The author is a writer based in New Jersey.

Julio Fernandez, PharmD

The National Comprehensive Cancer Network (NCCN) has recently updated its non-small cell lung cancer (NSCLC) guidelines. 

The updated NSCLC guidelines provide information on additional cisplatin-based postoperative adjuvant chemotherapy regimens. Results from recent studies on adjuvant chemotherapy have shown favorable results with cisplatin-based regimens. The International Adjuvant Lung Cancer Trial (IALT) reported a statistically significant survival benefit with cisplatin-based adjuvant therapy compared with observation at a median of 56 months in patients with completely resected NSCLC. Patients who received the cisplatin-based regimen demonstrated a significantly higher survival rate (44.5% vs. 40.4%) and disease-free survival (39.4% vs. 34.3%). The NCCN panel has also included cisplatin combined with vinorelbine, vinblastine, or etoposide as adjuvant chemotherapy regimens. The guidelines provide alternative treatments which are mainly carboplatin-based regimens for patients with comorbidities or who are unable to tolerate cisplatin. 

Another update to the guidelines involves the use of molecular markers to individualize therapy for patients. "Patients receiving individualized therapy will hopefully get more benefit and experience less unnecessary toxicity from medications that may not work in treating NSCLC," added Cooper. Pathologic evaluation is performed to determine the molecular abnormalities of lung cancer that may be able to predict sensitivity and resistance to epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKI).  Epidermal growth factor receptor (EGFR) is often over expressed in various malignancies. There is a significant association between EGFR and response to tyrosine kinase inhibitors (TKI).  K-ras is an effector of the EGFR pathway that has been found mutated in approximately 15%-30% of lung adenocarcinomas and to be associated with tobacco smoke exposure. K-ras mutations are associated with intrinsic TKI resistance. Therefore gene sequencing may be useful for selecting patients who may benefit from TKI therapy. 

NCSLC patients who have never smoked and whose tumors contain an EGFR mutation will respond to TKI therapy such as erlotinib (Tarceva, Genentech/OSI). Thus, the NCCN guidelines now state that erlotinib may be used with or without chemotherapy as a first-line agent in patients with advanced disease who have never smoked and whose tumors have a known EGFR mutation or gene amplification. "Learning where therapies like erlotinib will be beneficial to patients will be important in the future," stated Rowena Schwartz, Pharm.D., and pharmacy director at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Md. Erlotinib was approved in 2004 by the Food & Drug Administration for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapeutic regimen. 

"These guidelines are extremely beneficial to pharmacists because we often use them as a reference and to determine where therapies fit in the treatment spectrum," concluded Schwartz. 

THE AUTHOR is a writer based in New Jersey.

Articles

NCCN's new guidelines for nonsmall cell lung cancer contain new recommendations relating to drug therapy.

NCCN's new lung cancer guidelines called a useful reference

The meeting included presentations from FDA staff, representatives of the United States Pharmacopeia and the Institute for Safe Medication Practices (ISMP), and pharmaceutical and device manufacturers. Additionally, patient advocacy and education groups, pharmaceutical sponsors, and the general public were able to provide input during the question-and-answer session.  

"This was an opportunity to hear from all stakeholders regarding product label placement, style and type of information, the need for standard expression of strength, quantity of information, and use of color on labels," stated Carol Holquist, R.Ph., director, Division of Medication Errors & Technical Support, Center for Drug Evaluation and Research at the FDA.   

Different healthcare providers and agencies concentrate on different information on the container label. "Pharmacists and nurses pay more close attention to the drug name and concentration and not as much attention to the lot number and manufacturer. However, the lot number, expiration date, and manufacturer are important to the FDA for purposes of a drug recall," stressed Holquist.   

"There is a lot of information on the container labels. We must be consistent about which information is expressed on the label and how that information is stated," said Timothy Lesar, Pharm.D., director of pharmacy at the Albany Medical Center, who spoke on the pharmacist perspective at the workshop. The large amount of information placed on the container label distracts from the most important information, he said. 

"There was no consensus on what information could be eliminated from the label," added Holquist. "We have to see which was an FDA requirement, which was an ISMP requirement, and why that information was required to be on the label." 

