Cicchelli L, McLeod D: Lived experiences of nurses as family caregivers in advanced cancer. 

Epstein AS, Morrison RS: Palliative oncology: Identity, progress, and the path ahead. 

Ferriolli E, Skipworth R, Hendry P, et al: Physical activity monitoring: A responsive and meaningful patient-centered outcome for surgery, chemotherapy or radiotherapy? 

Fitch MI, Howell D, McLeod D: Screening for distress: Responding is a critical function for oncology nurses. 

Flynn KE, Reese J, Jeffery DD, et al: Patient experiences with communication about sex during and after treatment for cancer. 

Foust J, Vuckovic N, Henriquez E: Hospital to home health care transition: Patient, caregiver, and clinician perspectives. 

Griffiths P, Richardson A, Blackwell R: Outcomes sensitive to nursing service quality in ambulatory cancer chemotherapy: Systematic scoping review. 

Hawbaker S: Venous thromboembolism in the cancer population: Pathology, risk and prevention. J 

Karvinen K, McGourty S, Parent T, et al: Physical activity promotion among oncology nurses. 

Loprinzi P, Cardinal B, Winters-Stone K, et al: Physical activity and risk of breast cancer recurrence: A literature review. 

Mazor KM, Roblin DW, Greene SM, et al: Toward patientcentered cancer care: Patient perceptions of problematic events, impact and response. 

McLaughlin L, Mahon S: Understanding taste dysfunction in patients with cancer. 

Papastavrou E, Charalambous A, Tsangari H, et al: The burdensome and depressive experience of caring: What cancer, schizophrenia and Alzheimer’s disease have in common. 

Articles

News of Note

Lung cancer remains the leading cause of cancer death in the United States, with only 16% of patients living 5 years or more after they are diagnosed. Non–small-cell lung cancer (NSCLC) accounts for the majority of cases, with most of those cases being diagnosed in advanced stages.[1] Encouragingly, the overall treatment of NSCLC has undergone many changes in the last few years. While NSCLC remains a disease that is difficult to treat, advances are being made. From early-stage to advanced NSCLC, clinical trials in recent years have introduced treatment options that are having an impact on patient survival outcomes.

While treatment with chemotherapy for advanced NSCLC has long been accepted as the standard of care, use of chemotherapy in the neoadjuvant, adjuvant, and combined-modality settings for earlier-stage NSCLC has also proven to enhance survival. Clinical trials have provided survival data in both the neoadjuvant and adjuvant settings for patients with stages I to IIIA disease. This means that nurses are administering chemotherapy to more patients with earlier-stage NSCLC than ever before.

In 2003 and 2004, the age of molecularly targeted therapy in the treatment of advanced or recurrent lung cancer became a reality as agents such as gefitinib (Iressa) and erlotinib (Tarceva), both oral tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR), were approved for use in advanced NSCLC in the second-line/third-line monotherapy settings. Based on the ever-expanding scientific knowledge about tumor biomarkers and genotypes, the most efficacious use of molecularly targeted agents in NSCLC continues to evolve. Clinical trial data now support the recommendation for use of erlotinib as monotherapy in the first-line setting for patients with NSCLC who have known 

 mutations.[2] Crizotinib (Xalkori), a different molecularly targeted kinase inhibitor, was approved by the US Food and Drug Administration (FDA) in the spring of 2012 as monotherapy for patients who have advanced NSCLC and are anaplastic lymphoma kinase (ALK)-positive.[2]

Historically, triplet chemotherapy regimens did not prove to increase survival in advanced NSCLC, and the ceiling of doublet chemotherapy effectiveness seemed to have been reached. However, in 2006 the FDA approved bevacizumab  (Avastin), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), to be combined with paclitaxel and carboplatin for treatment of advanced NSCLC. The decision was based on an increase in overall survival data and showed that adding a third therapy (specifically a molecularly targeted therapy) to cytotoxic chemotherapy could prove efficacious in advanced NSCLC (excluding squamous cell histology, due to increased bleeding events in that population).[3] With the addition of molecularly targeted drugs to the armamentarium of cytotoxic chemotherapy treatments, we began to see an impact on overall survival. Expanding treatment options such as using switch or continuance-maintenance therapy with either cytotoxic chemotherapy or molecularly targeted therapy may also improve outcomes for certain patients with advanced NSCLC.

In the arena of advanced NSCLC, treatment options continue to evolve as methods of individualizing and personalizing systemic treatments are discovered. There is no longer a “one treatment fits all” approach in advanced NSCLC. As our physicians and scientists learn more about how to apply the individual characteristics of a patient’s tumor to the drugs we have available and those we are studying in clinical trials, we hope that the advances will continue to make a broader impact on patient survival.

The article by Elizabeth Waxman provides a clinically relevant and timely update as the treatment paradigm for NSCLC continues to evolve. Presenting the latest clinical trial data for systemic treatment of NSCLC from stage I to stage IV disease, Ms. Waxman discusses how the pertinent data are translated into treatment options. An overview is provided to show how personalized treatment decisions are made for patients with advanced NSCLC based on histology, mutation analysis, biomarkers, and individualized factors such as performance status. Additionally, she discusses the relatively new concepts of switch and continuance-maintenance therapy. This excellent overview article succinctly brings nurses up to date with the latest data related to the treatment of NSCLC.

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article

1. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. 

2. National Comprehensive Cancer Network (2012): NCCN Clinical Practice Guidelines in Oncology: NonâSmall-Cell Lung Cancer [v2.2012]. Available at 

http://www.nccn.org/professionals/physician_gls/pdf/nscl/pdf

3. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. 

Lung cancer remains the leading cause of cancer death in the United States, with only 16% of patients living 5 years or more after they are diagnosed.

