Clinical Insights: May, 2013

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-may-2013.
  • 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

Neoadjuvant Regimen May Not Require Chemotherapy in Some HER2-Positive Breast Cancer Patients

By Lauren M. Green

Some HER2-positive breast cancer patients may be able to receive targeted neoadjuvant therapy with lapatinib and trastuzumab without chemotherapy, according to findings of a study by the Translational Breast Cancer Research Consortium (TBCRC) published online April 8, 2013 in the Journal of Clinical Oncology (doi:10.1200/JCO.2012.44.8027).

In this phase II, single-arm, multicenter study, 64 HER2-positive women with invasive stage IIIII disease received a nonchemotherapy regimen of trastuzumab (4 mg/kg loading dose, followed by 2 mg/kg once weekly) and lapatinib (1000 mg once daily) over 12 weeks. Patients with estrogenreceptor (ER)— or progesterone-receptor (PR)– positive tumors also received one daily dose of letrozole (2.5 mg).

Tumors were biopsied on four occasions: baseline, weeks 2 and 8, and at the end of study treatment. The pathologic complete response (pCR) rate was determined by whether all invasive tumor had disappeared from the breast (ypT0-is), the most common definition employed in other neoadjuvant studies, according to the researchers. The other study goal was the pathologic response rate, defined by investigators as pCR plus residual invasive disease of ≤1 cm (ypT1a-b) at the time of surgery.

The nonchemotherapy regimen achieved a pCR of 27%; pCR in the ER-positive and ER-negative subsets was 21% and 36%, respectively. The researchers noted that even when using a stricter definition of pCR (no residual invasive cancer in the breast or axilla [ypT0-is; ypN0]), the pCR was 22%. The overall pathologic response rate was 49%; in ER-positive and ER-negative patients, it was 54% and 40%, respectively.

Disease progressed in just two patients—each with ER- and PR-negative tumors—during the treatment period, and the regimen was generally well tolerated, with 6% of patients discontinuing treatment due to adverse events. Diarrhea (grades 1-2) was the most common toxicity, reported in 63% of patients, followed by skin rash (grades 1-2) in 55% of participants. Other events included fatigue (32%) and nausea (31%).

Mothaffar F. Rimawi, MD, of Baylor College of Medicine, Houston, Texas, the lead study site, and colleagues noted that achieving this rate of pCR with targeted therapy but without chemotherapy suggests a subset of patients with HER2-positive breast cancer may exist who do not need chemotherapy. The biomarkers needed to identify this subset are currently being studied in tumor samples from this trial.

Nurse Perspective on Neoadjuvant Treatment

A. Nicole Spray, APRNHays Med Breast Care CenterHays, KS

Phase II research suggesting a neoadjuvant regimen that may not require chemotherapy in some HER2-positive breast cancer patients is very interesting and thought-provoking.

A subset of HER2-positive patients may have excellent neoadjuvant outcomes with the administration of trastuzumab and lapatinib, and the addition of letrozole in estrogen/progesterone-positive cancer. This would spare some patients the toxic side effects of chemotherapy that make cancer treatment difficult and complicated.

Certainly, this research is hypothesis-provoking, and additional research will need to be conducted comparing this particular regimen to current standard regimens that include chemotherapy. Additionally, research is needed to determine biomarkers to accurately identify this subset of patients who are eligible for this treatment option. Protocols for monitoring of progress and primary endpoints with this targeted neoadjuvant therapy will need to be determined as well.

Radiotherapy Increases Risk of Heart Disease in Some Women With Breast Cancer

By Ben Leach

While radiotherapy can be an effective treatment for early-stage breast cancer, incidental irradiation of the heart during treatment may increase the risk of developing ischemic heart disease, according to a recent study (N Engl J Med. 2013;368(11):987-998). The researchers explained that the risk is small for most women, however, and that their study should actually help physicians identify patients for whom radiotherapy is most appropriate.