"Over the past years, there's been a lot of improvement, but there is still room for more," said Lesar. "We realize that we have to do it together."  

Meeting participants provided suggestions to help distinguish look-alike products and minimize the risk of selecting the wrong product, including label standardization, these of colors, and "tall-man" letters (e.g., VinBLAStine and VinCRIStine). "The use of tall-man lettering may be beneficial. However, it could raise some concerns because it may be overused or used without any reasoning," said Holquist.  

"Sometimes color may prevent errors, but it can also lead to errors," added Lesar. "There may be two firms using similar colors. Some-times colors may appear similar depending on the lighting. Also, some people are color blind. This is a time when what is useful in one situation may not be useful in others." 

Another suggestion discussed was the standardization of the drug label and how much the label should be standardized. "We may need to standardize the label in an effort to reduce medication errors," said Holquist. "However, a standardized test would be needed to see how the stakeholders feel about the label."  

Lesar agreed that a test would be needed. "One question is, Is it better to standardize the label or to have a slightly distinguishable label? The meeting gave us a lot of good ideas, but they're still untested," he said. 

Last July, an Institute of Medicine (IOM) report estimated that, on average, a hospital patient is subject to at least one medication error per day, although error rates vary by hospital and most do not lead to injury. The report urged the Food & Drug Administration to work with other agencies and healthcare providers to address drug labeling and packaging to minimize errors. In response to this recommendation, the FDA held a one-day public workshop last month to discuss how to improve the labeling of intravenous drug containers.

FDA grapples with curbing IL drug container errors

The drug is a once-daily extended-release (ER) system designed to deliver paliperidone, the active metabolite of risperidone, through the OROS osmotic drug technology. The delivery system consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane that controls the rate at which water enters the tablet core, which in turn determines the rate of drug delivery. "The ER system allows for less peak-to-trough variability, and, from a clinical aspect, less variable levels mean more stable patients," stated Kristin Murphy, Pharm.D., CCP, a consultant pharmacist at a developmental center in New Jersey. 

"Paliperidone could be a second- or third-line agent for most patients; however, it does have potential advantages for some patients such as those with liver disease or hepatitis C," stated Ryan Carnahan, Pharm.D., M.S., BCPP, assistant professor, University of Oklahoma College of Pharmacy, and director of PACT Research at the university's College of Medicine. "Paliperidone may also be especially good for slow metabolizers due to the lack of clinically significant CYP450 inhibition or induction." Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 (CYP450), and there is no dose adjustment needed in patients with mild to moderate hepatic impairment.   

The recommended dose of paliperidone is 6 mg once daily, administered in the morning without regard to food. That's "especially important for psychotropics because compliance is a major issue in psychiatric patients," said Murphy. "In trials, paliperidone was taken without regard to meals. However, as pharmacists, we must keep in mind that exposure to paliperidone increases with food. So, it is important to remind patients to be consistent in the administration." 

The manufacturer recommends a dose adjustment for patients with mild to moderate renal impairment. The maximum recommended dose for patients with a creatinine clearance (CrCl) ≥50 to <80 ml/min is 6 mg once daily, and patients with a CrCl 10 to <50 ml/min, the maximum recommended dose is 3 mg once daily.  

Paliperidone will be available this month in unit-dose packs of 100 and bottles of 30 or 350 extended-release tablets. 

THE AUTHOR is a writer based in New Jersey. 

The Food & Drug Administration recently approved paliperidone (Invega, Janssen, L.P.), an atypical antipsychotic, for the treatment of schizophrenia, a disease that affects more than two million Americans. It is the first new treatment for schizophrenia to be approved since 2003.

FDA approves new drug for schizophrenia

The study by Amy Lee, M.D., and colleagues at the Mayo Clinic, presented at CHEST 2006, found that smokers admitted to the ICU who received NRT during their stay had a higher risk of death than smokers not receiving NRT. Researchers used the pharmacy profiles of 112 smoking patients admitted to the ICU who received NRT during their stay. The study also included a control of 112 patients. There were no statistically significant differences among the NRT and control groups in age, gender, ethnicity, and severity of illness as measured by the APACHE III prognostic model. 