Evolving and Expanding Treatment Options in NSCLC

Math, and everything associated with it, has always been my downfall. I’m not good at it and get easily frustrated by my inability to capture the abstract meaning of numbers. I need to put a label, a face, to numbers’ representation, and I struggle with my difficulty in doing this. But somehow, cancer statistics do not overwhelm me as much as other calculations do. I think this is because I can imagine a human being connected to the rising incidences and changing trends within my chosen specialty. Cases in point...

One in four deaths in the US is due to cancer.

[1] Sitting in my pew at church, I look across and ponder...of the 20 of us sitting here, 5 will die of cancer.

•  Avoiding tobacco use and maintaining a healthy body weight are important prevention measures for cancer of the pancreas.

[2] Look at the nurses attending the ONS Congress who go outside to smoke during breaks, and/or who are morbidly obese. Do they realize the personal health risk they are taking with their behaviors, or is the need to make lifestyle changes only considered with respect to  their patients?

• Little is known about cancer survival among Hispanics, particularly how it varies by subgroup

 (ie, Mexicans, Puerto Ricans, Cubans, Central Americans).[3] How do we consider these subgroups in our communities? Do we ignore the individual risk and cultural factors and ethnic implications and just lump everyone together whose first language is Spanish? As a student and increasing appreciator of the multicultural mosaic of the American landscape, I must also anticipate a different paradigm of cancer care in the immediate future. As we become a global composite of peoples, we must appreciate the risks and implications of being a globally sensitive provider of oncology nursing care. Think in terms of these pressing realities[4]:

•  More than 70% of new cases of, and deaths from, gastric malignancies occur in developing countries.

 Do you live in an area where there are immigrants from Eastern Asia, Eastern Europe, and South America?

•  Half of all cases of, and deaths from, primary liver cancer occur in China.

 What proportion of your patient caseload is represented by immigrants from China?

•  India, the most populous country in the world, accounts for nearly one-third of total cervical cancer deaths.

 What is the predominance of Indian women in your community?

•  The highest rate of oral cavity cancers is found in Melanesia, South-Central Asia, and Central and Eastern Europe, and the incidence has continued to rise in Eastern European Countries such as Hungary and Slovakia.

 What is your patient representation like from these countries of origin? As we acknowledge the need to individually tailor our nursing care, we must consider risk, culture, and the possibility of prevention in our critical thinking. This will be a pressing imperative sooner than we may realize.

2. Simard EP, Ward EM, Siegel R, et al: Cancers with increasing incidence trends in the United States: 1999 through 2008. 

3. Pinheiro PS, Williams M, Miller EA, et al: Cancer survival among Latinos and the Hispanic paradox. 

4. Jemal A, Bray F, Center MM, et al: Global cancer statistics. 

Cancer statistics do not overwhelm me as much as other calculations do. I think this is because I can imagine a human being connected to the rising incidences and changing trends within my chosen specialty.

What's in a Number?

ABSTRACT:  Non–small-cell lung cancer (NSCLC) remains a difficult-to-treat malignancy, and durable long-term survival is elusive for patients with advanced-stage disease. Chemotherapy, especially with platinum-based combinations, is the mainstay of treatment, yet these regimens yield only modest response and survival rates. Outcomes of recent clinical trials have shown that histology, mutation analyses, and biomarkers have an impact on the selection and combination of chemotherapeutic agents. Oral tyrosine kinase inhibitors and monoclonal antibodies are now part of the treatment schema. Other changes to the treatment paradigm include the duration of treatment and the use of maintenance therapy. Additionally, chemotherapy is now employed in earlier-stage disease in neoadjuvant, adjuvant, and combined-modality treatments. The aim of this article is to review the current systemic treatments for NSCLC.

A variety of agents and drug combinations (see 

) are used for the management of patients with non–small-cell lung cancer (NSCLC), depending on the stage of the disease and a number of patient factors that will be discussed in this article.

Cisplatin-based combinations (doublets) continue to be the cornerstone of treatment for patients with advanced NSCLC, following results of early studies that demonstrated a modest 1-year survival benefit (20% to 25%) with this modality.[1] For years, researchers have tried to determine the most effective doublet therapy, in terms of patient response and survival. Results of phase III clinical trials have shown equivocal response and survival rates in NSCLC patients treated with third-generation agents-such as the taxanes (paclitaxel and docetaxel), gemcitabine, and vinorelbine-combined with a platinum (either cisplatin or carboplatin).[2]

In 2008, Scagliotti et al published the findings of their phase III study comparing the efficacy of cisplatin-based doublets (gemcitabine, pemetrexed [Alimta]) in untreated patients with advanced-stage NSCLC. Although both combinations had equivocal efficacy, the main finding of the meta-analysis was that patients with either adenocarcinoma or large cell carcinoma who had received cisplatin-pemetrexed had better survival rates than those treated with cisplatin-gemcitabine. It should be noted that patients with squamous cell carcinoma treated with the cisplatin-gemcitabine combination had improved survival rates compared with patients who received the cisplatin-pemetrexed doublet. This study was the first to demonstrate survival differences based on histology.[3] Based on the results of this phase III clinical trial, histology is a significant factor in selection of chemotherapeutic agents for patients with untreated, advanced-stage NSCLC.

There is still some question as to which platin (cisplatin or carboplatin) is the more effective agent. Numerous studies have tried to answer this question.[2,4–6] Both drugs have benefits and toxicities. Treatment with cisplatin requires pre- and post-treatment hydration, thus prolonging the treatment time.[7] Side effects of cisplatin include, but are not limited to, nausea, vomiting, neurotoxicity, nephrotoxicity, and ototoxicity. Nausea and vomiting are better controlled with newer antiemetic medications.

