed. However, there are limited data on the use of this regimen in patients with germ cell tumors, which are responsible for 1% of cancers in American males.

Table. Drug Schedule

Treatment

Aprepitant (PO)

Placebo (PO)

Days 1-2

Dexamethasone

20 mg + 5HT3-RA

Dexamethasone

20 mg + 5HT3-RA

Day 3

Aprepitant 125 mg + 5HT3-RA

Placebo + 5HT3-RA

Days 4-5

Aprepitant 80 mg + 5HT3-RA

Placebo + 5HT3-RA

Days 6-7

Aprepitant 80 mg + dexamethasone 4 mg twice per day

Placebo + dexamethasone 8 mg twice per day

Day 8

Dexamethasone 4 mg twice per day

Dexamethasone 4 mg twice per day

5HT3-RA indicates 5-hydroxytryptamine-3 receptor antagonist; PO, orally.

Investigators with the Hoosier Oncology Group randomized patients who were receiving two identical courses of 5-day cisplatin-based chemotherapy to 125 mg of aprepitant on day 3 and 80 mg per day on days 4 through 7 or to placebo for their initial course. Patients then crossed over to the opposite treatment for their second course. Additionally, all patients received dexamethasone and a commercially available 5HT3 receptor antagonist (5HT3-RA; see Table for dosages). The researchers excluded palonosetron as a 5HT3-RA option because of its comparatively longer half-life than other 5HT3-RAs.

The primary endpoint was CR of both acute (days 1-5) and delayed (days 6-8) CINV, defined as no emetic episodes with no use of rescue medication.

Results in 60 patients who completed at least 5 days of both cycles showed a 42% overall CR rate with aprepitant, compared with 13% with placebo (P < .001). Eleven patients (16.2%) had at least one emetic episode during the aprepitant cycle versus 32 patients (47.1%) with placebo.

Thirty-eight patients (78%) reported that they preferred the aprepitant cycle while 11 patients (22%) cited a preference for placebo (P <.001).

The aprepitant and placebo arms had similar toxicity rates, but aprepitant-treated patients were less likely to need rescue antinausea medications.

Einhorn and associates noted that they used dexamethasone only on days 1 and 2 of the acute phase in order to reduce the adverse effects of corticosteroids. They suggest that the failure to use dexamethasone on all 5 days of the acute phase may be a study drawback, but emphasized that the optimal length of dexamethasone treatment has not been determined.

Future research, they wrote, should test the use of fosaprepitant in patients with germ cell tumors. Fosaprepitant is a water-soluble analog of aprepitant that is rapidly converted to aprepitant after intravenous injection.

The data showed that aprepitant, a potent and selective oral nonpeptide neurokinin-1 receptor antagonist (NK1-RA), is well tolerated and does not increase the frequency of adverse events.

Nurse Perspective on Aprepitant

Susan J. Keen, RN, OCN®Thoracic Nurse Navigator, Thomas Johns Cancer Hospital,CJW Medical CenterRichmond, VA

Cisplatin-based chemotherapy regimens are considered highly emetogenic treatment. In other words, patients receiving these drugs are likely to have nausea and vomiting. The treatment for germ cell tumors in males is one of these highly emetogenic regimens. In this study, patients did not receive aprepitant until day 3, and then continuing through day 7

The current criteria for using aprepitant with highly emetogenic chemotherapy is to take 125 mg on day 1 prior to chemotherapy, but with dexamethasone 12 mg and ondansetron 8 mg IV. Patients continue aprepitant 80 mg on days 2 through 4 with dexamethasone 8 mg. This regimen has proven to be very effective in controlling nausea and vomiting.

Although the study proved to be somewhat effective, better emetogenic control can be achieved by following the approved criteria for using aprepitant.

Hematologic Malignancies

Decitabine Outperforms Standard Treatments

in Older Patients With Acute Myeloid Leukemia

By Jill Stein

Decitabine produced a higher response rate than standard therapies in older patients with newly diagnosed acute myeloid leukemia (AML) without major differences in safety, according to the results of an open-label, phase III study (J Clin Oncol. 2012;30(21):2670-2677). The drug is an azanucleoside DNA methyltransferase inhibitor that is approved under the trade name Dacogen for patients with previously treated and untreated de novo and secondary myelodysplastic syndromes.