“We carried out this work because doctors could not reliably estimate the risk of heart disease in women treated with radiotherapy for breast cancer. Doctors can now estimate the risk and know that in most cases it will be very small, so that they can reassure their patients. In addition, the few women for whom radiotherapy poses undue risk can now be identified, so that alternative techniques can be considered,” said lead author Sarah Darby, PhD, University of Oxford, in a statement.

Darby and colleagues’ population-based analysis looked at major coronary events (defined as myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women in Sweden and Denmark who received radiotherapy for breast cancer between 1958 and 2001. Of those women, 963 had experienced major coronary events, whereas the other 1205 served as controls. The researchers estimated the mean radiation doses to the whole heart and to the left anterior descending coronary artery from information on the patient’s radiotherapy chart.

The researchers found that the overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03-27.72), with mean doses of 6.6 Gy for women with tumors in the left breast and 2.9 Gy for tumors in the right breast. They noted that exposure at 1 Gy is enough to raise the risk of ischemic heart disease.

In the study, the rate of major coronary events increased by 7.4% for each increase of 1 Gy of radiation that the heart received (95% CI, 2.9-14.5; P <.001). When the authors grouped women based on whether the mean radiation dose to the heart was less than 2 Gy, 2 to 4 Gy, 5 to 9 Gy, or ≥10 Gy, the percentage increases of major coronary events compared with the estimated rate if the dose of radiation had been 0 were 10%, 30%, 40%, and 116%, respectively.

According to the researchers, no significant difference was observed in the percentage increase per Gy when accounting for matching factors used in the selection of controls, tumor characteristics, or cancer treatments that were given in addition to radiotherapy. A higher rate of major coronary events was observed in women with cardiac risk factors compared with those who did not have such risk factors, but the percentage rate increase in the rate of major coronary events per Gy was similar for women with or without those risk factors at the time they were diagnosed with breast cancer.

The authors noted that a limitation of the study was the fact that individual computed tomography (CT)-based information on radiotherapy was not available for the women studied because they were treated prior to when three-dimensional CT-based planning was being implemented for radiotherapy. However, using data from CT-based planning scans, they found that the patient-to-patient variation in mean radiation dose to the heart was minimal.

In an accompanying editorial (N Engl J Med. 2013;368(11):1055-1056), Javid Moslehi, MD, co-director of the Cardio-Oncology Program at Brigham & Women’s Hospital and instructor in the Department of Medicine at Harvard Medical School/Dana- Farber Cancer Institute, wrote that this study may represent “just the tip of the iceberg” in the link between cardiac issues and radiotherapy, since radiation therapy has been associated with other cardiac conditions that were not included in this study, including pericardial disease, peripheral vascular disease, cardiomyopathy, valvular dysfunction, and arrhythmias.

“Given the widespread use of radiation therapy in the treatment of breast cancer, and the continually expanding arsenal of novel therapies, the current study calls for greater collaboration between oncologists and cardiologists,” Moslehi wrote. “An important lesson for the oncologist may be that the time to address concerns about cardiovascular ‘survivorship’ is at the time of cancer diagnosis and before treatment rather than after completion of therapy.”

Nurse Perspective on Radiotherapy

Marieta Branis, APN, NP-CJohn Theurer Cancer CenterHackensack, NJ

Currently, radiation therapy is an essential treatment modality used in conjunction with surgery, chemotherapy, and/or hormonal therapy for various types and stages of breast cancers. Women receiving radiotherapy treatments to the chest wall often inquire about the long-term effects of such treatments on the cardiac system.

Until now, there was little evidence that estimated the patient’s increased risk for cardiac disease as a result of the radiation therapy. The study conducted by Darby et al has quantified the risk of heart disease for those breast cancer patients treated with radiation and provides significant information for clinicians treating breast cancer, who now have the ability to predict the risk of heart disease for each woman treated with radiotherapy.

The findings of the study outlined that, indeed, there is a risk for heart disease in women treated with radiation, especially those women that received radiation to the left chest wall area. Furthermore, the study identifies that the risk is small, and it can be calculated based on the amount of radiation that is delivered to the patient, as well as the patient’s preexisting cardiac conditions.