Carboplatin side effects are milder nausea and vomiting (compared with cisplatin) and hematologic issues such as thrombocytopenia. Both drugs are associated with hypersensitivity reactions.[8]

Results of a meta-analysis demonstrated better response and prolonged survival for patients who received cisplatin-based therapy.[4] There was not a higher incidence of severe (grade 3 or 4) side effects in the cisplatin group compared with those who received carboplatin.[4] The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines support using either cisplatin or carboplatin for patients with advanced NSCLC[7]; therefore, treatment planning for the patient with NSCLC is determined by histology, performance status, age, and comorbidities.

For years, researchers have been investigating various combinations of drugs and other means of overcoming the plateau effect of standard chemotherapy. Early clinical trials using three cytotoxic chemotherapy agents (triplet therapy) were tried, with the result that triplet therapy was more toxic and did not improve survival rates compared with doublet therapy.[9,10] The consensus among investigators is that newer agents, with a different toxicity profile and mechanism of action, are needed to improve the response and survival rates.[7,11,12] Some targeted therapies, such as the monoclonal antibodies bevacizumab (Avastin) and cetuximab (Erbitux), have been combined with chemotherapy in clinical trials.[7]

In 2006, the US Food and Drug Administration (FDA) approved bevacizumab as first-line treatment for advanced NSCLC in combination with carboplatin and paclitaxel.[7] Bevacizumab is a recombinant monoclonal antibody that prevents vascular endothelial growth factor (VEGF) from binding to its receptor, thereby slowing tumor growth and preventing metastasis. Results of a phase III clinical trial randomizing untreated patients with advanced NSCLC to carboplatin and paclitaxel with or without bevacizumab demonstrated a survival benefit for patients who received all three drugs.[13] Subsequent clinical trials have also shown response and survival benefit with the addition of bevacizumab to doublet chemotherapy.[7] Both the ASCO and NCCN treatment guidelines recommend combining bevacizumab with chemotherapy, based on clinical trial findings.[14,15]

Cetuximab has also been studied in clinical trials. It targets the epidermal growth factor receptor (EGFR) pathway at the extracellular level, preventing ligands from binding with the EGFR receptors.[16] The results of two phase III clinical trials demonstrated slightly improved response and survival rates for those who received cetuximab with chemotherapy.[17,18] Currently, cetuximab is approved for the treatment of metastatic colorectal cancer and squamous cell head and neck cancer, but not for advanced NSCLC.[7]

Tyrosine Kinase Inhibitors as First-Line Therapy

Small tyrosine kinase inhibitors (TKIs) target the intracellular EGFR pathways, thereby blocking downstream signaling as well as growth and proliferation of cancer.[7] Two such agents are gefitinib (Iressa) and erlotinib (Tarceva). Results of phase III randomized clinical trials comparing chemotherapy plus an oral TKI (gefitinib, erlotinib) against chemotherapy alone did not show improved survival with addition of the oral TKI.[19–22] Therefore, oral TKIs in combination with chemotherapy were not approved for first-line treatment of patients with advanced NSCLC.

Recent studies have evaluated the oral TKIs as monotherapy (single-agent) first-line treatment for advanced NSCLC. One large phase III trial, the Iressa Pan-Asia Study (IPASS), randomized untreated East Asian patients to chemotherapy (carboplatin and paclitaxel) or gefitinib; the results demonstrated improved response and progression-free survival rates for patients who received gefitinib.[23]

Another phase III randomized clinical trial evaluated erlotinib vs carboplatin-gemcitabine as first-line treatment for NSCLC. This was a smaller study in which 549 patients were screened but 384 patients were excluded because their tumor did not express the EGFR-activating mutation (exon 19 deletion or exon 21 L858R point mutation); therefore, 165 patients were randomized to the two arms. Once again, the results demonstrated longer progression-free survival for patients who received erlotinib.[24] Based on the findings from these two studies, and from other clinical trials that demonstrated longer survival with an oral EGFR TKI agent over chemotherapy, the NCCN recommends erlotinib as first-line therapy in patients whose tumors express the EGFR-activating mutation.[15]

Crizotinib (Xalkori), another small-molecule agent, may also be used as first-line treatment providing that the patient’s tumor expresses the 

 mutation, and that this mutation status is known at the time of treatment intiation. (Crizotinib was approved by the FDA in August 2011 for treatment of NSCLC patients whose tumors express the 

 mutation.) If the mutation status is not known (the mutation test results are pending), then the oncologist can delay treatment (if the patient agrees to wait) until notified of the results or just begin treatment with other agents. If, after treatment is started, the patient’s tumor does express the 

mutation, then crizotinib could be used after initial treatment is completed (see section on Second and Third-Line Therapy). NCCN guidelines recommend crizotinib as first-line therapy for patients with the 

One of the newer roles of chemotherapy, at least in lung cancer, is that of maintenance therapy. The idea behind maintenance therapy, long used in hematologic malignancies, is to prevent the cancer from recurring, and, in some cases, to maintain the responses achieved with first-line therapy.[7] Continuation maintenance therapy is defined as: “continuation of one or more drugs used during first-line therapy beyond four to six cycles.” Switch maintenance therapy is alternative therapy (with a chemotherapy agent different from that used in first-line therapy) given to patients who have had response or stabilization of disease after four to six cycles of first-line therapy. Maintenance therapy is used when there is stabilization of disease, whereas second-line therapy is used for patients with disease progression.[25]

Pemetrexed and erlotinib were the first two drugs approved by the FDA for maintenance therapy in patients with lung cancer.[7] Results of a phase III randomized study showed some improvement in progression-free and overall survival for patients who received pemetrexed rather than best supportive care following first-line platinum-based chemotherapy.[26] It should be noted that in this study, pemetrexed was not used in the first-line platinum-based treatment.