Hagop M. Kantarjian, MD, chairman of the Leukemia Department at the University of Texas MD Anderson Cancer Center in Houston, and associates elsewhere randomized 485 patients with AML 1:1 to receive 20 mg/m2 of decitabine per day as a 1-hour intravenous infusion for 5 consecutive days every 4 weeks or “treatment choice.” Individuals assigned to the treatment choice arm indicated, with advice from their physician, their preferred treatment: either supportive care intended to maximize their quality or life or 20 mg/m2 of cytarabine per day as a subcutaneous injection for 10 consecutive days every 4 weeks. Supportive care and low-dose cytarabine are the most common AML treatments.

Study participants were aged ≥65 years and had de novo or secondary AML with poor- or intermediate-risk cytogenetics. The primary endpoint was overall survival (OS).

At the study’s 2009 cutoff, there was a nonsignificant but favorable trend toward an increased median OS with decitabine (7.7 months; 95% CI, 6.2-9.2 months) compared with treatment choice (5.0 months; 95% CI, 4.3-6.3 months). The estimated hazard ratio for death was 0.85 (95% CI, 0.69-1.04).

Also at the 2009 cutoff, the complete remission (CR) rate plus the CR rate without platelet recovery (CRp) was significantly higher in the decitabine group versus the treatment-choice arm (17.8% vs 7.8%, respectively; P = .001).

These results give clinicians an opportunity to treat a particularly challenging population with chemotherapy that exhibits an acceptable toxicity profile.”

—Melissa Baker

An unplanned analysis based on mature data obtained at the 2010 cutoff showed that the OS difference favoring decitabine became significant (nominal P = .037).

Decitabine was well tolerated. The most common drug-related adverse events with decitabine were thrombocytopenia and neutropenia. Also, the incidence and severity of side effects that prompted withdrawal from treatment or death were similar between arms despite a longer treatment duration with decitabine.

The authors acknowledged that the study’s open-label design was a limitation. However, they explained that the open-label design was needed to compare the optimal regimen of intravenous decitabine with the conventional subcutaneous cytarabine regimen.

Acute myeloid leukemia is a common adult leukemia, with approximately 12,330 new cases diagnosed each year in the United States, the researchers wrote. While the disease is more common in elderly patients, treatment choices in this group are limited, especially in individuals with poor performance status and comorbidities. Several professional cancer societies recently added low-intensity cytarabine, 5-azacytidine, and decitabine to their AML treatment recommendations.

Nurse Perspective on Decitabine

Melissa Baker, RN, MSN, OCN®, APN-CAdult Blood & Marrow Stem Cell Transplantation ProgramJohn Theurer Cancer CenterHackensack, NJ

Results of this multicenter phase III trial indicated that decitabine achieved a higher response rate, with a possible survival advantage, compared with low-dose cytarabine or supportive care in this difficult-to-treat, older population with AML.

These results give clinicians an opportunity to treat a particularly challenging population with chemotherapy that exhibits an acceptable toxicity profile. Although the data on overall survival are vague, it is comparable to what can be achieved with “treatment choice” options.These results give clinicians an opportunity to treat a particularly challenging population with chemotherapy that exhibits an acceptable toxicity profile. Although the data on overall survival are vague, it is comparable to what can be achieved with “treatment choice” options.

Treatment options for older patients with leukemia continue to expand, providing effective forms of therapy while at the same time decreasing their side effects. Oncology nurses are vigilant advocates not only for quantity, but also for quality of life. As treatment options continue to grow, oncology nurses will be challenged to understand and translate this knowledge into practice to improve patient care.

Nurses play an integral role in patient education. Tailoring the information according to individual needs will enhance recall and ultimately improve patient outcomes such as satisfaction, compliance, and coping mechanisms.

Older adults with cancer often experience different physical and psychosocial needs than younger patients with cancer. Nurses need to be aware of the needs and implications related to the care of older adults receiving chemotherapy. Focusing on strategies for managing symptoms and treatment side effects, in addition to addressing polypharmacy, comorbidities, transportation, and social obstacles in this population, is of paramount importance.