This is reassuring evidence for those concerned about long-term effects of radiation therapy and the quality of life of breast cancer survivors. In addition, the data presented in this study will help practitioners identify those patients who have an increased risk for developing heart disease as a result of radiation therapy. This is good news, since now we have a great tool to use prior to initiation of radiation therapy, and the possibility to avoid potentially harmful long-lasting side effects.

Prostate Cancer

Digital Rectal Exam Remains a Critical Component of Prostate Cancer Screening

By Ben Leach

A recent study has found that, while not 100% accurate, digital rectal examination (DRE) should remain a standard for screening for prostate cancer and may even be able to identify cases of the disease that are not picked up by the prostate-specific antigen (PSA) test (Can J Urol. 2012;19(6):6542-6547).

The PSA and DRE have been mainstays in screening for the disease, and an abnormal DRE or an elevated PSA test may indicate that a prostate needle biopsy (PNB) is required to diagnose the disease. Though previous research has shown that PSA tests are more accurate when predicting the result of a PNB when compared with DRE, no previous study has explored the effectiveness of the DRE compared with PSA when adjusted for age.

In this study, the researchers reviewed the medical charts of 806 men who received an ultrasound- guided PNB between September 2001 and December 2008. Serum PSA levels were considered normal if they fell into specific thresholds based on age (<50 years, PSA <2.5 ng/mL; 51-60 years, PSA <3.5 ng/mL; 61-70 years, PSA <4.5 ng/mL; and >70 years, PSA <6.5 ng/mL). A DRE was categorized as “normal” if the prostate was considered to be smooth, age-appropriate, benignly asymmetric, or uniformly enlarged.

Of the 806 men in the cohort, 516 (64%) had a normal DRE, with the remaining 290 (36%) identified as having an abnormal DRE. Among the entire cohort, 306 men (38%) were diagnosed with prostate cancer, and of those, 136 men (44%) had an abnormal DRE. Of the 136 men with an abnormal DRE and a prostate cancer diagnosis, 43 (31%) had a normal age-specific PSA value according to the thresholds. The authors of the study found no differences in the cancer detection rates when they stratified by the type of abnormality identified with a DRE.

“It is important to acknowledge that age-specific PSA cutoffs contribute some limitations in prostate cancer screening,” said study author Jay D. Raman, MD, associate professor of Surgery in the division of Urology at Penn State Milton S. Hershey Medical Center in Hershey, Pennsylvania “In particular, while age-specific thresholds increase the sensitivity in younger men, these same cutoff values lower the sensitivity in older men.”

The authors concluded that, based on the cohort of patients in this study, an abnormal DRE had a sensitivity of 44%, a specificity of 68%, a positive predictive value of 46%, and a negative predictive value of 67% for detecting prostate cancer on biopsy.

The authors acknowledged that the study had several limitations. In addition to the fact that it is a retrospective analysis, inter-observer variability was possible because the DRE status was evaluated by one of five urologists, and the results were limited to one academic medical center, making it unclear as to whether these conclusions are indicative of a larger cohort of similar patients. However, the authors concluded that DRE remains an important part of prostate cancer screening.

“Our study confirms that the digital rectal exam remains an important part of screening such patients because 31% of cancers in our study would have been missed by using age-specific PSA cutoffs alone,” Raman said.

Genetic Basis for Poor Prognosis in Prostate Cancer Identified

By Bem Leach

While many patients diagnosed with prostate cancer are cured with radical primary treatment or can simply be monitored to see if their disease progresses, other patients die from the disease, with family history playing a significant role. A new study suggests that germline mutations of BRCA1/2—mutations closely associated with the progression of breast cancer—could play a significant role in more-aggressive cases of the disease. (J Clin Oncol. doi:10.1200/ JCO.2012.43.1882).