In 2010, erlotinib was approved for use in maintenance therapy based on results of the SATURN (Sequential Tarceva in Unresectable NSCLC) trial.[7,27] In this study, patients were eligible to participate following completion of four courses of cisplatin-based chemotherapy with stable disease (without evidence of disease progression), and were randomized to erlotinib or placebo. Immunohistochemistry testing for EGFR protein overexpression was performed for all study participants. The results demonstrated longer progression-free survival for patients who received erlotinib, regardless of EGFR expression status.[27]

ASCO’s updated treatment guidelines recommend discontinuing first-line treatment for NSCLC after four courses of chemotherapy in patients who have stable disease but no further response (decrease in tumor size) to treatment.[25] The ASCO guidelines call for doublet chemotherapy as first-line treatment, for at least four but no more than six cycles of treatment; for patients who have stable disease or a response after four chemotherapy treatments, the guidelines recommend immediate treatment with an “alternative, single-agent chemotherapy.” The agents recommended for switch maintenance therapy are pemetrexed, for patients with nonsquamous histology; erlotinib, for patients whose 

 mutation status may or may not be known or positive; and docetaxel, for all patients regardless of histology. If patients have significant toxicities with first-line doublet therapy, the guidelines state that it is also reasonable to give them a break from treatment, and not administer maintenance therapy.

Chemotherapy in Neoadjuvant and Adjuvant Treatment

Chemotherapy has long been the primary treatment for patients with advanced, metastatic NSCLC. Researchers have evaluated the use of chemotherapy in earlier stages of disease to enhance survival. Findings from a meta-analysis of seven randomized clinical trials, totaling 988 patients with stages I to IIIA disease, showed significant benefit for patients who received platinum-based chemotherapy before surgery compared with those who did not receive chemotherapy.[28]

Adjuvant therapy is now standard treatment for patients who have had surgery. Results of the International Adjuvant Lung Cancer Trial Collaborative Group (IALT) showed higher survival rates for patients who received postoperative cisplatin-based chemotherapy.[29] The findings of the IALT group were confirmed by the Lung Adjuvant Cisplatin Evaluation (LACE) Group. The LACE group completed a meta-analysis of five randomized clinical trials, with a total of 4,584 patients, which validated survival benefit for patients who receive cisplatin-based chemotherapy.[30]

There are now many options available to the patient with disease progression following first-line chemotherapy. Any chemotherapy agent that is different from first-line therapy and not used as maintenance therapy could be employed for disease recurrence/progression. The chemotherapy agents recommended for second-line therapy are the same ones recommended for maintenance therapy: docetaxel, pemetrexed, and erlotinib.[7] The results of two phase III clinical trials showed response and survival benefit for patients who received docetaxel as second-line therapy.[31,32] Another phase III clinical trial compared docetaxel vs pemetrexed in the second-line setting.[33] The response rates were similar in both treatment arms. One of the differences between the two treatment arms was that there were higher hematologic toxicities in the docetaxel arm, but both docetaxel and pemetrexed are reasonable treatment choices in the second-line setting.

Erlotinib is approved for treatment in both the second- and third-line settings.[7] The approval of erlotinib in these settings is based on results of an international randomized clinical trial of erlotinib vs best supportive care. The results demonstrated improvement in response and survival rates and in quality of life, and a decrease in cancer-related symptoms.[34]

For second- or third-line treatment, there is yet another option for selected patients with advanced NSCLC. Crizotinib received accelerated FDA approval in August 2011, to treat certain patients with locally advanced or metastatic NSCLC who express the abnormal anaplastic lymphoma kinase (

) gene.[35] The approval of crizotinib was based on response rates, not survival data. Currently, two phase III studies of crizotinib are underway, with the endpoint of progression-free survival.[36]

 
Biomarkers Used in the Management of NSCLC  

Treatment selection is now based on histology and biomarkers, which have prognostic and predictive value (see 

). The prognostic value of a biomarker is in determining which tumors are likely to recur and lead to death, regardless of the treatment. Predictive markers indicate which patients would respond to certain agents, and would be helpful in selecting patients for appropriate treatment. The following are used as biomarkers in NSCLC: EGFR, ERCC1, RRM1, KRAS, and EML4-ALK.[37] Mutation of 

 has predictive value in terms of response to EGFR-inhibitor agents such as erlotinib.[23]

The excision-repair cross-complementation group 1 (ERCC1) is an enzyme protein that is involved in the final step of the nuclear excision repair (NER) pathway, which is one of the DNA repair pathways.[37] The NER pathway recognizes and repairs platinum-DNA adducts that are formed when cisplatin binds to DNA, causing strand breaks that inhibit replication and lead to cell death.[38,39] When high levels of ERCC1 are present, the damaged cell is able to repair itself and is therefore platinum-resistant; conversely, low ERCC1 levels suggest platinum sensitivity.[39,40]

The enzyme ribonucleotide reductase is composed of two subunits, RRM1 and RRM2, both of which are required for DNA synthesis and repair. The chemotherapy agent gemcitabine targets RRM1 by inhibiting ribonucleotide reductase, and thereby blocking the DNA synthesis pathway. When RRM1 overexpression is present, it can overcome the chemotherapeutic effects of gemcitabine, rendering the drug ineffective.[37]

RAS proteins are proto-oncogenes that are involved in signal transduction pathways.

 is one of three genes in the RAS “family” and has a role in cell growth and signaling.[41,42] There is a substitution of a purine for a pyrimidine in the 

 mutations are associated with resistance to both EGFR inhibitors and chemotherapy.[43]

The echinoderm microtubule-associated protein-like 4 gene (

) and the anaplastic lymphoma kinase gene are two separate genes located on chromosome 2p.[37] The 

 gene is the fusion of these two separate genes.[36] The presence of the fusion gene, in transgenic mouse models, leads to the development of numerous lung adenocarcinomas.[44] Further research demonstrated that cancer cell lines that had the 

 mutation were effectively inhibited by ALK inhibitors.[45] The knowledge of these biomarkers will enable the oncology team to select beneficial treatment for patients with NSCLC.