Colorectal Cancer

Adjuvant Chemotherapy May Offer Survival Benefit

in Older Patients With Colon Cancer

By Jill Stein

Patients 75 years of age or older with stage III colon cancer may expect a survival benefit from adjuvant chemotherapy that rivals that previously reported in younger patients, according to a recent study (J Clin Oncol. 2012;30 (21):2624-2634).

“From the perspective of a practicing clinician, these results suggest that consideration of adjuvant systemic therapy is absolutely warranted for patients older than 75,” Hanna K. Sanoff, MD, assistant professor in the Division of Hematology and Oncology at the Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, and her coauthors wrote.

The researchers evaluated the effectiveness of any adjuvant chemotherapy for patients aged ≥75 years with stage III colon cancer using information from four data sets: the SEER cancer registry linked to Medicare claims (SEER-Medicare), the New York State Cancer Registry linked to Medicare claims, the NCCN Outcomes Database, and the Cancer Care Outcomes Research & Surveillance Consortium.

Overall, 5489 patients with resected stage III colon cancer who were diagnosed between 2004 and 2007 were included in the analysis.

While individuals aged ≥75 years account for 40% of the colorectal cancer population in the United States, and about 50% of colorectal cancer deaths, they are underrepresented in clinical studies of colorectal cancer chemotherapy, Sanoff et al noted. As a result, there are limited efficacy data for this group of patients, which means that their oncologists have no “clear standards to guide treatment decisions.”

The present study, which was undertaken to examine actual practice patterns and outcomes, found that the use of adjuvant therapy was inversely associated with increasing age and greater comorbidity.

Chemotherapy receipt was associated with a survival benefit across the four cohorts. The significant 40% reduction in mortality risk associated with chemotherapy use in the SEER-Medicare cohort (hazard ratio = 0.60; 95% CI, 0.53- 0.68) is comparable to the survival benefit found in clinical trials.

Hopefully, with data from studies like this one, we will see a shift in attitudes toward treating the elderly with chemotherapy.”

—Laura Metcalfe

Sanoff et al also examined whether the addition of oxaliplatin provided additional survival benefit. Oxaliplatin has been shown to increase cure rates for resectable stage III cancer in clinical trials, but very few patients in the pivotal trials were 75 years of age or older, which means that the benefit shown in those studies had not been documented in the older population.

The researchers’ analysis found, however, that oxaliplatin offered no more than a small incremental benefit.

The authors emphasized that their study was not able to measure quality of life; thus, the effect of adjuvant therapy on quality of life in older patients with cancer remains an important unknown.

Nurse Perspective on Adjuvant Chemotherapy

Laura Metcalfe, MSN, RN, APN, C, AOCNS®John Theurer Cancer CenterHackensack, New Jersey

Having read the results of this study, I will say that while I am gratified that this area is being researched, I am not at all surprised by the results. The American Cancer Society reports that the median age at which colon cancer is diagnosed is 71 (www.aicr.org). Traditionally, age 65 has been used as the cutoff for defining the elderly. However, it has long been recognized that it is important to differentiate between chronologic and biologic age when assessing a patient’s ability to tolerate chemotherapy (www.cancernetwork.com).

I am sure we all know an octogenarian—or even a nonagenarian—with a better performance status than some 50-year-olds! Despite this, I have observed a lot of bias toward not treating the elderly with chemotherapy, and have encountered an attitude from patients and their families who feel that either the patient has already lived a long life and “we all have to die from something” or that the patient is “too old” or “too frail” to handle chemotherapy. Sadly, I also frequently encounter this attitude in other healthcare professionals.

When assessing a patient’s ability to tolerate chemotherapy, many factors are taken into consideration. Performance status and comorbidities are looked at in all patients, not only the elderly. Dosages may or may not need to be attenuated in any patient based on this assessment. The elderly are no exception to this, nor are they the rule. As with any patient, the physician must have a frank discussion with elderly patients that includes the benefits and risks of chemotherapy in their specific situation. All patients should be given the opportunity to make an informed decision about what offers them the best opportunity of improving their chances of survival when faced with a colon cancer diagnosis.

In my own practice I have found that the elderly generally tolerate chemotherapy very well. Hopefully, with data from studies like this one, we will see a shift in attitudes toward treating the elderly with chemotherapy.

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