Excluding advanced age, family history of prostate cancer is the strongest risk factor for the disease. Genome-wide association studies have identified more than 70 DNA sequences associated with a risk of developing prostate cancer. Previous research has found that BRCA1 and BRCA2 mutations are relatively rare in prostate cancer, occurring in only 0.44% and 1.2% of cases, respectively. However, that still amounts to thousands of patients around the world, since more than 900,000 new cases of prostate cancer are diagnosed worldwide annually, and research has suggested an association between BRCA2 mutations with a more aggressive tumor phenotype and poor overall survival (OS).

In this retrospective analysis, patients from two ongoing prospective studies, the United Kingdom Genetic Prostate Cancer study (UKGPCS) and Epidemiological Study of BRCA1/2 Mutation Carriers (EMBRACE), were analyzed. A total of 2019 patients were eligible, which included 18 BRCA1 mutation carriers, 61 BRCA2 mutation carriers, and 1940 noncarriers. Researchers evaluated the association between BRCA1/2 status and OS, cause-specific overall survival (CSS), CSS in localized prostate cancer metastasis- free survival (MFS), and CSS from metastasis.

The researchers found that prostate cancer with germline BRCA1/2 mutations were more frequently associated with a Gleason score ≥8, T3/T4 stage, nodal involvement, and metastases at diagnosis than prostate cancer in patients who did not exhibit those mutations. Additionally, the CSS was longer in noncarriers than in carriers (15.7 years vs 8.6 years). Patients with localized prostate cancer had significantly higher 5-year CSS and MFS if they were noncarriers compared with carriers (96% vs 82 and 93% vs 77%, respectively).

“These data turn the BRCA2 gene into the first genetic factor for prostate cancer prognosis,” Elena Castro, MD, a member of the Prostate Cancer and Genitourinary Tumours Clinical Research Unit at the Spanish National Cancer Research Centre, said in a statement. “The results of this study suggest the need for a paradigm shift in the clinical management of patients with prostate cancer who are carriers of mutations in the BRCA genes; current treatment standards for these patients appear to be insufficient and there are no specific action guidelines.”

Lung Cancer

Study Confirms Low Testosterone Levels Prevalent in Lung Cancer Patients Taking Crizotinib

By Ben Leach

A new study has confirmed that low testosterone is a side effect experienced by a large proportion of patients taking crizotinib for the treatment of anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC)—in this case, 84% of patients from a multinational sample—and that this low testosterone is associated with other side effects such as sexual dysfunction or depression. (Cancer. 2013. doi:10.1002/cncr.28089). Additionally, researchers found that hormone replacement therapy is an effective method of managing these side effects.

Crizotinib inhibits several different tyrosine kinases associated with the development of NSCLC, including ALK. When the FDA approved crizotinib for the treatment of patients with locally advanced or metastatic NSCLC, a companion diagnostic used to identify which patients have an ALK rearrangement was also approved. In clinical trials, patients experienced an improved overall response rate. Side effects reported in the clinical trials included gastrointestinal disturbance, visual side effects, peripheral edema, and liver function test abnormalities.

“With advances in targeted therapies and in the biomarkers we can use to select who to best give these new treatments to, we’re starting to see drugs being approved more quickly and based on the results from far smaller numbers of patients than ever before,” said D. Ross Camidge, MD, PhD, investigator at the University of Colorado Cancer Center, director of the Thoracic Oncology Clinical Program at University of Colorado Hospital, and lead author of this new study, in a statement. “That’s great: it helps streamline the path of these drugs into clinics where they can benefit patients who desperately need them. However, it also puts the onus on clinicians who then start using these drugs in day-to-day practice to recognize either subtle or later onset side effects that may have been missed during the initial testing.”

In a previous study, researchers found that patients taking crizotinib had a total testosterone that was below the lower limit of normal. In those patients, the levels of testosterone returned to normal after the drug was stopped. Researchers sought to determine the etiology of the effect of low testosterone, its symptomatic significance, and the effectiveness of testosterone replacement to manage these symptoms.