In treating advanced NSCLC, the paradigm has shifted. Treatment is now determined by histology, biomarkers, and holistic assessment (age, performance status, comorbidities). Treatment for NSCLC now follows a personalized approach. Slowly, progress is being made for treatments aimed at a minority of patients whose tumors have gene mutations, with improvement in response and survival rates. There is still work to be done to improve response and survival outcomes for patients with NSCLC whose tumors do not express gene mutations.

1. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. Non-Small Cell Lung Cancer Collaborative Group. 

2. Schiller JH, Harrington D, Belani C, et al: Comparison of four chemotherapeutic regimens for advanced non-small cell lung cancer. 

3. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small cell lung cancer. 

4. Ardizzoni A, Boni L, Tiseo M, et al, for the CISCA (Cisplatin versus Carboplatin) Meta-Analysis Group: Cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer: An individual patient meta-analysis. 

5. Hotta K, Matsuo K, Ueoka H, et al: Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small cell lung cancer. 

6. Soria JC, LeChevalier T: Is cisplatin still the best platinum compound in non-small cell lung cancer? 

7. Tyson LB, Ginex PK: Non-small cell lung cancer, in Houlihan NG, Tyson LB (eds): Site-Specific Cancer Series: Lung Cancer. Pittsburgh, PA, Oncology Nursing Society Publications Department, 2012, pp 99â130. 

8. Castells M, Maatulonis UA: Infusion reactions to systemic chemotherapy [2010]. Available at 

http://www.uptodate.com/contents/infusion-reactions-to-systemic-chemotherapy

Chemotherapy is now employed in earlier-stage disease in neoadjuvant, adjuvant, and combined-modality treatments. The aim of this article is to review the current systemic treatments for NSCLC.

Current Treatment Options for Non–Small-Cell Lung Cancer

Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic disorder characterized by an elevated uric acid level, elevated serum potassium and phosphorus levels, and a decreased calcium level. Most often seen 12 to 72 hours after administration of systemic chemotherapy for a hematologic malignancy, TLS occasionally may be present prior to the start of therapy. Hematologic malignancies of concern include those that have a high proliferative rate, such as Burkitt’s lymphoma, lymphoblastic lymphoma (LBL), and B–acute lymphoblastic leukemia (B-ALL). Patients with ALL, acute myelogenous leukemia (AML), or chronic lymphocytic leukemia (CLL) who have a high WBC counts could be at risk. Lower-risk patients include those who have indolent lymphomas. Patients with diffuse large-cell lymphoma (DLCL) would be considered at intermediate risk for TLS.[1]

The patient, “Mr. B,” is a 64-year-old male with a history of CLL and a WBC count of 64,000 cells/mm

. He was treated with bendamustine (Treanda) at 100 mg/m

 on days 1 and 2. Later in the day, after the second dose, the patient called the prescriber and complained of left flank pain and shortness of breath. He was instructed to return to the infusion room, where a review of systems revealed additional complaints of reduced urine output, dysuria, and anorexia. He had no cardiac complaints. Blood tests revealed a blood urea nitrogen (BUN) level of 50 mg/dL, a serum creatinine of 4.9 mg/dL, and a uric acid level of 19 mg/dL. His serum electrolyte levels were abnormal, with potassium at 5.4 mmol/L, phosphate at 8.9 mg/dL, and calcium at 6.9 mg/dL. An electrocardiogram revealed tall T waves and a heart rate of 88 beats per minute. His home medication list was reviewed by the nurse and included allopurinol at 300 mg daily.

IV fluids of normal saline were started at an infusion rate 200 mL/hour, and the patient was admitted to a medical oncology nursing unit with telemetry, having been diagnosed with tumor lysis syndrome (TLS) with acute kidney injury (AKI).  An indwelling urinary bladder catheter was inserted; 50 mL of urine was obtained and this was sent for urine analysis and a test of urine electrolytes. The patient was then prescribed rasburicase (Elitek) at 6 mg IV as a one-time dose and sodium polystyrene sulfonate at 15 grams orally.

TLS is the result of large numbers of malignant cells dying and releasing their intracellular components-potassium, phosphorus, nucleic acids, and proteins-into the bloodstream. Proteins and nucleic acids are broken down by the liver enzyme xanthine oxidase into uric acid.[2,3] The excess amount and rapid influx of these substances into the bloodstream may rapidly overwhelm the excretory capacity of the kidneys, resulting in elevated blood levels. Because the kidneys cannot excrete the excess uric acid, it begins to precipitate in the kidneys, resulting in uric acid nephropathy[4] and subsequently AKI.

Concurrently, the kidneys attempt to eliminate the excess potassium in the blood, and this results in a fluid volume deficit.[2] The reduced intravascular volume, in turn, translates to decreased perfusion to the kidneys, causing AKI. Increased intravascular phosphorus also causes the kidneys to increase their output to bring down this elevated level. The excess phosphorus binds with serum calcium, resulting in calcium-phosphate precipitates in the kidneys and thereby exacerbating the renal problem.[2,4] The development of AKI in this setting is multifactoral and requires aggressive intervention.

According to the classification system developed by Cairo and Bishop,[4] TLS may be designated as either laboratory TLS or clinical TLS. Laboratory TLS is present when there are elevations in uric acid, potassium, and phosphorus levels (25% above baseline) and a reduced calcium level (25% below baseline). Clinical TLS is present when the creatinine level is 1.5 times the upper limit of normal or higher, or if the patient has seizures or cardiac dysrhythmias, or if there is sudden death.

 
Signs and Symptoms Associated With Tumor Lysis Syndrome 

Patients may experience a variety of signs and symptoms related to TLS. Body systems primarily affected include the heart, kidneys, and gastrointestinal (GI) and neuromuscular systems.[5] Cardiac dysrhythmias due to hyperkalemia may be fatal. AKI and hematuria may be present. Neuromuscular symptoms include tetany, and gastrointestinal symptoms include nausea and vomiting. 

 outlines the signs and symptoms associated with TLS.