Development of nicotine withdrawal symptoms can worsen the prognosis of some critically ill patients. The diagnosis of nicotine withdrawal may be difficult to make because patients may have conditions that mimic nicotine withdrawal. "The advantage of using NRT in hospitalized patients is evidently the prevention and treatment of withdrawal symptoms. ICU patients may be in that setting because they are critically unstable," Terceros said. "Nicotine is a central nervous system stimulant and, depending on the dose used, it may cause tremors, tachycardia, increased blood pressure, and respiratory failure due to central paralysis and peripheral blockade of respiratory muscles."  

NRT has been widely prescribed for patients who want to quit smoking. Several prescription or over-the-counter dosage forms of NRT are available in the United States, including the nicotine patch, inhaler, nasal spray, gum, and lozenge. NRT is intended to help reduce the  withdrawal symptoms caused by the loss of nicotine from cigarettes. Symptoms begin within a few hours of abstinence, peak within a few days, and last about four weeks.  

"There are other therapies for nicotine withdrawal symptoms, which include bupropion and varenicline. However, neither of these therapies may be practical for ICU patients. The patient would need to receive bupropion or varenicline for one to two weeks before the withdrawal symptoms can be fully controlled. Therefore, acute symptom relief will not be adequate. Moreover, bupropion can cause tachycardia, arrhythmias, hypertension, and hypotension. These and other cardiac side effects may aggravate the ICU patient's condition and/or management," Terceros noted.  

Terceros believes that the study by Lee and colleagues identifies the need for further research on the effects of NRT on ICU patients. Their findings make healthcare providers aware of the potential risk of using NRT in the ICU setting. 

THE AUTHOR is a writer based in New Jersey.  

A recent study by researchers at the Mayo Clinic College of Medicine has raised questions about the safety of administering nicotine replacement therapy (NRT) to smokers in the intensive care unit (ICU). Until now, use of NRT was not thought to be associated with serious adverse events. In fact, the Agency for Healthcare Research & Quality (AHRQ) recommends smoking cessation treatment for hospitalized patients.

Does nicotine replacement therapy hurt ICU patients?

The University of Pittsburgh School of Medicine has been awarded an $8.4 million five-year grant by the National Institute of General Medical Sciences, part of the National Institutes of Health, to lead the multidisciplinary, multicenter consortium. 

Sepsis can be fatal within a few hours, and it is often not diagnosed until it is too late. "Septic patients present with various underlying disease states, infecting pathogens, and degrees of inflammatory response," stated Ty Kiser, Pharm.D., BCPS, assistant professor, department of clinical pharmacy at the University of Colorado Health Sciences Center. "Sepsis is still difficult to diagnose and treat, because we still have much to learn about the pathogenesis of sepsis itself. Our understanding of the causes and course of sepsis has improved drastically, but many of our most plausible experimental therapies have fallen short in clinical trials. To date, there is no magic bullet that we can use to treat all patients with septic shock. We have to use our best interpretation of the literature and try to apply the most appropriate care to each individual patient."  

All patients will be followed for a full year after their recovery to detect any long-term differences in health and mortality rates. "This is an effective protocol," said Martin J. Ohlinger, Pharm.D., assistant professor of pharmacy practice at the University of Toledo College of Pharmacy. "Rivers and his colleagues proved that in their study. It may not be perfect, and all research is subject to critique, especially within the 'real-world' setting, but it's the best evidence we have supporting early aggressive therapy in septic shock." 

According to Kiser, the program will help establish the crucial time line for appropriately assessing and managing patients with sepsis, evaluating more than one approach to early resuscitation. "Additionally, the program will establish cost-effectiveness of the resources utilized in early goal-directed treatment [EGDT] and look at many different biomarkers of sepsis and may help delineate their usefulness," he said. 

In the original trial conducted by Rivers, 263 patients were randomly assigned to receive either six hours of EGDT or standard treatment before admission to the ICU. In-hospital mortality was 30.5% in the patients who received EGDT, compared with 46.5% in the standard treatment group. 

"The protocol requires intensive monitoring and the coordination of many healthcare team members," stated Kiser. It also calls for healthcare facilities to utilize standard "sepsis bundles" or develop their own protocols to ensure that patients receive appropriate care, he added.  