In this study, three groups of patients were analyzed. These groups included 32 crizotinib-treated patients assessed at the University of Colorado Cancer Center and other sites, 19 patients from the previous study assessed at the University of Colorado Cancer Center, and 19 patients with metastatic NSCLC who never received crizotinib to serve as a control population.

The researchers found that the mean total testosterone levels were -25% below the lower limit of normal in 32 crizotinib-treated patients, with a total of 27 of 32 patients (84%) falling below that level compared with +29% above the lower limit of normal in patients who were not treated with crizotinib.

Additionally, levels of albumin and sex hormonebinding globulin, two proteins that bind to testosterone and are able to store the hormone, experienced a rapid decline when patients were treated with crizotinib, as did levels of folliclestimulating hormone, luteinizing hormone, and free testosterone. The researchers said these findings suggest that crizotinib affects the body’s ability to both store and produce the hormone.

In nine patients who were assessed for the benefits of testosterone replacement, five of those patients (55%) reported improvement in symptoms of hypogonadism between 2 and 3 months after beginning treatment with hormone replacement therapy. All five patients who had testosterone replacement and whose hormone levels were raised above the lower limit of normal reported improved symptoms.

Camidge said that this knowledge of the link between crizotinib use and testosterone levels will allow clinicians to have more open conversations about these symptoms and discussions on how to manage them.

“With each breakthrough we’re really trying to put people with advanced cancer back in control of their own lives,” said Camidge. “The more we can make these highly effective new treatments tolerable, the closer we are to achieving that goal.”

Nurse Perspective on Crizotinib

Susan J. Keen, RN, OCNThoracic Nurse NavigatorThomas Johns Cancer HospitalCJW Medical CenterRichmond, VA

In the last decade, there have been amazing developments in lung cancer treatment. When drugs are developed and research begins, we do not always find all of the side effects of the drugs, such as crizotinib.

Anaplastic lymphoma kinase (ALK)—positive lung cancer comprises a small percentage of adenocarcinoma lung cancer patients. With the research focusing on the genetic components of the cells, we are seeing that there are more than just the two lung cancer types, non-small cell and small cell. This new research allows treatments to be more successful for the target patient population.

We can find more side effects when we actually put more patients on the new treatments. Physicians now can be more in tune with how to treat low testosterone levels in the patient receiving crizotinib. It is important when we are treating patients that we ask about their sexual life also. If patients are having problems, this can cause a significant burden on top of already having cancer. If clinicians better understand the side effects of a particular treatment, then they can better manage the side effects so that patients will adhere to their therapies.

Ovarian Cancer

Intraperitoneal Chemotherapy May Be Better Option for Patients With Low Levels of BRCA1

By Lauren M. Green

Patients with epithelial ovarian cancer (EOC) and low levels of the BRCA1 protein had significantly improved overall survival (OS) when their platinum-based chemotherapy was delivered abdominally by injection, according to findings of a Gynecologic Oncology Group (GOG) study (Br J Cancer. 2013;108(6):1231-1237).

GOG-172 was a multi-institutional, randomized, phase III trial of intravenous (IV) versus intraperitoneal (IP) chemotherapy in patients with EOC or primary peritoneal cancer (PPC). No test is currently available to determine which patients may benefit from the more aggressive IP regimens, though a number of phase III trials have shown a survival advantage when this route is used for patients with advanced EOC.

For this analysis, archival tissues were analyzed from 393 patients with stage III EOC or PPC, representing 95% of the clinical trial’s participants. BRCA1 expression in the tumor samples was assessed using immunohistochemistry (IHC). Fortyeight percent of the samples (n = 189) had aberrant (low or absent) BRCA1 expression, and 52% had normal expression (n = 204).

OS was similar between the two groups when route of administration was not factored in. However, when the treatment regimen was taken into account, researchers found a statistically significant correlation between tumor expression of BRCA1 and route of administration, most notable in the aberrant group, which had the best results when receiving IP chemotherapy.