The patient with TLS is acutely ill and requires astute nursing care to avoid complications from AKI and electrolyte imbalances. Hydration is critical. IV fluids are administered at a rate of 2 to 3 L/m

/day to promote diuresis, with the goal of a urinary output exceeding100 mL/m

/hour.[4,6] Some patients may require a diuretic such as mannitol to promote diuresis, but this needs to be considered on an individualized basis. Strict intake-and-output and daily weight measurement are essential to assess and monitor the patient’s fluid balance. Historically, sodium bicarbonate has been added to IV fluids to alkalinize the urine, with the goal of enhancing uric acid excretion. However, alkalinization may promote calcium phosphate and uric acid renal precipitation, thereby causing metabolic acidosis, so its use is not recommended.[1,7] Alkalinization is avoided in patients who are going to receive rasburicase.[1] Because Mr. B was scheduled to receive rasburicase, his IV fluids consisted of normal saline. Also, nephrotoxic agents such as non-steroidal anti-inflammatory agents (NSAIDs) are to be avoided.[6]

Electrolyte imbalances must be managed to prevent serious adverse events. Avoid adding calcium, potassium, and phosphates to IV fluids.[4] Medications containing potassium and phosphorus must be avoided. In addition, the patient’s diet may need to be modified to reduce potassium and phosphorus intake.[8]

 develops quickly, often within 6 to 72 hours after chemotherapy has started.[9] Asymptomatic patients, like Mr. B, may be managed with oral or rectal (if patient is not neutropenic or thrombocytopenic) sodium polystyrene sulphonate (1 g/kg with 50% sorbitol).[4] Symptomatic patients are managed with IV glucose and rapid-acting insulin to force potassium back into the cells.[1,4,9] Cardiac monitoring is required for patients with hyperkalemia, to monitor for dysrhythmias.

 is managed with ongoing hydration, diuresis, avoiding calcium infusions, and oral phosphate binders such as aluminum hydroxide (for 1 to 2 days only) or oral calcium carbonate (only if the serum calcium level is low).[1,6,9] Dextrose and insulin administered intravenously have also been used to manage elevated phosphate levels.[10] 

 is treated only if the patient has cardiac toxicity or neuromuscular symptoms (such as seizures, tetany), as calcium can combine with phosphorus and worsen precipitation in the soft tissues.[2] If ordered, calcium gluconate is administered while the patient is monitored for bradycardia using cardiac monitoring.    

 Allopurinol is used to prevent formation of uric acid in at-risk patients. The drug is available both orally and as an IV formulation. Patients need to be monitored for rash, a common side effect. By interfering with xanthine oxidase, allopurinol interferes with the conversion of purines into hypoxanthine and then into xanthine, both of which are uric acid precursors.[4] As a result, there are elevated levels of both hypoxanthine and xanthine, and these could potentially precipitate in the kidneys. Allopurinol will not degrade existing uric acid in the blood, so it is not as effective in reducing pre-existing elevated levels as it is in preventing uric acid formation.[11] Doses administered range from 200 to 400 mg/m

/day divided in up to three doses per day (eg, every 8 hours).[1] Metabolized by the cytochrome P450 system, allopurinol affects the metabolism of 6-mercaptopurine.

 
Use of Rasburicase in the Management of Tumor Lysis Syndrome 

 is recombinant urate oxidase. and it converts uric acid to allantoin, which is very soluble and therefore easier for the kidneys to eliminate.[12] It quickly reduces uric acid levels.[13,14] The most common side effects of rasburicase include headache, rash, fever, and vomiting, which are mostly mild.[13] Hypersensitivity reactions have occurred in less than 1% of patients; they requires permanent drug discontinuation when the reaction is serious.[15,16] Dosing ranges from 0.2 mg/kg IV over 30 minutes daily for up to 5 days to a single dose of 6 mg IV over 30 minutes.[13–15] The US Food and Drug Administration approved dose of rasburicase is 0.2 mg/kg over 30 minutes IV daily for 5 days.[16] 

 provides additional information related to rasburicase.

The nurse prepares to treat Mr. B with rasburicase as prescribed. A medication reconciliation is performed to ensure that allopurinol has been placed on hold. Allopurinol may interfere with rasburicase activity, as allopurinol reduces uric acid formation and rasburicase acts on uric acid to convert it to allantoin. Patient allergies are checked and the patient’s history is reviewed for a known diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency. The negative history findings are confirmed with the patient. Hemolysis may occur in patients with G6PD deficiency who receive rasburicase, and it is therefore contraindicated.[16] Also, the nurse checks to ensure that Mr. B has no prior history of asthma or severe allergies to other medications or to rasburicase or urate oxidase.[17] In Mr. B’s case, none of these issues were present. If they are present, however, the nurse should discuss the findings with the prescriber. If required, allopurinol may be restarted about 24 hours after rasburicase has been administered.

 
Nursing Management of Patients With Tumor Lysis Syndrome  

Mr. B was educated as to the signs and symptoms of a hypersensitivity reaction (HSR) and instructed to report their presence immediately to the nurse. Making sure emergency medications were readily available and his vital signs (VS) were assessed, the nurse started Mr. B’s rasburicase infusion to run over a period of 30 minutes. By staying at the patient’s bedside for at least 5 minutes to monitor for signs and symptoms of a HSR, and by continuing to monitor the patient and VS during the remainder of the infusion as per hospital policy,[17] the nurse ensured that the drug was safely administered. The nurse was prepared to stop the infusion and manage signs and symptoms of a HSR. Mr. B tolerated the infusion without any symptoms.