"The protocol is very resource-demanding," said Kiser. "It requires physicians, nurses, pharmacists, respiratory therapists, and other healthcare providers to work closely together to ensure patients are adequately assessed and monitored, given appropriate fluid resuscitation, started on appropriate antimicrobial therapy and vasoactive agents, and receive appropriate oxygenation and ventilation. The questions in the real world will be: How well are institutions doing with replicating the care that was provided in Rivers' protocol? and, If institutions are unable to maximize their adherence to the protocol, will they still see the impressive morbidity and mortality benefits?" 

Protocolized Care for Early Septic Shock (ProCESS), a new multicenter research consortium, is beginning a large-scale study to determine whether specific interventions can halt the progression to severe sepsis or septic shock. Every year, about 750,000 people in the United States are affected with severe sepsis and about 200,000 people die from it. Sepsis is a syndrome characterized by a systemic response to infection that can rapidly lead to death. It is the leading cause of death in noncoronary intensive care units.

Can interventions halt severe sepsis progression?

Until recently, immunosuppressive drug levels have been used to prevent toxicity, but not for preventing rejection or infection. "There are tests to monitor the levels of immunosuppressives, but they do not assess the patient's immune status if he or she is on a combination of immunosuppressives," said Adriana Zeevi, Ph.D., professor of pathology and surgery and codirector of the Tissue Typing Laboratory at the University of Pittsburgh. 

ImmuKnow (Cylex Inc.) is a blood test just cleared by the Food & Drug Administration that is designed to measure the strength of a patient's immune system from a single drop of blood. The assay detects cell-mediated immunity in immunocompromised patients by detecting intracellular adenosine triphosphate (ATP) synthesis in CD4 cells. ATP is a key marker of immune function, can be used to measure lymphocyte activity, and is a source of energy for cells. Because the CD4 lymphocytes coordinate cell-mediated responses through immunoregulatory signaling, the measurement of CD4 activation reflects the degree of immune cell function. 

The cellular immune response of the assay is made by comparing the ATP concentration of the blood specimen to fixed ATP level ranges. The ATP level ranges for ImmuKnow were established by testing 155 healthy adults and 127 transplant recipients with the assay. A cumulative frequency of the differences was used to select the ATP levels that give the best balance of results between immunocompromised and nonimmunocompromised individuals.  

There are three measurable immunological response zones: strong, weak, and the target zone, which is associated with minimal risk of clinical complications. An ATP level of 225 ng/ml or less corresponds to a low immune response, while an ATP level of 525 ng/ml or more corresponds to a strong immune response. The target zone is defined as an ATP level between 226-524 ng/ml.   

Cylex recommends that the results of the test be used in conjunction with clinical presentation and the patient's medical history as well as other clinical indicators when establishing the patient's immune status.  

Some patients are too immunosuppressed, which can lead to lethal infections and to withholding or decreasing the dose of the medications. One of the major challenges of reducing the dose of immunosuppressives is how rapidly to assess the impact on a patient's immune system. "This assay allows physicians to see when the patient's immune system is responding, so we are able to maintain the patient on a stable status," she added. 

A recent meta-analysis, published in the Sept. 15 issue of 

, discusses the results of 504 solid organ transplant patients using the ImmuKnow assay. The analysis showed that patients with an ATP level of 25 ng/ml were 12 times more likely to develop an infection, while patients with an ATP level of 700 ng/ml were 30 times more likely to reject the transplanted organ. Patients who maintained ATP levels between 130 and 450 ng/ml were at minimal risk for infection or rejection, with a target value of 280 ng/ml. At this level, the patient would have a 96% chance of avoiding infection or organ rejection. 

The manufacturer states that one of the limitations of the assay is that ImmuKnow results may be unpredictable in some patients immediately following transplantation because of immune system instability caused by surgical trauma, anesthesia, transfusion, or lymphopenia. 

Zeevi believes that cost is not an issue with the use of the product. "The main advantage of this assay is that it helps decrease toxicity from immunosuppressives," she commented. 

Over the years, long-term use of immunosuppressive medications has shown that they reduce morbidity and mortality in transplant patients. One of physicians' challenges is to balance the risk of organ rejection caused by underimmunosuppression with the risk of drug toxicity, secondary infections, and posttransplant lymphoproliferative disorders caused by overimmunosuppressing the patient.