Patients with aberrant BRCA1 expression receiving IP chemotherapy had a median OS of 84 months, versus 48 months (P = .0002) in those with aberrant expression who received their chemotherapy intravenously, representing a 3-year survival advantage. For patients with normal BRCA1 expression receiving IP or IV chemotherapy, median OS was 58 months and 50 months, respectively (P = .818). Median progression-free survival was 35 months in the aberrant BRCA1/IP group, compared with <20 months in the other three subgroups.

The researchers noted that the prognostic value of aberrant BRCA1 expression was independent of other factors, such as the patient’s age, microscopic versus gross residual disease, and histologic subtype.

“Our findings suggest that IHC assessment of BRCA1 expression should be prospectively studied as a guide for the decision to use chemotherapy,” said the study’s lead author, Jamie Lesnock, MD, and coauthors. Lesnock is with the Division of Gynecology Oncologic at the Magee-Women’s Hospital at the University of Pittsburgh Medical Center in Pennsylvania. “The significant survival advantage in patients with aberrant BRCA1 expression treated with IP chemotherapy suggests that we can make a substantial improvement in this specific group of patients.”

If the study results are confirmed, another potential advantage would be that patients with normal BRCA1 expression could be spared the more severe side effects associated with IP therapy, the researchers noted.

The National Cancer Institute estimates that 22,240 new cases of EOC will be diagnosed in 2013, and that 14,030 women will die of the disease.

Colorectal Cancer

Cetuximab Increases Resection of Liver Metastases With Curative Intent

By Lauren M. Green

The addition of cetuximab to chemotherapy as first-line treatment of KRAS wild-type unresectable colorectal liver metastases resulted in a higher rate of metastasectomy and longer survival than chemotherapy alone, according to findings of a study from researchers in the People’s Republic of China published online April 8, 2013, in the Journal of Clinical Oncology.

Overall survival (OS) in patients with colorectal liver metastases (CLMs) is significantly improved in patients whose tumors are completely removed; however, fewer than 20% of patients with CLMs are considered candidates for the surgery. Even with administration of neoadjuvant systemic (“downsizing”) chemotherapy, the rate of liver resection in these patients has been low.

For this phase III trial, conducted by researchers at Zhongshan Hospital, Fudan University, Shanghai, 116 patients with histologically confirmed wild-type KRAS colorectal adenocarcinoma whose primary tumors had been resected—but whose secondary liver metastases were determined unresectable by a multidisciplinary team—were deemed evaluable for study.

Patients were randomly assigned to receive either FOLFIRI (fluorouracil, leucovorin, and irinotecan) or mFOLFOX6 (modified fluorouracil, leucovorin, and oxaliplatin) plus cetuximab (n = 59) or one of the two chemotherapy regimens alone (n = 57).

Treatment began between 2 and 4 weeks after primary surgery and continued until the patient was considered a candidate for liver metastases (LM) resection, based on tumor response, or until treatment was discontinued due to disease progression or toxicity. The median number of treatment cycles prior to surgery was six.

In the cetuximab arm, 20 patients were considered eligible for radical LM surgery, versus nine patients in the chemotherapy-only group. After attrition due to refusal of surgery or inability to resect at exploration, 18 patients in the cetuximab group and five in the chemotherapy-alone cohort had surgical resection of their CLM, a significant difference (odds ratio, 4.37; P <.01).

Three-year OS among patients in the cetuximab group versus the chemotherapy-only group was 41% and 18%, respectively, with a median survival time of 30.9 months versus 21 months. Objective response was also better in the cetuximab arm, 57.1% versus 29.4% in the chemotherapy-alone group.

Toxicity was observed to be mild in the two arms. A higher incidence of a reversible, acne-like rash was seen in the cetuximab-containing arm; patients experiencing grade 2 and 3 skin reactions showed greater treatment benefit than those with 0-1 skin reactions. No significant differences in grades 3 and 4 adverse events were found between the two groups.

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