When blood specimens are drawn and sent to the laboratory, special care and prompt processing are required, as rasburicase present in the patient’s blood also acts ex vivo to convert uric acid to allantoin, yielding false-low test results. The specimen should be drawn into a prechilled blood tube containing heparin and immersed in an ice-water bath. It must be sent to the laboratory promptly, as it needs to be processed within 4 hours after being drawn.[16,17] Blood testing for patients with TLS treated with rasburicase is done 4 hours after dosing and repeated every 6 to 8 hours until TLS has resolved. In addition to uric acid levels sent to the laboratory in chilled tubes on ice, other specimens obtained include those for renal function tests, electrolytes, levels of calcium, phosphorus, and LDH.[1]

Patients’ renal, cardiac, neuromuscular, and gastrointestinal systems may develop signs and symptoms related to TLS, requiring physical assessments and frequent monitoring, with the frequency dependent upon the severity of TLS and the patient’s complaints and assessment findings. Safety measures are crucial, and the electrolyte disorders place the patient at risk of seizures and dysrhythmias. These patients are critically ill and at risk for injuries such as falls, so precautions against patient falls are critical. Additional nursing measures are highlighted in 

When caring for a patient with TLS, astute nursing care is required for positive patient outcomes. Assessments and monitoring are required for prompt management of complications and patient safety. Because of the skilled nursing care that Mr. B received, along with supportive medications and hydration, his renal function improved, with increased urine output, normalization of electrolytes, and return of his appetite.

Jeanne Held-Warmkessel serves on the speakers bureau for Cephalon.

1. Coiffier B, Altman A, Pui C-H, et al: Guidelines for the management of pediatric and adult tumor lysis syndrome: An evidence-based review. 

2. Davidson MB, Thakkar S, Hix JK, et al: Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. 

3. Kaplow R: Pathophysiology, signs, and symptoms of acute tumor lysis syndrome.  

4. Cairo MS, Bishop M: Tumour lysis syndrome: New therapeutic strategies and classification. 

5. Howard SC, Jones DP, Pui C-H: The tumor lysis syndrome. 

6. Zojer N, Ludwig H: Hematological emergencies. 

7. Fojo AT:  Metabolic emergencies. In DeVita VT, Lawrence TS, Rosenberg SA (eds): DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology, ed 8. Philadelphia, Lippincott Williams & Wilkins, 2008, pp 2446â2455.

8. Gobel BH: Management of tumor lysis syndrome: Prevention and treatment.  

9. Flombaum CD: Metabolic emergencies in the cancer patient. 

10. Muslimani A, Zakalaik D, Chisti MM, et al: How we treat tumor lysis syndrome.  

11. Abu-Alfa AK, Younes A: Tumor lysis syndrome and acute kidney injury: Evaluation, prevention, and management. 

12. Pui C-H: Rasburicase: A potent uricolytic agent. 

13. Jeha S, Kantarjian H, Irwin D, et al: Efficacy and safety of rasburicase, a recombinant urate oxidase (ElitekTM>), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: Final results of a multicenter compassionate use trial. 

14. McDonnell AM, Lenz KL, Frei-Lahr DA, et al: Single-dose rasburicase 6 mg in the management of tumor lysis syndrome in adults. 

15. Cortes J, Moore JO, Maziarz RT, et al: Control of plasma uric acid in adults at risk for tumor lysis syndrome: Efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. 

16. sanofi-aventis: Elitek (rasburicase) package insert.  Bridgewater, NJ, 2009.

Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic disorder characterized by an elevated uric acid level, elevated serum potassium and phosphorus levels, and a decreased calcium level.

A Patient With  Tumor Lysis Syndrome

The prevention of patient falls is a major healthcare imperative. Falls are associated with avoidable morbidity and mortality, compromised quality of life, and considerable economic burden. Consider the following. Falls:

•  Account for more than 70%                                                         of all injury-related admissions to hospitals for people over 65 years of age;

•	Occur in approximately one-third of all people over age 65 and about half of all people over 80 years old;

•  Are the leading cause of hip fractures;

•  Promote loss of independence and are the main reason for admission to an extended-care facility;

•  Are responsible for approximately 16,000 deaths per year in people over age 65; and

•  Account for more than $19   billion in health-related expenses annually.[1–4]

Falling in old age is considered a geriatric syndrome, one element of a cluster of common age-related problems that frequently co-occur in practice. Other geriatric syndromes include altered continence, changes in mental status, immune senescence, malnutrition, depression, and skin compromise. In the context of falls, these geriatric syndromes frequently have roles in either causation or consequences.

For older cancer patients, falls can have critical negative sequelae. Older patients who fall may experience fracture, head injury, infection and delirium (if the fall occurs after required surgery), exacerbated bleeding, and prolonged hospitalizations. Despite the potentially serious consequences of falls in older cancer patients, however, definitive research in this area is lacking.

Two studies of older men treated with androgen-deprivation therapy for prostate cancer revealed that the treatment-associated accelerated osteoporosis, and functional and physical impairments (ie, fatigue, muscle weakness/wasting), could contribute to an increased risk of falls.[1,5] In the palliative care setting, the incidence of delirium, correlated with the common, frequently high use of neuroleptic medications, was associated with fall risk.[6]

Overcash and colleagues[7–9] reported on three domains of falls in older cancer patients. In one study, older patients were contacted by telephone following their fall to determine characteristics of the fall episode. The majority of falls occurred at home (75%), in a forward direction (55%).[7] The investigators noted 80% of the participants stated that, subsequent to the fall, they had changed behaviors they faulted as the cause. (For example, in an effort to prevent future falls, they limited activities during times they felt physically weak, and used assistive devices more often.)

A preliminary survey study noted that men were more likely to fall compared with women.[8] A third study, which investigated the impact of a comprehensive geriatric assessment on the incidence of falls, concluded that responses obtained from an activities of daily living screening could help to predict fall risk.[9] Community-dwelling elderly with a history of cancer were also the target of research by Spoelstra and colleagues, who reported a high frequency of falls in this group.[10] In the sample studied, symptomatic predictors of falling included the presence of incontinence, pain, and depression.

Although promoting a culture of safety is the entire interdisciplinary team’s shared responsibility, nurses are essential core members in achieving the level of healthcare provider commitment necessary to reduce patient falls.[11] Within cancer care, oncology nurses often drive initiatives to reduce actual and near-miss falls, as assessment and prevention are critical aspects of their professional role.

Of fundamental importance is the fact that falls rarely have a single cause.[12] Rather, multiple intrinsic and extrinsic variables interface to precipitate falls. Within the cancer experience, intrinsic or host factors relate to individual characteristics that may heighten risk. These risk factors include:

 mostly acute confusion but also organic dementia;

 pain, incontinence (bowel and urinary), anemia/fatigue;

 (ie, particularly arthritis, stroke, postural hypotension) 

 (ie, especially use of benzodiazepines, sedatives/hypnotics, analgesics, antihistamines with the potential to alter cognitive function);

 (ie, diagnosis of metastatic disease, malnutrition/cachexia, evidence of deconditioning);

 (ie, altered gait, balance, endurance, strength); and

 (ie, vision deficit, peripheral neurotoxicity, diagnosis of spinal cord compression with either motor/sensory changes).

Other factors that have been noted to increase fall risk include a prior history of falls and lack of social support (ie, patient lives alone).

 
Extrinsic Modifications to Reduce Fall Risk

The removal of risk factors is one category of major intervention to reduce falls. 

 summarizes changes in the patient’s immediate care environment that may be effective. The second category encompasses introduction of teaching and early reporting. These categories involve modification of extrinsic factors, those within the patient’s environment. Possibilities include:

•  Using a screening tool to distinguish early and ongoing risk characteristics (particularly as the patient’s status changes over time);

•  Clearly identifying patients at   risk for falls;

•  Educating the patient and family about risk profiles;

– Removing medications   potentially associated with        adverse effects (ie, delirium,         agitation);

–  Managing symptom distress 		associate with unaccompanied       mobility (ie, diarrhea, urinary        frequency);

•  Using bed and chair alarms for early reporting;

•  Hourly rounding for needs assessment and toileting requirements; and

•  Requesting a physical therapy consultation.[8,9,13]

Acknowledging cancer as a phenomenon of aging, falls take precedence as a major concern for oncology nurses-one that will grow in importance as the number of older adults with cancer increases in the future. The growing pool of cancer survivors will translate into an expansion of the number of older adults treated and monitored for the iatrogenic sequelae of cancer. The prevention of falls in this expanding population will become a critical competency for oncology nurses.

1. Hussain S, Breunis H, Timilshina N, et al: Falls in men on androgen deprivation therapy for prostate cancer. J Geriatr Oncol 1(1):32â39, 2010.

2. Stevens JA, Corso PS, Finkelstein EA, et al: The costs of fatal and non-fatal falls among older adults. Injury Prevent 12(5):290â295, 2006.

3. Centers for Disease Control and Prevention: Self-reported falls and fall-related injuries among persons aged > or = 65 years-United States, 2006. MMWR Morb Mortal Wkly Rep 57(9):225â229, 2008.

4. Kannus P, SievÃ¤nen H, Palvanen M, et al: Prevention of falls and consequent injuries in elderly people. Lancet 366(9500):1885â1893, 2005.

5. Bylow K, Dale W, Mustian K, et al: Falls and physical performance deficits in older patients with prostate cancer undergoing androgen deprivation therapy. Urology 72(2):422â427, 2008.

6. Pauteux S, Herrmann FR, Zulian GB: Factors associated with falls in patients with cancer hospitalized for palliative care. J Palliat Med 11(6):878â884, 2008.

7. Overcash JA, Rivera HR, Van Schaick J: An analysis of falls experienced by older adult patients diagnosed with cancer. Oncol Nurs Forum 37(5):573â580, 2010.

8. Overcash J: Prediction of falls in older adults with cancer: A preliminary survey. Oncol Nurs Forum 34(2):341â346, 2007.  9. Overcash, Beckstead J: Predicting falls in older patients using components of a comprehensive geriatric assessment. Clin J Oncol Nurs 12(6):941â949, 2008.

10. Spoelstra S, Given B, Von Eye A, et al: Falls in the community-dwelling elderly with a history of cancer. Cancer Nurs 33(2):149â155, 2010.

11. Gray-Miceli D: Preventing falls in acute care. In: Capezuti E, Zwicker D, Mezey M, et al, eds. Evidence-Based Geriatric Nursing Protocols for Best Practice. Ed 3. New York, NY:  Springer Publishing; 2008:161â198.

12. Holley S: A look at the problem of falls among people with cancer. Clin J Oncol Nurs 6(4):193â197, 2002.

13. Miller L, Limbaugh CM: Applying evidence to develop a medical oncology fall-prevention program. Clin J Oncol Nurs 12(1):158â160, 2008.

The prevention of patient falls is a major healthcare imperative. Falls are associated with avoidable morbidity and mortality, compromised quality of life, and considerable economic burden.

ONCOLOGY Nurse Edition Vol 26 No 8 | Oncology Nurse Edition

News of Note

Evolving and Expanding Treatment Options in NSCLC

What's in a Number?

Current Treatment Options for Non–Small-Cell Lung Cancer

A Patient With Tumor Lysis Syndrome

Falls in Older Adults With Cancer: A Call to Action

Clinical Hypnosis for the Palliative Care of Cancer Patients

Contemporary Issues in NSCLC

Vismodegib, a Hedgehog Pathway Inhibitor for Adults With Locally Advanced or Metastatic Basal Cell Carcinoma